Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy During Recover From Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation
Phase: PHASE2
Conditions: Medulloblastoma, Neuroectodermal Tumor
Sponsor: University of Florida

 
 
 
Re-MATCH: 
Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor 
Adoptive T Cell Therapy during Recovery from Myeloablative 
Chemotherapy and Hematopoietic Stem Cell Transplantation 
 
Food and Drug Administration Investigational New Drug Application 14,058 
University of Florida Institutional Review Board Protocol 201500502 
(Previously 128-2013) 
 
Duane A. Mitchell, M.D., Ph.D. (Principal Investigator) 
 
 
 

Re-MATCH Protocol 
 
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Version: 20180628 
Summary of Protocol Changes 
Version Date 
Sections 
Revised 
Purpose 
20130913 1230 RB N/A 
- Initial UF Protocol Release 
20140410 0800  
RB 
Entire 
Document 
- Re-formatted for improved readability 
- Corrected typographical errors 
Title Page 
- Added IRB number 
- Deleted non-UF investigators 
List of Possible 
Abbreviations 
- Added Myeloablative (MA) 
2 
- Clarified how subjects will be analyzed 
Study Synopsis 
- Clarified the primary and secondary objectives 
- Limited inclusion to first localized recurrence 
- Clarified the study design 
- Added language to outline the timing for non-mobilized 
leukapheresis 
- Clarified use and timing of GM-CSF and G-CSF 
3 
- Updated titles and work location s  
- Added Jianping Huang, MD, PhD 
4 
- Updated locations and amended the list of supervising personnel  
5 
- Updated to reflect completion of reviews and approvals 
- Updated to reflect new study completion time frame 
6 
- Removed reference to the Phase I Aims since that portion of the 
study was completed at Duke University 
- Updated Phase I study data 
- Limited inclusion to first localized recurrence 
7 
- Clarified the primary and secondary objectives 
8 
- Clarified the primary efficacy endpoint and  how subjects will be 
analyzed 
- Added language to outline the timing for non-mobilized 
leukapheresis 
- Clarified use and timing of GM-CSF and G-CSF 
9 
- Limited inclusion to first localized recurrence 
10 
- Limited inclusion to first localized recurrence 
- Clarified eligibility criteria for cardiac parameters  
- Deleted reference to Phase I of the study   
11 
- Deleted reference to Duke personnel 
14 
- Deleted requirement for signed and dated eligibility checklist before 
enrollment 

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Summary of Protocol Changes 
Version Date 
Sections 
Revised 
Purpose 
15 
- Added language to outline the timing for non-mobilized 
leukapheresis 
- Amended language for PBSC mobilization and leukapheresis to 
outline the collection goals for leukapheresis and TTRNA and DC 
vaccine 
- Clarified eligibility criteria for cardiac parameters  
17 
- Clarified types of events requiring prompt  reporting 
19 
- Amended language for PBSC mobilization and leukapheresis to 
outline the collection goals for leukapheresis and TTRNA and DC 
vaccine 
20 
- Updated shipping address for pathology slides 
- Clarified which infectious disease markers are required 
Study Road  
Map 
- Revised and expanded to include all study requirements referenced 
in other sections of the protocol 
21 
- Added language to indicate that samples collected at Duke from 
Phase I subjects will be analyzed at UF with Phase II samples 
- Clarified the starting point for survival analysis     
- Deleted reference to Duke follow-up track record 
22 
- Removed all reference to Duke's Safety Oversight Committee and 
Regulatory Officer and added language related to the use and role of 
an independent external monitor 
24 
- Deleted reference to Duke’s Phase I RE-START protocol   
- Amended monthly PI meeting to conference calls 
26 
- Removed reference to Regulatory Officer and added language 
related to the use of an independent external monitor 
20140808 0830 RB 
 
 
 
 
 
 
 
 
 
 
 
2.1 
- Clarified dose of TTRNA-DCs as 1x107 cells. 
6.1 
- Replaced “our institution” with “Duke University” since Dr. 
Mitchell relocated to the University of Florida. 
6.2 
- Corrected grammatical error. 
- Deleted reference to IFNγ since this cytokine is no longer used. 
6.4 
- Added section identifier for reference in the table of contents. 
- Formatting & grammatical changes. 
- Modified section to indicate that the Phase I study is complete.  
8 
15.3.1 
15.3.2 
- Changed TTRNA-xALT infusion duration and vital sign 
monitoring. 
- Clarified dose of TTRNA-DCs as 1x107 cells. 
15.2.1 
- Corrected typographical error. 

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Summary of Protocol Changes 
Version Date 
Sections 
Revised 
Purpose 
16.2 
- Modified section to reflect that the preparation, delivery, and 
administration of TTRNA-xALT will be according to Standard 
Operating Procedures and that subject identifiers will be double-
verified prior to administration. 
- Changed TTRNA-xALT infusion duration and vital sign 
monitoring. 
17.3 
29.1 
- Corrected grammatical error. 
- Modified section to reflect use of the most current CTCAE, version 
4. 
- Modified adverse event descriptions to be consistent with CTCAE 
version 4.   
 
19 
- Modified title to reflect addition of “External Sites” section. 
19.1 
- Added new section to describe how samples will be collected/ 
prepared/shipped between external sites and the University of 
Florida. 
19.2 
19.3 
19.5 
- Modified the language in these sections (TTRNA Isolation, 
Amplification of RNA, and Procedure for TTRNA-DC and 
TTRNA-xALT Generation) to be consistent with recent changes to 
the Chemistry, Manufacturing, and Control section of the IND. 
20.2 
STUDY ROAD 
MAP 
- Modified language to indicate that the Type and Screen is only 
required if clinically indicated. 
- Modified language to indicate that oral Tums are only required if 
standard of care. 
20140916 1130 RB 2.1 
- Corrected KPS to be greater than or equal to 50% to be consistent 
throughout document.  
10.2 
11.2 
13 
20.1 
- Added language to allow potential enrollment of subjects who have 
had tumor tissue snap frozen at outside institutions.  
15.2.1 
15.3.2 
- Changed tissue transport to ‘aseptic’ to be consistent with IND. 
20141013 1245 RB 10.1 
- Added the ability to obtain Tissue Consent by telephone.  
20141014 1240 RB 2.1 
10.2 
- Added carriers of Hepatitis B and/or Hepatitis C virus to exclusion 
criteria. 
4 
- Updated the name of the University of Florida study location.   
17.4 
17.4.1 
17.4.2 
17.4.3 
- Added new section identifiers for reference in the Table of 
Contents. 
17.4.3 
- Defined the adverse event reporting windows.   

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Summary of Protocol Changes 
Version Date 
Sections 
Revised 
Purpose 
20.2 
- Deleted reference to the Td manufacturer and injection location. 
- Deleted reference to Hepatitis B vaccination and titers. 
STUDY ROAD 
MAP 
- Deleted reference to Hepatitis B vaccination and titers. 
- Moved non-mobilized leukapheresis assessments before pre-
induction or salvage chemo assessments to align with study 
activities. 
23 
23.1 
23.2 
23.3 
23.4 
- Added new section identifiers for reference in the Table of 
Contents. 
23.1 
- Added the University of Florida Health Cancer Center DSMB. 
25 
- Moved the first paragraph to Section 23.2. 
- Deleted the second paragraph since content is covered in Section 
17.4.2. 
- Revised the third paragraph and moved it to Section 23.2 
25.2 
- Revised the fourth paragraph and moved it to Section 23.1. 
26 
- Deleted section since content is covered in Section 23. 
29 
29.1 
- Moved language to Sections 17.4.1 and 17.4.2.  
20141218 1430 RB 2.1 
8 
15.4 
16.1 
20.2 
STUDY ROAD 
MAP 
- To serve as a baseline measure, a new time point for the collection 
of peripheral blood for immunologic monitoring was added prior to 
non-mobilized leukapheresis. 
15.2.2 
15.3.3 
19.4 
- Two new, “Leukapheresis for Peripheral Blood Mononuclear Cells 
(PBMCs)”, sections were added to outline specific parameters for 
PBMC collection.  The “Procedure for PBSC Mobilization and 
Leukapheresis” and “Procedure Leukapheresis” sections were re-
named and amended to provide each institution the flexibility to 
follow their local standards and to provide guidelines for PBSC 
mobilization and apheresis duration.  The “Leukapheresis and PBSC 
Mobilization” section was deleted since the content was already 
covered in other protocol sections.        
2.1 
8 
10.2 
15.2.3 
15.3.4 
- Language was added to clarify that focal boost radiotherapy for 
local control is allowed. 

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Version Date 
Sections 
Revised 
Purpose 
19.5 
- Language was amended for clarity and to correlate with minor 
changes to the manufacturing processes. 
Entire 
Document 
30 
30.1 
- Reference to study-specific documents (Standard Operating 
Procedures, Batch Records, and Source Document Worksheets) was 
added throughout the entire protocol.  A new “Appendices” section 
was added that lists each document number and title referenced in 
the narrative sections. 
20150306 0715 RB 2.1 
10.1 
11.2 
- Language was amended to clearly define subjects who have 
received and failed definitive standard radiotherapy. 
19.4 
- ‘Leukapheresis’ was replaced with ‘PBMCs’, ‘DMSO’ was 
replaced with ‘Cryoserv’, ‘production’ was replaced with 
‘stimulation’, and ‘cell’ was replaced with ‘DC’ to more clearly 
outline the manufacturing process.  ‘Ph’ was amended to “PH’. 
8 
15.3.1 
- The instructions for peripheral blood stem cell administration were 
amended to allow each institution the flexibility to infuse the cells in 
accordance with local guidelines.  
2.1 
8 
15.4 
16.1 
20.2 
STUDY ROAD 
MAP 
- Select immune monitoring time points were amended to allow for 
flexibility in collection time.  The requirement for bimonthly 
immune monitoring samples was revised to ‘if feasible’ to 
accommodate subjects who may not be seen at the main institution.  
8 
15.3.1 
15.3.2 
16.2 
- The terms ‘up to’ were added to the acetaminophen and benadryl 
pre-medication language to allow for dosing flexibility, 
20150622 0930 RB 8 
15.3.1 
15.3.2 
- To provide institutions the flexibility to follow local guidelines, IV 
was added as a route of administration for Sargramostim and 
Filgrastim.  
20.2 
STUDY ROAD 
MAP 
- To enhance DC trafficking, Td booster will be administered to all 
subjects regardless of vaccination history. 
23.2 
- At the request of the Medical Monitor, written reports will be 
generated biannually to correlate with DSMB reports. 
20151015 0730 RB Title Page 
- As a result of the conversion to the electronic myIRB system, the 
new IRB number was added.  
2.1 
10.1 
15.3.2 
- To minimize variability, Group B subjects with an ANC < 1000/µL 
and/or platelet count < 100,000/µL at time of non-myeloablative 
work-up will receive vaccine therapy but will not receive non-
myeloablative conditioning. 

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Version Date 
Sections 
Revised 
Purpose 
 
2.1 
8 
15.1 
15.2.1 
15.3.2 
- The language regarding DCs and/or xALT release criteria or 
targeted dose was amended for clarity.   
2.1 
8 
15.3.2 
- The infusion of PBSCs 72 hours following fludarabine, if 
successfully collected, was added for Group B patients to 
potentially enhance the immune response.   
2,2 
- The schema was updated to state that the pheresis collection is sent 
to UF. 
4 
- The names of the external study sites were added. 
5 
- The grant end date was updated. 
6.4  
- Language was amended for clarity. 
15.2.3 
15.3.4 
- The storage recommendations for collected PBSCs were removed 
to allow for institutional variation. 
15.3.5 
- Reference to the collection of back-up PBSCs was removed since 
the cells, if successfully collected, will be administered to all Group 
B subjects.  
16.2 
- Language was amended to incorporate the infusion of the TTRNA-
xALT product in accordance with SOP-UFBTIP-132.  
17.4.3 
- Language was amended to delineate what adverse events will be 
recorded. 
19.3 
- Language was amended to update the sterility testing location and 
type of testing. 
19.4 
- Language was amended to align with the Chemistry, 
Manufacturing, and Control language. 
STUDY ROAD 
MAP 
- PBSCs were added to the Consolidation or NMA Chemo time point 
to correlate with the narrative sections of the protocol. 
30.1 
- Reference to the SOP for the “Administration of ALT” was added. 
20160303 1200 RB 3 
3.1 
3.2 
4 
8 
21.1 
21.6 
25 
25.1 
- 
Key study personnel updated throughout protocol to reflect current 
individuals with assigned study duties. 
17.4.3 
- 
The duration of adverse event follow-up was modified for clarity.   

Re-MATCH Protocol 
 
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Summary of Protocol Changes 
Version Date 
Sections 
Revised 
Purpose 
 
2.1 
8 
15.4 
16.1 
20.2 
STUDY ROAD 
MAP 
- 
A plus or minus 1 day window was added to the day 4 
assessments to provide scheduling flexibility. 
20160505 1749 
DAM 
2.1 
9 
10.1 
11.2 
- 
Language regarding disease status eligibility was clarified. 
20160908 1515 
KW 
31 
- 
Single Patient-Specific Protocol (UF Site Only) was added as 
Addendum A to protocol 
20170220 1100 
KW 
Overall 
Document 
- 
Table of Contents updated for pagination 
- 
Footer updated with new version date. 
- 
Additional editorial, typographical and formatting changes have 
been made throughout the body of the protocol, along with minor 
changes for document consistency, all of which are tracked but not 
individually listed. 
2.1 
10.1 
- 
Performance status age range modified to align with NIH criteria. 
2.1  
10.1 
- 
Language regarding additional eligibility requirements updated to 
clarify applicability to both consolidation and NMA 
chemotherapy. 
2 
2.1 
8 
10.1 
15.3.5  
- 
Description of Group B regimen in these sections revised for 
consistency with other sections of the protocol. 
2.1 
8 
- 
Language regarding localized relapse and disseminated disease 
clarified for consistent interpretation across sites. 
2.1 
15.2.3 
15.3.4 
- 
Minimum number of stem cells for harvest in Group A subjects 
specified in this section for clarity and consistency. 
2.1 
8 
15.3.2 
15.3.4 
- 
Goal for stem cell harvest in Group B subjects added to this 
section for clarity and consistency. 
2.1 
8 
- 
For subject safety and to minimize variability, Group B subjects 
with no peripheral blood stem cells (PBSCs) for rescue will have 
NMA conditioning withheld and move to immunotherapy from 
salvage chemotherapy if all other eligibility has been met. 

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2.1 
8 
15.4 
- 
Timeframes and windows for follow-up visits clarified. 
2.2-2.4 
- 
Study schema updated to more accurately reflect existing protocol 
procedures. 
3.2 
4.0 
25.1 
25.2 
- 
Duke and Stanford removed from study due to underperformance 
and/or inability to complete all requirements to activate trial at 
respective sites. 
5 
- 
Projected time frame to complete study modified. 
10.2 
15.1 
15.2.1 
- 
Maximum steroid dose amended to more closely align with 
exclusion criteria in brain tumor protocols. 
15.3.2 
- 
Timing of organ performance assessment clarified. 
- 
Pulmonary function parameters that were inadvertently deleted 
from this section in prior protocol revision re-inserted. 
15.3.2 
19.4 
- 
Modified to allow subjects to receive all available T cells if target 
dose is not met.  This provision exists in the ICF. 
17.4.2 
17.4.3 
- 
Regulatory definitions and reporting requirements for adverse 
events clarified. 
- 
Timeframe for following adverse events added for clarity. 
17.5 
- 
Requirements for concomitant medication collection and 
documentation added for clarity.   
20.2 (Roadmap) 
- 
Pre-Induction or Salvage Chemo testing done as part of standard 
care for these patients removed. 
- 
Timeframe for pre-immunotherapy Td booster and labs clarified.   
20180628 
2.1  
8.0  
15.3  
20.2 Study Road 
Map 
 
- 
Modify administration of GM-CSF to maintain consistent 
manufacturing across all of our adoptive cellular therapy trials.   
For the remaining subjects in this trial, we will embed the GM-
CSF with the DC vaccines rather than administering 
intravenously. 
- 
Remove GM-CSF as part of Group A and Group B consolidation 
of NMA chemo since it will be embedded with DC vaccine. 
2.1 
8.0  
15.3  
 
- 
Provide a window for G-CSF administration to allow for 
management per institutional guidelines and treating Transplant 
physician discretion. 
3 
- 
Remove Timothy Driscoll since Duke is no longer participating in 
this trial. 
3.1  
25 
 
- 
Remove David Pincus and Barbara Frentzen who left the 
University of Florida and are no longer affiliated with the trial. 
3.2  
- 
Remove Stanford personnel since Stanford is no longer a 
participating site. 

Re-MATCH Protocol 
 
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4  
- 
Remove David Pincus who left UF and is no longer affiliated with 
the trial. 
 
5  
- 
Update projected time frame to complete trial. 
16.1  
 
- 
Add provision for continued DC vaccination for subjects who 
have additional DC vaccines available (beyond planned 3 
vaccines) and will not receive T-cell infusion either because of the 
inability to manufacture a viable product or failure of the product 
to meet release criteria. 
20.2 and Study 
Road Map 
 
 
- 
Clarify procedures related to pre-leukapheresis laboratory 
assessments to allow for institutions to follow local standards (i.e., 
some institutions perform basic metabolic panels while others 
perform comprehensive metabolic panels). 
20.2  
- 
Clarify Td administration to reflect standard dosing and ensure 
consistency in administration across sites. 
 
 

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LIST OF POSSIBLE ABBREVIATIONS 
 
Ab 
Antibody 
AB 
Alpha Beta/ Antibody 
ABC 
Automated Blood Count 
ABMT 
Autologous Bone Marrow Transplantation 
ACTB 
Beta Actin 
ACD 
Acid Citrate Dextrose 
ACLS 
Advanced Cardiac Life Support 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALL 
Acute Lymphoblastic Leukemia 
ALK PHOS 
Alkaline Phosphatase 
ANOVA 
Analysis Of Variance 
Anti-HB 
Anti- Hepatitis B 
ANC 
Absolute Neutrophil Count 
ANLL 
Acute Non-Lymphatic Leukemia 
AML 
Acute Myelogenous Leukemia 
APAAP 
Alkaline Phosphatase Antialkaline Phosphatase Complex 
APC 
Allophycocyanin 
ALPS 
Autoimmune LymphoProliferative Syndrome 
ALT 
Autologous Lymphocyte Transfer 
nALT 
Naïve Autologous Lymphocyte Transfer 
xALT 
Ex vivo Activated Autologous Lymphocyte Transfer 
αCD3 
anti-cell differentiation antigen 3 
αIFN-γ 
anti-interferon alpha 
αTNF-α 
anti-tumor necrosis factor-alpha 
αIL2 
anti-interleukin 2 
AST 
Aspartate Aminotransferase 
ACTIVATE 
A Complementary Trial of an Immunotherapy Vaccine Against 
Tumor-Specific EGFRvIII 
AT 
Ambient Temperature 
AUC 
Area under the concentration time curve 
BD-FACS 
Becton-Dickinson Fluorescence Activated Cell Sorting 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BMT 
Bone Marrow Transplant 
BMTU 
Bone Marrow Transplant Unit 
BSA 
Bovine Serum Albumin 
BSN 
Bachelors of Science in Nursing 
BTSC 
Brain Tumor Stem Cells 
BTIP 
Brain Tumor Immunotherapy Program 
BU 
Busulfan 
BUN 
Blood Urea Nitrogen 
C 
Chemotherapy 
Ca 
Calcium 

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Cc 
Cubic Centimeters 
C3D 
Cancer Clinical Database 
CA 
California 
CaBIG 
Cancer Biomedical Informatics Grid 
cDNA 
Complimentary Deoxyribonucleic Acid 
CDPP 
Cisplatin 
CEA 
Carcinoembryonic Antigen 
caAEARS 
Cancer Adverse Event Reporting System 
CD133 
Cell Differentiation 133 
CEF 
Cytomegalovirus, Epstein Barr virus, Flu virus 
CDE 
Common Data Elements 
CFA 
Complete Freund’s Adjuvant 
CFC 
Cytokine Flow Cytometry 
CLIA 
Clinical Laboratory Improvement Act 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNC 
Clinical Neurologic Change 
CNS 
Central Nervous System 
CO2 
Carbon Dioxide 
Con-A 
Concanavalin A 
Co-PI 
Co-Primary Investigator 
CPC 
Cancer Protocol Committee 
Cr 
Serum Creatinine 
CR 
Complete Response 
CRF 
Conformance Review Checklist 
CSF 
Cerebro Spinal Fluid 
CSI 
Craniospinal Irradiation 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T-Lymphocyte 
CTLA4 
Cytotoxic T-Lymphocyte Antigen 4 
CTX 
Cyclophosphamide 
DC 
Dendritic Cell 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DLCO 
Diffusion Capacity of Carbon Dioxide 
DMSO 
Dimethyl Sulfoxide 
DMZ 
Data Management Zone 
DNA 
Deoxyribonucleic Acid 
DNase 
Deoxyribonuclease 
D. Sci. 
Doctor of Science 
DSMB 
Data Safety Monitoring Board 
dT 
Diphtheria and Tetanus 
DTH 
Delayed-type Hypersensitivity 
DTRI 
Duke Translational Research Institute 
DUMC 
Duke University Medical Center 

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EAE 
Experimental Autoimmune Encephalomyelitis 
EBRT 
External Beam Radiation Therapy 
ECHO 
Echocardiography 
EDTA 
Ethylenediaminetetraacetic Acid 
EKG 
Electrocardiogram 
EGFR 
Epidermal Growth Factor Receptor 
EGFRvIII-KLH 
EGFRvIII conjugated to Keyhole Limpet Hemocyanin 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
ELISPOT 
Enzyme-linked Immunospot 
ERADICATe 
Evaluation of Recovery from Drug-Induced lymphopenia using 
Cytomegalovirus-specific T-cell Adoptive Transfer 
FACS 
Fluorescence Activated Cell Sorting 
FACT-Br 
Functional Assessment of Cancer Therapy for Brain Tumors 
FACT-accredited 
Foundation for the Accreditation of Cellular Therapy 
FDA 
Food and Drug Administration 
FEC 
Forced Expiratory Capacity 
FEV 
Forced Expiratory Volume 
FEV1 
Forced Expiratory Volume at 1 second 
FITC 
Fluorescein Isothiocyanate 
FOXP3 
Forkhead Box P3 
FTP 
File Transfer Protocol 
GADPH 
Glyceraldehyde-3-phosphate dehydrogenase 
GBM 
Glioblastoma Multiforme 
GFP 
Green Fluorescent Protein 
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
G-Tube 
Gastrostomy Tube 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
H&E 
Hematoxylin and Eosin 
HABS 
Human Monoclonal Antibodies 
HB 
Hepatitis B 
HbsAg 
Hepatitis B Surface Antigen 
HD 
High Dose 
HDC 
High Dose Chemotherapy 
hCD133 
Human Cell Differentiation 133 
HER2 
Human Epidermal growth factor Receptor 2 
hGADPH 
Human glyceraldehyde-3-phosphate dehydrogenase 
hHPRT 
Human Hypoxanthine Phosphoribosyltransferase 
HIPPA 
The Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPRT 
Hypoxanthine Phosphoribosyltransferase 
HLA 
Human Leukocyte Antigens 
HMO 
Health Management Organization 
HSC 
Hematopoietic Stem Cells 
HVTN 
HIV Vaccine Trials Network 

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IBC 
Institutional Biosafety Committee 
ICCC 
International Classification of Childhood Cancer 
IFN 
Interferon 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL-1β 
Interleukin 1B 
IL-2 
Interleukin-2 
IL-4 
Interleukin-4 
IL-6 
Interleukin-6 
IL-12 
Interleukin-12 
IL-10 
Interleukin-10 
IL-13 
Interleukin-13 
IL-15 
Interleukin-15 
IND 
Investigational New Drug 
IP10 
Human interferon-inducible protein 10 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
Potassium 
Kg 
Kilogram 
KLH 
Keyhole Limpet Hemocyanin 
KLEB 
Poorly Differentiated Endometrial Cell Line 
KPS 
Karnofsky Performance Status 
L 
Liters 
LIMS 
Laboratory Information Management System 
LMD 
Leptomeningeal Disease 
LPS 
Lansky Performance Score 
M² 
Meters Squared 
MA 
Myeloablative 
MAb 
Monoclonal Antibody 
MAbs aCD28 
Monoclonal Antibodies anti-CD28 
MB 
Medulloblastoma 
MAD 
Maximally Achievable Dose 
MAGE 
Melanoma Antigens 
M.D. 
Medical Doctor 
MEL 
Melphalan 
METS 
Metastasis 
Mcg 
Micrograms 
MG 
Malignant Glioma 
Mg 
Magnesium 
Mg 
Milligrams 
MHC 
Major Histocompatibility Complex 
MIN 
Minutes 
Ml 
Milliliters 
mIU/ml 
Million International Units/ Milliliter 
MMSE 
Mini-Mental Status Examination 

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MRCP 
Member of the Royal College of Physicians 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MTD 
Maximal Tolerated Dose 
MTIC 
Maximal Tolerated Inhibitory Concentration 
Na 
Sodium 
NA 
Non-adherent 
NC 
North Carolina 
NCC 
Nucleated Cell Count 
NDC 
National Documentation Center 
NEJM 
New England Journal of Medicine 
NEPSY 
Neuropsychological Assessment 
NCI 
National Cancer Institute 
NCI CTC 
National Cancer Institute Common Toxicity Criteria 
NG-Tube 
Nasogastric Tube 
NJ 
New Jersey 
NIAID 
National Institute for Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NINDS 
National Institutes of Neurological Diseases and Strokes 
NK 
Natural Killer 
NMA 
Non-Myeloablative 
NR 
Not Recorded 
NSC  
Cancer Chemotherapy National Service Center 
NY 
New York 
OS 
Overall Survival 
OVA 
Ovalbumin 
PALS 
Pediatric Advanced Life Support 
PBLs 
Peripheral Blood Lymphocytes 
PBMC 
Peripheral Blood Mononuclear Cells 
PBS 
Phosphate Buffered Saline  
PBSC 
Peripheral Blood Stem Cell 
PBSCT 
Peripheral Blood Stem Cell Transplant 
PBTC 
Pediatric Brian Tumor Consortium 
PBTFI 
Pediatric Brain Tumor Foundation Institute 
PCP 
Pneumocystis Carinii Pneumonia 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PE 
Phycoerythrin 
PEPvIII 
Peptide variant III 
PFS 
Progression Free Survival 
PFS-12 
Progression Free Survival, 12 Months 
PHA 
Phytohemagglutinin 
Ph.D. 
Doctorate of Philosophy 
PHI 
Private Health Information 
PI 
Principal Investigator 
PNETS 
Primitive Neuro Ectodermal Tumors 

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PO 
Per Os (by mouth) 
polyAAA 
Poly Adenosine Tail 
PR 
Partial Response 
PRTBC 
Preston Robert Tisch Brain Tumor Center 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QA/QC 
Quality Assessment/ Quality Control 
Qdot 
Quantum dot 
QOL 
Quality of Life 
® 
Registered 
RAC 
Recombinant DNA Advisory Committee 
RE-MATCH 
Recurrent Medulloblastoma and Primitive Neuroectodermal 
Tumor Adoptive T Cell Therapy during Recovery from 
Myeloablative Chemotherapy and Hematopoietic Stem Cell 
Transplantation 
reMB/PNETS 
Recurrent Medulloblastoma/Primitive Neuro Ectodermal Tumors 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Re-START 
REcurrent GBM Stem cell Tumor Amplified RNA 
immunotherapy Trial 
RDC 
Remote Data Capture 
RN 
Registered Nurse 
RNA 
Ribonucleic Acid 
RPA 
Ribonuclease Protection Assay 
RPMI 
Roswell Park Memorial Institute  
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
Rx 
Treatment 
S 
Surgery 
SAE 
Serious Adverse Event 
SEB 
Staphylococcal Enterotoxin B 
SEER 
Surveillance, Epidemiology, and End Results 
SD 
Standard Deviation 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamate Pyruvate Transaminase 
SH 
Subtractive Hybridization 
SIADH 
Syndrome of Inappropriate Antidiuretic Hormone 
SOP 
Standard Operating Procedure 
SOX2 
Sex Determining Region Y Box 2 
SPORE 
Specialized Programs of Research Excellence 
SPICE 
Specialized Program for Incredibly Complex Evaluations 
SQ 
Subcutaneous 
TAA-40 
Top 40 Tumor Associated Antigens 
TAA 
Tumor Associated Antigens 
TBI 
Total Body Irradiation 
TCR 
T-cell Receptor 
Td 
Tetanus and Diphtheria Toxoids 

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TERT 
Telomerase 
TGF-β1-2 
Transforming Growth Factor Beta1-2 
TILs 
Tumor Infiltrating Lymphocytes 
TLR 
Toll Like Receptor 
TM 
Trademark 
TMZ 
Temozolomide 
TNF 
Tumor Necrosis Factor 
TNF-α 
Tumor Necrosis Factor- Alpha 
Tregs 
Regulatory T-cells 
TRP-2 
Tyrosinase Related Protein 2 
TTP 
Time to Progression 
TTRNA 
Total Tumor mRNA 
UF 
University of Florida 
µg 
Micrograms 
µl 
Micro liters 
US 
United States 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
Vβ 
V Beta 
VCR 
Vincristine 
VICTORI 
Dose-Finding and Safety Study of Autologous, Tumor-Specific 
Antigen-Pulsed Dendritic Cell Immunotherapy for Malignant 
Brain Tumors 
VP 
VePesid® 
VP-16 
Etoposide 
WA 
Washington 
 

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TABLE of CONTENTS 
1. 
STUDY TITLE .........................................................................................................21 
2. 
DESCRIPTION OF CLINICAL TRIAL...............................................................21 
2.1 
Study Synopsis ............................................................................................. 21 
2.2 
Multi-Site Study Schema ............................................................................. 28 
2.3 
Study Schema for Group A .......................................................................... 29 
2.4 
Study Schema for Group B .......................................................................... 30 
3. 
PRINCIPAL INVESTIGATOR (PI) AND STUDY STAFF ................................31 
3.1 
KEY STUDY PERSONNEL ....................................................................... 31 
3.2 
KEY STUDY PERSONNEL EXTERNAL SITES ..................................... 34 
4. 
STUDY LOCATION(S) ..........................................................................................36 
5. 
TIME REQUIRED TO COMPLETE THE STUDY ............................................37 
6. 
BACKGROUND ......................................................................................................37 
6.1 
Significance and Overall Rationale ............................................................. 37 
6.2 
Immunotherapy for Pediatric Brain Tumors ................................................ 38 
6.3 
Rationale for Current Study ......................................................................... 39 
6.4 
Re-MATCH Phase I Study .......................................................................... 40 
7. 
OBJECTIVES/SPECIFIC AIMS/STUDY QUESTIONS ....................................40 
7.1 
Hypotheses ................................................................................................... 40 
7.2 
Study Objectives .......................................................................................... 40 
8. 
STUDY DESIGN ......................................................................................................41 
9. 
STUDY POPULATION ..........................................................................................46 
10. INCLUSION CRITERA .........................................................................................47 
10.1 
Inclusion Criteria ......................................................................................... 47 
10.2 
Exclusion Criteria ........................................................................................ 48 
10.3 
Inclusion of Women and Minorities ............................................................ 49 
11. DESCRIPTION OF THE RECRUITMENT PROCESS .....................................49 
11.1 
Recruitment .................................................................................................. 49 
11.2 
Screening and Enrollment ............................................................................ 50 
12. SAMPLE SIZE JUSTIFICATION ........................................................................51 
13. DESCRIPTION OF INFORMED CONSENT PROCESS ..................................51 
14. VOLUNTEER SCREENING PROCEDURES .....................................................51 
15. STUDY PROCEDURES/STUDY INTERVENTIONS ........................................52 
15.1 
Overview ...................................................................................................... 52 
15.2 
Chemotherapy for Group A ......................................................................... 52 
15.2.1 Induction Therapy ........................................................................................ 52 
15.2.2 leukapheresis for peripheral blood mononuclear cells (pbmcs) .................. 53 
15.2.3 PBSC Mobilization and Leukapheresis ....................................................... 53 
15.2.4 Guidelines for Induction Therapy and PBSC collection.............................. 54 
15.3 
Consolidation ............................................................................................... 54 
15.3.1 Pre-transplant Evaluation ............................................................................. 54 
15.3.2 NMA Salvage Chemotherapy for Group B ................................................. 57 
15.3.3 leukapheresis for peripheral blood mononuclear cells (pbmcs) .................. 60 
15.3.4 PBSC Mobilization and Leukapheresis ....................................................... 61 
15.3.5 Guidelines  for  Salvage Chemotherapy and PBSC collection .................... 61 
15.4 
Post-transplant Immunotherapy ................................................................... 62 

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16. EXPERIMENTAL STUDY PROCEDURES (DC + XALT THERAPY) ..........62 
16.1 
DC Vaccination ............................................................................................ 62 
16.2 
TTRNA-xALT Administration .................................................................... 62 
17. SAFETY, TOXICITY, AND ADVERSE EVENTS ..............................................63 
17.1 
Toxicity associated with Standard Therapy (HDC + PBSCT) .................... 63 
17.2 
Immunotherapy Related Dose-limiting Toxicity ......................................... 64 
17.2.1 Phase II Toxicity Monitoring ....................................................................... 64 
17.2.2 Monitoring of Non-Overlapping Vaccine Related Toxicity ........................ 64 
17.2.3 Monitoring of Vaccine Related Mortality.................................................... 64 
17.2.4 Monitoring of Chemotherapy-Related Mortality ......................................... 64 
17.3 
Management of Toxicities ........................................................................... 64 
17.4 
Adverse Event Reporting and Documentation ............................................ 66 
17.4.1 Adverse events ............................................................................................. 66 
17.4.2 serious adverse events .................................................................................. 66 
17.4.3 adverse event documentation ....................................................................... 66 
17.5 
Concomitant Medication .............................................................................. 67 
18. DESCRIPTION OF PROTOCOL DRUGS OR DEVICES ................................68 
18.1 
Preparation and Administration of Standard of Care Therapeutic Agents .. 68 
18.2 
Cyclophosphamide ....................................................................................... 68 
18.3 
Mesna ........................................................................................................... 69 
18.4 
Etoposide...................................................................................................... 70 
18.5 
Temozolomide (Temodar®) ......................................................................... 72 
18.6 
Carboplatin ................................................................................................... 73 
18.7 
Thiotepa ....................................................................................................... 75 
18.8 
Fludarabine phosphate ................................................................................. 76 
19. PREPARATION, ADMINISTRATION, AND TRANSPORT OF 
EXPERIMENTAL THERAPEUTIC AGENTS (DC + XALT THERAPY) ..............77 
19.1 
External Sites ............................................................................................... 77 
19.2 
TTRNA isolation ......................................................................................... 77 
19.3 
Amplification of RNA ................................................................................. 77 
19.4 
Procedure for TTRNA-DC and TTRNA-xALT Generation ....................... 78 
20. LABORATORY EVALUATIONS ........................................................................79 
20.1 
Baseline and Eligibility ................................................................................ 79 
20.2 
Data and Specimens to be Accessioned ....................................................... 79 
20.3 
Laboratory and Clinical Evaluation Facilities ............................................. 82 
21. DATA ANALYSIS ...................................................................................................83 
21.1 
Progression Free Survival (PFS) and Overall Survival (OS)....................... 83 
21.2 
Radiographic Response and Progression Criteria for Patients with Residual 
Disease 
83 
21.3 
Radiographic Response and Progression Criteria for Patients with Complete 
Resection 
84 
21.4 
Special Circumstances ................................................................................. 85 
21.5 
Survival ........................................................................................................ 87 
21.6 
Statistical Analysis of Longitudinal Immunologic Measures ...................... 87 
21.7 
T cell Cytokine Production .......................................................................... 88 
21.8 
Cytokine Flow Cytometry............................................................................ 88 
21.9 
Statistical Analysis for Polyfunctional Response ........................................ 89 
21.10 Serology ....................................................................................................... 89 

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21.11 Statistical Analysis ....................................................................................... 89 
21.12 Toll-Like Receptor Agonist Activity ........................................................... 90 
21.13 Statistical Analysis ....................................................................................... 90 
21.14 Tumor Associated Antigen (TAA) Profile in Recurrent Tumors ................ 90 
21.15 Statistical Analysis ....................................................................................... 90 
22. DATA MANAGEMENT .........................................................................................91 
22.1 
Data Management and Quality Control ....................................................... 91 
22.2 
Laboratory Data Transmission and Accountability ..................................... 91 
23. DATA AND SAFETY MONITORING PLAN .....................................................91 
23.1 
Data Safety Monitoring Board ..................................................................... 91 
23.2 
Independent Medical Monitor...................................................................... 91 
23.3 
Independent External Monitor ..................................................................... 92 
23.4 
Principal Investigator ................................................................................... 92 
24. RISKS/BENEFITS ASSESSMENT .......................................................................92 
24.1 
Potential Benefits ......................................................................................... 92 
24.2 
Potential Risks ............................................................................................. 93 
24.2.1 Allergic Reactions to DC Immunization or TTRNA-xALT ........................ 93 
24.2.2 Cerebral Edema ............................................................................................ 93 
24.2.3 Infection ....................................................................................................... 93 
24.2.4 Delayed Autoimmune Diseases ................................................................... 93 
24.2.5 Phlebotomy .................................................................................................. 94 
24.2.6 Leukapheresis .............................................................................................. 94 
24.2.7 MRI .............................................................................................................. 94 
24.3 
Allergic Reactions to Contrast Agents ......................................................... 94 
24.4 
GM-CSF and G-CSF Risks .......................................................................... 95 
24.5 
Unknown Risks ............................................................................................ 96 
24.6 
Confidentiality ............................................................................................. 96 
24.7 
Treatment Alternatives & Financial Reimbursement .................................. 96 
25. KEY STUDY PERSONNEL ...................................................................................96 
25.1 
Key Study Personnel External Sites ............................................................ 99 
25.2 
Principal Investigator Leadership Plan ...................................................... 100 
26. WITHDRAWAL FROM THE PROTOCOL .....................................................101 
27. MODIFICATIONS TO THE PROTOCOL ........................................................101 
28. CONTINUING REVIEW AND FINAL REPORT .............................................101 
29. REFERENCES .......................................................................................................102 
30. APPENDICES ........................................................................................................104 
30.1 
Referenced Documents .............................................................................. 104 
31. ADDENDUM A ......................................................................................................106 
31.1 
Single Patient-Specific Protocol (UF Site Only) ....................................... 106 
 
 
 

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1. STUDY TITLE 
Re-MATCH: Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy 
during Recovery from Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation 
2. DESCRIPTION OF CLINICAL TRIAL  
This is a dual-arm, prospective Phase II clinical trial of adoptive cellular therapy targeting recurrent 
medulloblastoma (MB) and recurrent supratentorial primitive neuroectodermal tumors (PNETs).  Group A will 
consist of patients undergoing hematopoietic recovery from high-dose chemotherapy and autologous peripheral 
blood stem cell transplant.  Group B will consist of patients undergoing non-myeloablative salvage chemotherapy 
and autologous peripheral blood stem cell transplant   The 12-month progression-free survival (PFS) rate of all 
patients will be compared collectively to a historical cohort, as patients did not have statistically different survival 
outcomes in the historical data set whether they received myeloablative (MA) or non-myeloablative (NMA) 
chemotherapy for recurrent disease.  The PFS and OS in each arm will be analyzed descriptively to explore 
whether therapeutic outcomes may differ on the two treatment arms in this study.    
 
2.1 Study Synopsis 
 
Title: 
Re-MATCH: Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell 
Therapy during Recovery from Myeloablative Chemotherapy and Hematopoietic Stem Cell 
Transplantation 
Study Drug: Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs) and tumor-specific 
ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT) 
Rationale: 
Vaccination and adoptive T cell strategies targeting unfractionated tumor antigens in humans in 
other contexts have been safe and effective. DC vaccinations targeting tumor antigens in children 
with MB and PNETs and other brain tumors have been shown to be feasible and safe.  The 
prognosis for patients with recurrent MB/PNETs (reMB/PNET), particularly for those who have 
failed prior definitive focal +/- craniospinal irradiation, is dismal. High Dose Chemotherapy 
(HDC) + PBSCT have been used as a standard of care in recent years in recurrent disease but are 
seldom curative. MA and NMA chemotherapy induces a profound lymphopenia that would be 
predicted to prevent the induction of effective immune response to anti-tumor vaccination.  
However, recent studies have shown, somewhat counterintuitively, that vaccination during 
recovery from profound but transient lymphopenia or the adoptive transfer of tumor-specific 
lymphocytes into lymphodepleted hosts leads to dramatic in vivo T cell expansion and potent 
immunologic and clinical responses to immunotherapy. The use of TTRNA-pulsed DCs to expand 
tumor-specific lymphocytes ex vivo may provide a source of lymphocytes that preferentially 
expand in this lymphopenic environment and serve as a source of responder cells to subsequent 
DC vaccination. 
 
We and others have successfully employed the use of DCs loaded with total tumor RNA as an 
innovative strategy to induce cellular immune responses against the repertoire of, as yet, largely 
uncharacterized antigens present in malignant brain tumors.  Tumor cells from MB/PNETs are 
often limited and cannot be reliably isolated or propagated in sufficient quantity to serve directly 
as a source of antigen for use in human vaccination protocols.  We have, however, been able to 
reproducibly amplify the RNA content from as few as 500 isolated tumor cells using RT-PCR 
(Reverse Transcriptase-Polymerase Chain Reaction) and in vitro transcription from amplified 
cDNA (complimentary Deoxyribonucleic Acid) templates to generate RNA libraries in sufficient 

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quality and quantity for clinical scale immunotherapy trials.  We have also demonstrated that 
subtractive hybridization of RNA from normal brain can be used to enrich for antigens expressed 
exclusively within malignant brain tumor cells and possibly increase the specificity and safety 
profile of total tumor RNA directed immunotherapy. 
Primary 
Objective: 
Phase II: 
1. To determine if DC + xALT therapy extends progression-free survival compared to historical 
benchmarks during recovery from HDC + PBSCT (Group A) or salvage chemotherapy (Group 
B) in pediatric patients with reMB/PNETs.  
Secondary 
Objectives: 
1. To determine the objective radiographic response rate of MA and NMA chemotherapy coupled 
with DC + xALT therapy in patients with residual disease 
2. To determine if magnitude and persistence of anti-tumor humoral or cellular immunity 
correlates with clinical outcome 
3. To evaluate changes in cytokine profile and Toll-Like Receptor (TLR) activation status in 
pediatric patients with reMB/PNETs after HDC (Group A) or salvage chemotherapy (Group 
B) and during DC + xALT therapy 
4. To characterize the immunologic phenotype of lymphocyte subsets (naïve, effector, memory, 
regulatory) and NK cells in patients with reMB/PNETs at diagnosis and during experimental 
therapy 
5. To identify potential tumor specific antigens as vaccine candidates through characterizing the 
frequency of expression of the top 40 tumor associated antigens (TAA40) identified in common 
malignancies in recurrent MB/PNETs 
6. To determine the progression-free survival and overall survival rate in pediatric patients with 
recurrent MB/PNETs receiving DC + xALT therapy after HDC plus PBSCT (Group A) 
compared to a historical benchmark 
7. To determine the progression-free survival and overall survival rate in pediatric patients with 
recurrent MB/PNETs receiving DC + xALT therapy after salvage chemotherapy (Group B) 
compared to a historical benchmark 
Inclusion 
Criteria: 
Screening: 
• Age ≤ 30 years of age. 
• Suspected first recurrence/progression of MB/PNET since completion of definitive focal +/- 
craniospinal irradiation.  Disease progression prior to receiving definitive focal +/- craniospinal 
irradiation will not disqualify patients from enrollment if they have subsequently failed 
definitive radiotherapy and are at first recurrence/progression at time of enrollment. Patients 
who are unable to receive radiation therapy due to genetic disorders that put them at significant 
risk for radiation-induced secondary malignancies (i.e. Gorlin’s syndrome or NF1 mutation) are 
eligible for enrollment at first disease recurrence/progression.   
Re-MATCH protocol: 
• Patients must have histologically confirmed reMB/PNET that is a first relapse/progression after 
completion of definitive focal +/- craniospinal irradiation. Patients with a first 
relapse/progression who are unable to receive radiation therapy due to genetic disorders that put 
them at significant risk for radiation-induced secondary malignancies (ie. Gorlin’s syndrome or 
NF1 mutation) are eligible for enrollment. 
• Patients with neurological deficits should have deficits that are stable for a minimum of 1 week 
prior to registration.  
• Karnofsky Performance Status (KPS) of > 50% (KPS for > 16 years of age) or Lansky 
performance Score (LPS) of ≥ 50 (LPS for ≤ 16 years of age) assessed within 2 weeks prior to 
registration and documented in the medical record or on SDW-UFBTIP-004.  Patients who are 

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unable to walk because of paralysis but who are up in a wheel chair will be considered 
ambulatory for the purposes of the performance score. 
• Bone Marrow: 
- ANC (Absolute neutrophil count) ≥ 1000/µl (unsupported)* 
- Platelets ≥ 100,000/µl (unsupported)*  
- Hemoglobin > 8 g/dL (may be supported) 
*Patients on Group B with ANC < 1000/µL and/or platelet count < 100,000/µL prior to 
NMA will be allowed to get vaccine and ALT infusion; however, NMA conditioning will 
be withheld. 
• Renal:  
-Serum creatinine ≤ upper limit of institutional normal  
• Hepatic:  
- Bilirubin ≤ 1.5 times upper limit of normal for age.  
- SGPT (Serum Glutamic Oxaloacetic Transaminase) (ALT) ≤ 3 times institutional upper limit 
of normal for age.  
- SGOT (AST) ≤ 3 times institutional upper limit of normal for age. 
• Patients of childbearing or child-fathering potential must be willing to use a medically 
acceptable form of birth control, which includes abstinence, while being treated on this study. 
• Patient or patient guardian consent to PBSC and/or bone marrow harvest following registration 
if PBSC or bone marrow (CD34 count of at least 2x106/kg) has not been previously stored and 
available for use. 
• Signed informed consent according to institutional guidelines must be obtained prior to 
registration. 
 
Additional 
Eligibility 
Requirements 
Prior 
to 
Initiation 
of 
Consolidation 
or 
NMAChemotherapy: 
• Renal 
- GFR of at least 70 ml/min/1.73m2 (Group A only). 
• Cardiac:  
- ECHO cardiogram with an ejection fraction of > 45% or Multiple Gated Acquisition (MUGA) 
scan within normal limits (Group A only).  Patients in Group B will be eligible if the ejection 
fraction is < or equal to 45% but will receive Fludarabine only during NMA conditioning prior 
to vaccine + ALT infusion. 
- EKG without clinically significant arrhythmias (Group A only). 
• Pulmonary 
- DLCO, FEV1, FEC (diffusion capacity) > 50% of predicted (corrected for hemoglobin and 
alveolar volume). (Group A only) 
- Crying Vital Capacity if too young to perform pulmonary function tests (Group A only). 
- Chest X-ray without significant abnormalities and a pulse oximetry reading of > 93% in room 
air at rest and following a brisk 6-minute exercise resulting in a target heart rate of at least 
100/min.  These two tests would be required for any patient in Group A who cannot co-
operate for the DLCO test due to neurologic deficits and for all patients in Group B.  Patients 
in Group B who do not meet this requirement will still be eligible but will receive Fludarabine 
only during NMA conditioning. 
Exclusion 
Criteria: 
• Pregnant or need to breast feed during the study period (Negative serum pregnancy test 
required). 
• Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness. 

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• Known immunosuppressive disease, human immunodeficiency virus infection, or carriers of 
Hepatitis B or Hepatitis C virus. 
•  Patients with active renal, cardiac (congestive cardiac failure, myocardial infarction, 
myocarditis), or pulmonary disease. 
• Patients receiving concomitant immunosuppressive agents for medical condition. 
• Patients who need definitive radiotherapy for treatment of reMB/PNET. Focal boost 
radiotherapy may be delivered prior to immunotherapy if required for local control.    
• Patients receiving any other concurrent anticancer or investigational drug therapy.  
• Patients with any clinically significant unrelated systemic illness (serious infections or 
significant cardiac, pulmonary, hepatic or other organ dysfunction). 
• Patients with inability to return for follow-up visits or obtain follow-up studies required to assess 
toxicity to therapy.   
Study 
Design: 
This prospective Phase II multi-institutional clinical trial will evaluate the progression-free 
survival of autologous tumor-specific T cell immunotherapy (TTRNA-xALT) in conjunction 
with TTRNA-loaded dendritic cell vaccine in patients with first recurrence of medulloblastoma 
(reMB)/supratentorial primitive neuroectodermal tumors (PNETs) after completion of definitive 
radiation therapy.   Up to 42 patients will be enrolled to treat 35 evaluable patients with 
reMB/PNET with DC + xALT therapy.  Following surgical resection, biopsy, or cytology 
examination with confirmatory pathologic diagnosis, patients will be enrolled into HDC (Group 
A) or NMA salvage chemotherapy (Group B) based on eligibility for HDC.  Patients with 
localized relapse and have not failed HDC+PBSCT previously will be enrolled into Group A as 
HDC+PBSCT is considered an acceptable standard-of-care in the relapsed disease setting. 
Patients with disseminated disease, have previously failed HDC+PBSCT, or are otherwise 
considered poor candidates for HDC based on overall health status, but otherwise meet eligibility 
criteria, will be enrolled into Group B and will receive a salvage chemotherapy regimen 
followed by non-myeloablative cyclophosphamide/fludarabine lymphodepletive conditioning 
and PBSCT prior to DC + xALT therapy.  For purposes of this protocol, localized relapse will be 
defined as recurrence in the same CNS location as the original tumor or a single location 
outside of the primary site. Disseminated disease will be defined as new lesions with little 
evidence of being contiguous with prior resection cavity, or intraventricular spread, or 
dissemination along any anatomically definable subcortical white matter tracts. 
  
Group A: 
Patients enrolled into Group A will receive Induction chemotherapy that will include 
cyclophosphamide, etoposide, and temozolomide.  Leukapheresis for collection of autologous 
peripheral blood stem cells (PBSCs) and peripheral blood mononuclear cells (PBMCs) for DC and 
T cell generation will occur prior to and during induction cycles of chemotherapy and will continue 
until adequate quantities of nucleated cells are obtained.  The leukapheresis products will be 
aliquoted for future autologous PBSC rescue during Consolidation and used to generate the 
TTRNA-xALT and multiple doses of the TTRNA-DCs for future use during Post-transplant 
Immunotherapy. After completion of Induction, eligible patients will proceed to Consolidation 
with high dose chemotherapy consisting of carboplatin, etoposide, and thiotepa, followed by 
autologous PBSC rescue.  The following day, Post-transplant Immunotherapy begins with infusion 
of the TTRNA-xALT and injection of the first TTRNA-DC vaccine  embedded with GM-CSF 150 
ug followed by G-CSF (5 micrograms/kg/day beginning no later than day 6 until count recovery). 
Patients will receive TTRNA-xALT at 3x107 cells/kg at vaccine #1 in combination with the first 

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of three biweekly fixed doses of TTRNA-DC (1x107 cells) with GM-CSF.   Vaccines #2 and #3 
will consist of intradermal DC with GM-CSF vaccination only.  
 
Enrolled patients with reMB/PNETs will receive 3-4 cycles of induction therapy consisting of two 
four week cycles of intravenous cyclophosphamide (2 gm/m2/day for 2 days as Cycles 1 and 2) 
followed by two four week cycles of oral etoposide 30 mg/m2/day for 14 days plus oral 
temozolomide (TMZ) (150 mg/m2/d for 5 days as Cycles 3 and 4).  Patients will undergo a non-
mobilized leukapheresis prior to induction chemotherapy for harvest of peripheral blood 
mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation. Afterwards, 
mobilized peripheral blood stem cells (PBSC) will be collected after each induction chemotherapy 
cycle until enough peripheral blood stem cells (PBSCs) are harvested for autologous stem cell 
rescue (minimum of 2x106 CD34+ PBSCs/kg)  Patients who have radiographic or histologic 
evidence of progression will be replaced.  If either DCs and/or xALT do not meet release criteria 
or targeted dose then the patient may remain on study and receive the qualified product but will 
be replaced for the purposes of safety and efficacy assessment. For the purpose of this study, 
progression will be defined as a new lesion confirmed by biopsy or resection, positive 
cerebrospinal fluid (CSF) cytology, or radiographic progression as defined by protocol criteria.  
Following recovery from the 3rd or 4th cycle of induction chemotherapy (ANC > 1000 cells/µL), 
patients will undergo disease restaging and organ function evaluation. Patients will be admitted to 
the Pediatric Bone Marrow Transplant Unit (BMTU) and receive Carboplatin (either 500 mg/m2 
or a dose calculated based on Calvert’s formula and a AUC (Area under the concentration time 
curve) 7 mg/ml/min, whichever is less) on days -8, -7, and -6, followed by thiotepa 300 mg/m2 
and etoposide 250 mg/m2 daily on days -5, -4, and -3.  Three days after HDC (Day 0), patients 
will receive PBSC rescue. DC + xALT therapy will begin 24 hours after PBSCT.  These patients 
will receive TTRNA-xALT (3x107/kg i.v.) and TTRNA-DCs (1x107 cells i.d.) following the 
transplant as vaccine #1.  Patients will receive 3 biweekly TTRNA-DC vaccines with GM-CSF as 
long as clinically stable. Patients will also receive G-CSF  5 microgram/kg/day beginning no later 
than day 6 until ANC recovers to >1000 cells/µL.   
 
NOTE:  Patients who are no longer candidates for HDC will be eligible to transfer from Group A 
to Group B.  
 
Group B: 
Patients enrolled into Group B will receive NMA salvage chemotherapy that will include cycles 
of etoposide, and temozolomide followed by cyclophosphamide and fludarabine.  Enrolled 
patients with reMB/PNETs will receive salvage chemotherapy consisting of 2-4 cycles of oral 
etoposide 30 mg/m2/day for 14 days plus oral temozolomide (TMZ) 150 mg/m2/d for 5 days 
monthly until Immunotherapy preparation is complete.  Patients will undergo a non-mobilized 
leukapheresis prior to salvage chemotherapy for harvest of peripheral blood mononuclear cells 
(PBMCs) for TTRNA-xALT and TTRNA-DC generation. Afterwards, mobilized leukapheresis 
will be attempted after each salvage chemotherapy cycle until enough peripheral blood stem cells 
(PBSCs) are harvested for autologous stem cell infusion (goal of 2x106 CD34+ PBSCs/kg).  
Subjects who do not mobilize any peripheral blood stem cells or do not undergo leukapheresis, 
will continue with immunotherapy without NMAchemotherapy.  If either DCs and/or xALT do 
not meet release criteria or targeted dose, then the patient may remain on study and receive the 
qualified product but will be replaced for the purposes of safety assessment. Patients who progress 
prior to receiving immunotherapy may remain on study as long as they continue to meet the other 
eligibility criteria.  Patients may receive the first 3 vaccines as long as they are clinically stable 

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and remain eligible.  Subsequently, for the purpose of this study, progression will be a new lesion 
confirmed by biopsy or resection, positive cerebrospinal fluid (CSF) cytology (when previously 
negative), or radiographic progression as defined by protocol criteria.  Following surgery and 
leukapheresis, adequate organ function testing will be repeated prior to initiation of 
cyclophosphamide and fludarabine conditioning.  Drug administration and dosage for the 
lymphodepletive conditioning may be adjusted based upon hematologic performance and organ 
function testing results as per protocol.  After completion of NMA salvage chemotherapy and 
starting 11 days before Immunotherapy, patients will receive 2 days of cyclophosphamide I.V. at 
1g/m2, followed by 5 days of fludarabine I.V. at 25 mg/m2.  Approximately 72 hours following 
fludarabine, PBSCs, if available, will be infused.  Approximately 96 hours following the final dose 
of fludarabine, Immunotherapy begins with infusion of TTRNA-xALT and injection of the first 
TTRNA-DC vaccine. Patients will receive G-CSF after DC + xALT therapy until ANC recovers 
to >1000 cells/µL.  Patients will receive TTRNA-xALT at 3x107 cells/kg with the 3 total biweekly 
fixed doses of TTRNA-DC (1x107 cells i.d.) with GM-CSF 150 ug. The NMA recovery will 
incorporate G-CSF at 5 microgram/kg/day beginning no later than day 6 until ANC recovers to 
>1000 cells/µL. 
 
NOTE:  Patients on Group B with ANC <1000/µL and/or platelet count <100,000/µL prior to 
NMA will be allowed to get vaccine and ALT infusion; however, NMA conditioning will be 
withheld. 
 
Based on prior chemotherapy history and/or hematologic performance, patients enrolled on 
Group B receiving salvage chemotherapy may need to have adjustment to the planned 
chemotherapy regimen at the discretion of the treating physician(s). Focal boost radiotherapy 
may be delivered prior to immunotherapy if required for local control. As no salvage 
chemotherapy regimens in the recurrent setting of MB or PNETs have been found to be curative 
or achieve significantly prolonged disease-free survival, we do not anticipate any clinical impact 
of adjustments to the planned regimen in assessing PFS endpoint. All chemotherapy regimens will 
be recorded and any deviation from the prescribed regimen above noted.  
 
The primary efficacy endpoint will be 12-month progression-free survival (PFS-12) rate after 
treatment with DC + xALT therapy as a surrogate for overall survival.  Gururangan et al. reported 
that PFS-12 for patients with recurrent disease after initiating treatment with HDC + PBSCT or 
standard salvage therapy was 33% (95% confidence interval of 10%, 59%) and two-year PFS of 
0%.  The population of patients that will be treated in the current protocol in Group A is similar to 
the subset of patients treated on the Gururangan regimen.  Due to the complexity and expense of 
adoptive cellular therapy treatment, if the true PFS-12 associated with DC + xALT therapy is 33%, 
there would be limited interest in further investigation of this treatment regimen without significant 
modification to improve efficacy.  However, if the true PFS-12 were 55% or greater, there would 
be interest in studying this treatment regimen within the context of larger confirmatory Phase II or 
III clinical trials.  Within Group B, a good historical benchmark for this patient population 
receiving a standardized salvage regimen is not readily available.  However, previously published 
studies have shown that patients unable to receive HDC and receive salvage regimens for recurrent 
disease generally have poorer prognosis than patients in Group A with localized disease relapse 
receiving HDC + PBSCT. These differences, however, did not result in a statistically significant 
difference in survival outcomes between patients receiving HDC+PBSCT vs salvage 
chemotherapy.  Therefore, we will conservatively use the benchmark described above for analysis 

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of all patients collectively for the primary 12-month PFS endpoint. With that assumption, the 
overall sample size justification described above is for evaluable patients on both treatment arms.  
 
Therefore, the study is designed to differentiate between a PFS-12 rate of 33% (null hypothesis) 
and 55% (alternative hypothesis).  With a total of 35 patients enrolled in the Phase II trial, this 
assessment has 90% power assuming a type I error rate of 0.10.  There is also 97% power to 
differentiate between PFS-12 rates of 33% and 60%.  PFS and OS for patients enrolled on Group 
A and Group B will also be analyzed separately as a descriptive analysis to explore the possibility 
that treatment outcomes may differ significantly on the two treatment arms in this study.  
 
Immune Monitoring: 
Peripheral blood will be drawn prior to non-mobilized leukapheresis, prior to immunotherapy, 1 
day post Vaccine #1, 4 (+/- 1) days post Vaccine #1, weekly post Vaccine #1 for six weeks, and 
bimonthly, if feasible, until progression for T cell kinetics. Blood will be processed in accordance 
with SOP-UFBTIP-126.  DCs will be given intradermally and divided equally to both inguinal 
regions. Vaccines #2 and #3 will occur at 2 week intervals following the first dose.   
 
Patients will be followed bi-monthly (+/- one month) for the first year post-immunotherapy, then 
every 3 months (+/- one month) until tumor progression and death due to any cause.  As part of 
standard care for these patients, upon tumor progression, participants may undergo stereotactic 
biopsy or resection. As this is not a research procedure, consent will be obtained separately.  If 
tissue is obtained, it will be used to confirm tumor progression histologically and to assess 
immunologic cell infiltration and antigen expression profile in recurrent lesions.  
 
 

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2.2 Multi-Site Study Schema 
 
  
 

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2.3 Study Schema for Group A 
 
 
 
 

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2.4 Study Schema for Group B 
 
  
 

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3. PRINCIPAL INVESTIGATOR (PI) AND STUDY STAFF 
DUANE A. MITCHELL, M.D., PH.D. (PI) 
Phyllis Kottler Friedman Professor of Neurosurgery 
Associate Professor of Neuroscience, Pathology, Immunology, and Laboratory Medicine 
Co-Director, Preston A. Wells, Jr. Center for Brain Tumor Therapy 
Director, University of Florida Brain Tumor Immunotherapy Program 
Address: McKnight Brain Institute, Department of Neurosurgery, PO Box 100265, MBI Room L1-181, 
University of Florida, Gainesville, FL 32610 
Phone Number:  Office (352) 294-5232 
Fax Number: 352-392-8413   
Email Address:  duane.mitchell@neurosurgery.ufl.edu 
 
GERALD GRANT, M.D. (NEUROSURGERY CHAIR) 
Associate Professor of Surgery, 
Associate Professor of Pediatrics  
Address:  Lucile Packard Children’s Hospital at Stanford University 
300 Pasteur Drive Stanford CA 94305  
Edwards Bldg, R211 MC 5327 
Phone Number: 650-497-8775 
Fax Number: 650-725-5086   
Email Address:  ggrant2@stanford.edu 
 
SRIDHARAN GURURANGAN, M. R.C.P (UK). (NEURO-ONCOLOGY CHAIR) 
Greene Professor of Pediatric Neuro-Oncology  
Director, Pediatric Neuro-Oncology 
Preston A. Wells, Jr. Center for Brain Tumor Therapy  
Address: McKnight Brain Institute, Department of Neurosurgery, PO Box 100265, MBI Room L1-183, 
University of Florida, Gainesville, FL 32610 
Phone Number: 352-294-8347 
Fax Number: 352-392-8413 
Email Address: sridharan.gururangan@neurosurgery.ufl.edu 
 
 
 
3.1 KEY STUDY PERSONNEL 
Duane A. Mitchell, M.D., Ph.D. (Principal Investigator) is the Phyllis Kottler Friedman Professor of 
Neurosurgery,  Associate Professor of  Neuroscience, Pathology, Immunology, and Laboratory Medicine.,   
Co-Director of the Preston A. Wells, Jr. Center for Brain Tumor Therapy, and Director of the University 
of Florida Brain Tumor Immunotherapy Program.  Dr. Mitchell has considerable translational research 
experience involving the immunologic treatment of cancer.  Dr. Mitchell is a graduate of the prestigious NIH-
sponsored Medical Scientist Training Program (MD/PhD Program) and received his Ph.D. under the guidance of 
Dr. Eli Gilboa, a world-renowned tumor immunologist and pioneer of the RNA transfected DC platform that will 

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serve as the antigen presentation platform in this investigation.   He has devoted his research efforts on the 
development of immunotherapeutic approaches to the treatment of malignant brain tumors, and has served as PI 
on seven FDA and IRB approved Phase I/II clinical trials investigating immunotherapy in patients with malignant 
brain tumors.  He is the Chair of the Immunotherapy Working Group for the NCI Pediatric Brain Tumor 
Consortium and a panel member of the Immunotherapy Working Group for the NCI Brain Malignancy Steering 
Committee. The study outlined in this proposal will be conducted under FDA IND-BB-14058 covering the use 
of adoptive T cell therapy and amplified total tumor RNA-pulsed DCs in pediatric patients with recurrent 
MB/PNETs.   He will be responsible for supervising all aspects of the study; including writing and disseminating 
all study results and reports. He will also be ultimately responsible for ensuring the regulatory compliant execution 
of this trial and coordinating the multidisciplinary interactions of the investigators and administrators involved 
with this study.  Overall coordination of the multi-site phase II trial will be assisted by Dr. Gerald Grant, Stanford 
University (Neurosurgery Chair) and Sri Gururangan, University of Florida (Neuro-Oncology Chair).  A 
Leadership Plan for this collaboration with Dr. Mitchell functioning as lead PI and Immunotherapy Chair has 
been developed and is outlined below (Section 21.1 Leadership Plan). 
 
 
 
William Slayton, M.D. is Professor, Division Chief, and Program Director of Pediatric 
Hematology/Oncology at the University of Florida with over 20 years of experience in the care of pediatric 
patients.  Dr. Slayton has an active clinical protocol involving the use of high-dose chemotherapy followed by 
autologous stem cell rescue in children with CNS tumors and extensive experience in treating children with CNS 
tumors using intensive chemotherapy that will be utilized as the backbone for the clinical trial design investigating 
the safety and immunologic effects of adoptive lymphocyte transfer and DC vaccination during hematopoietic 
recovery from high-dose chemotherapy.  http://hemonc.pediatrics.med.ufl.edu/faculty-and-staff/attending-
physicians/dr-william-slayton/ 
 
John R. Wingard, M.D. is the Price Eminent Scholar and Professor of Medicine, Deputy Director for 
Research of the UF Health Cancer Center, and Director of the Bone Marrow Transplant Program for the 
University of Florida.  Dr. Wingard is a renowned expert in bone and stem cell transplantation as well as active 
clinical researcher. He also oversees the pediatric and adult stem cell transplantation programs and in such 
capacity coordinates the care of patients receiving high-dose chemotherapy and stem cell transplantation at the 
University of Florida including children with CNS tumors.  Dr. Wingard has extensive experience in the collection 
and dissemination of autologous and allogeneic cellular products to patients at multiple FACT-accredited 
institutions and will assist Dr. Mitchell in the multi-site coordination of collection of leukapheresis specimens, 
peripheral blood stem cell products, bar-coded storage and dissemination of cellular products, and batch records 
for the cellular products generated on this protocol.  The UF stem and bone marrow transplant program maintains 
state-of-the-art facilities and technologies for autologous cell product delivery to pediatric and adult patients. 
http://hemonc.medicine.ufl.edu/about-us/meet-the-team/john-r-wingard-md/ 
  
David R. Nelson, M.D. is Professor of Medicine, Molecular Genetics and Microbiology, Director, UF 
Clinical and Translational Science Institute, and Associate Dean for Clinical Research.  He has met with Dr. 
Mitchell several times to outline the many facets of this protocol that can leverage the extensive clinical research 
infrastructure supported by the NIH-funded CTSI at the University of Florida.  Dr. Nelson will oversee the 
coordination of the multi-site collection and registration of clinical data into a clinical database, coordinate the 
availability of the clinical research hospital and infusion center for this protocol, as well as coordinate the 
interaction between clinical research sites.  Additionally, the CTSI maintains extensive biorepository and tissue 
distribution capabilities as one of only 12 CAP-certified biorepositories in the United States.  The CTSI-supported 
biorepository and distribution capabilities will be leveraged to coordinate the collection of tumor tissues and 

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leukapheresis specimens from participating centers and disseminate autologous vaccine products to subjects 
enrolled at sites outside of the UF health network.   
https://www.ctsi.ufl.edu/ 
http://biorepository.pathology.ufl.edu/ 
http://gastroliver.medicine.ufl.edu/hepatology/faculty-staff/david-r-nelson-m-d/ 
 
Scott Rivkees, M.D. (Other Significant Contributor) is Professor and Chairman of Pediatrics and Chair of 
the Child Health Research Institute at the University of Florida. Dr. Rivkees has met several times with Dr. 
Mitchell to coordinate the Re-MATCH protocol within the extensive UF pediatric health system.  Dr. Rivkees 
currently oversees the active partnership between the UF and Orlando Regional Medical Center (ORMC) 
including Arnold Palmer Children’s Hospital. ORMC extends the patient network of the UF health system by 
over 2 million subjects, and Dr. Rivkees is attending physician at both UF/Shands medical center and Arnold 
Palmer Children’s with active on-site rotating work between both centers.  He will facilitate the interactions 
between Dr. Mitchell and his clinical research team with the pediatric oncology and clinical research teams both 
at UF and ORMC to enhance recruitment and enrollment of subjects served by the Florida health system.  He will 
also ensure that all physical and intellectual resources available within the Department of Pediatrics at the 
University of Florida are available to Dr. Mitchell in support of this protocol.  
http://research.pediatrics.med.ufl.edu/researchers/research-faculty/scott-rivkees/ 
 
Brian D. Cleaver, Ph.D. is Director of the Powell Gene Therapy Center (PGTC) and Human Applications 
Laboratory at the University of Florida.  Dr. Cleaver has extensive experience (>10 years) in the FDA-
regulated cGMP manufacturing of cellular and gene vector products for use in clinical trials.  He has directed 
GMP manufacturing of products for use at single-site, multi-site, and even international clinical studies and is an 
expert in the regulatory compliant manufacturing of GMP materials.  Dr. Cleaver and his staff within the PGTC 
will be responsible for the generation of cellular products used in this protocol and the regulatory oversight, record 
keeping, and release of qualified cellular products for this study.   
http://www.gtc.ufl.edu/core/gtc-apps.htm 
http://urology.ufl.edu/about-us/faculty-staff-directory/brian-d-cleaver-phd/ 
 
 
Anthony T. Yachnis, M.D. is Professor of Pathology and Medical Director of Anatomical Pathology at the 
University of Florida.  He is a board-certified neuropathologist with over twenty years of clinical experience. In 
such capacity, he reviews and performs confirmatory diagnosis on all brain tumor specimens collected at 
University of Florida (>600 annually) and will ensure the pathologic eligibility criteria for patients enrolled in 
this study are met. He will also evaluate the histochemical analysis of lymphocytic infiltrates in tumor specimens, 
and perform all neurotoxicity evaluations.  Dr. Yachnis will interact with the study team in the coordination of 
collection of tumor materials collected at the UF site and will perform the confirmatory diagnostic evaluation of 
specimens collected from external sites. 
http://pathlabs.ufl.edu/team/pathologists/yachnis-a 
 
William A. Friedman, M.D. (Other Significant Contributor) is Professor and Chairman of Neurosurgery at 
the University of Florida and Co-Director of the Preston A. Wells, Jr. Center for Brain Tumor Therapy.  
Dr. Friedman is a highly experienced neurosurgeon specializing in the care of patients with malignant brain 
tumors. As Co-Director of the Preston Wells Center with Dr. Mitchell, his major interests are in the advancement 
of novel therapeutics for pediatric and adult patients with malignant brain tumors.  Dr. Friedman’s role will be to 
facilitate the utilization of the vast financial, physical, and environmental resources within the Department of 
Neurosurgery and Preston Wells Brain Tumor Center in support of this protocol.  He will meet regularly with Dr. 

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Mitchell in the coordination of this study and ensure that all institutional resources are leveraged appropriately.  
Dr. Friedman is also actively overseeing the partnership with the Orlando Regional Medical Center’s 
neurosurgical practices and thus will be able to assist in the recruitment and enrollment of subjects from the 
ORMC network. Additionally, Dr. Friedman will ensure that the clinical research and regulatory staff of the 
department are available in support of this protocol including requisite CRC, regulatory, administrative, and 
nursing support.  Dr. Mitchell and Friedman are coordinately responsible for staffing any additional specialized 
needs in support of the research mission of the Preston A. Wells, Jr. Center for Brain Tumor Therapy.  In such 
capacity, up to $20M in unrestricted funds are available to Drs. Mitchell and Friedman to support clinical research 
activities.  The capacity to support unforeseen budget shortfalls from the clinical trial award supporting this 
protocol is an additional administrative role that Dr. Friedman would facilitate in collaboration with Dr. Mitchell.  
http://neurosurgery.ufl.edu/faculty-staff/our-faculty/william-a-friedman-md/ 
http://neurosurgery.ufl.edu/faculty-staff/clinical-research-staff/ 
http://news.medinfo.ufl.edu/articles/lead-story/10-million-wells-foundation-gift-will-enable-uf-to-speed-brain-
tumor-remedies/ 
 
Jianping Huang, M.D., Ph.D. is an Associate Research Professor and Director of Clinical Laboratory 
Operations for the UF Brain Tumor Immunotherapy Program.  She previously functioned as Head of 
Molecular Immunology at the Laboratory for Tumor Immunology at the National Cancer Institute and has 
extensive experience in adoptive cellular therapy of patients with cancer and in the immunologic monitoring of 
patients enrolled in cancer immunotherapy trials.  She will oversee the interactions between the UFBTIP 
laboratory and GMP facility and function as the primary supervisor of the research staff involved in cellular 
product manufacturing and QA/QC testing.  She will also oversee the immunologic monitoring of subjects 
enrolled on this protocol.  
 
Elias J. Sayour, M.D. is a pediatric oncologist who conducted his research fellowship on the 
immunotherapy of malignant brain tumors.  Dr. Sayour will function as an integrative co-investigator at the 
University of Florida. He will assist in the enrollment, evaluation, and medical management of patients enrolled, 
and in the evaluation of clinical data and laboratory analysis on acquired tissue and blood specimens.  
 
Jeffrey Drake is a research associate with considerable experience in molecular biology techniques and cell 
culture.  He will be responsible for working with the cGMP facility and staff in the generation of clinical-grade 
RNA and the generation of autologous dendritic cells and tumor-specific lymphocytes.  
 
Marcia B. Hodik, RN, BSHS, CCRC is a registered nurse with over 20 years of pediatric nursing 
experience.  She has functioned as a study coordinator for Gastroenterology and Hepatology. She currently holds 
certification as a Certified Clinical Research Coordinator and is the president of the local ACRP Chapter.  She 
will be responsible for screening and enrolling patients, ensuring protocol compliance and collecting and 
recording study data.  
 
Paul Kubilis, MS is a biostatistician dedicated full-time to research efforts within the Department of 
Neurosurgery.  He is committed to delivering understandable and useful results that help investigators achieve 
their research goals. He has extensive knowledge in study design, data analysis and presentation of data for 
publication.  He will collaborate with Dr. Mitchell on data analyses and manuscript preparation.  
 
3.2 KEY STUDY PERSONNEL EXTERNAL SITES 
 
 

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CHILDREN’S NATIONAL MEDICAL CENTER, WASHINGTON, D.C.  
111 MICHIGAN AVE., N.W. 
WASHINGTON, D.C. 20010 
http://www.childrensnational.org/ 
 
Roger J. Packer, M.D.  is Professor of Neurology & Pediatrics, Senior Vice President of the Center for 
Neuroscience, and Director of the Brain Tumor Institute at Children’s National Medical Center in 
Washington, D.C.  Dr. Packer is a renowned pediatric neuro-oncologist that leads the brain tumor program at 
CNMC, one of the nation’s leading pediatric medical centers.  He has been a colleague and associate of Dr. 
Mitchell’s for several years through interactions within the NCI-funded Pediatric Brain Tumor Consortium 
(PBTC) and has a strong interest in the implementation of novel therapeutics for children with malignant brain 
tumors. He will supervise the implementation of the Re-MATCH protocol within CNMC and ensure that the vast 
expertise, infrastructure, and resources that the center maintains in support of the treatment of pediatric patients 
is appropriated in support of this protocol.  Dr. Packer will be available to assist Dr. Eugene Hwang in the routine 
care of patients enrolled on this protocol as well.  
http://www.childrensnational.org/research/faculty/bios/cnr/packer_r.aspx 
 
Anthony Sandler, M.D. is the Diane and Norman Bernstein Professor of Pediatric Surgery, Senior Vice 
President and Surgeon-in-Chief of the Joseph E. Robert Center for Surgical Care, and Principal 
Investigator of the Immunology Initiative in the Sheik Zayed Institute at Children’s National Medical 
Center.  Dr. Sandler’s primary interest is in the immunologic treatment of pediatric brain tumors.  The Shiek 
Zayad Institute at CNMC was established with a $150 million philanthropic gift to advance novel therapeutics 
for pediatric patients.  Dr. Sandler has hosted Dr. Mitchell as a visitor to the Shiek Zayad Institute to tour the 
outstanding basic and clinical research facilities established at CNMC.  In addition to his strong scientific and 
clinical interests in immunotherapy, Dr. Sandler is an experienced pediatric neurosurgeon.  He will oversee the 
surgical obtainment and transfer of tumor specimens of suitable quality for vaccine preparation.  He will also be 
responsible for the routine pre- and post-operative care of subjects enrolled on the Re-MATCH protocol.   
http://innovationinstitute.childrensnational.org/about-us/team/1001 
 
Eugene I. Hwang, M.D. is a pediatric neuro-oncologist and Director of the Pediatric Neuro-Oncology 
Fellowship Program at Children’s National Medical Center.  Dr. Hwang received his pediatric neuro-
oncology fellowship training at Duke University and worked with Dr. Mitchell during the development of the Re-
MATCH protocol.  He has a strong interest in pediatric immunotherapy and is collaborating with Dr. Mitchell on 
novel initiatives within the Pediatric Brain Tumor Consortium.  Dr. Hwang will play an active role in the care of 
patients enrolled on this protocol and in the integration of the Re-MATCH protocol with the outstanding clinical 
research team at CNMC.  He will also oversee the collection and transport of leukapheresis products to the GMP 
facility at University of Florida for vaccine and T cell preparation and be directly responsible for vaccine 
administration for subjects enrolled at CNMC.  
http://www.childrensnational.org/findadoctor/profiles/eugene-hwang-4385.aspx 
 
CHILDREN’S HOSPITAL LOS ANGELES 
4650 SUNSET BLVD 
LOS ANGELES, CA 90027 
http://www.chla.org 
 
Girish Dhall, M.D. is Clinical Director of Neuro-Oncology at Children’s Hospital Los Angeles.  He is an 
experienced  pediatric hematology/oncologist who will oversee the management of subjects enrolled on the 
protocol at CHLA.  Dr. Dhall will also direct the collection and dissemination of leukapheresis products for 

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vaccine and T cell preparation to the University of Florida and the administration of vaccine products to subjects 
enrolled at CHLA.  
http://www.chla.org/site/apps/kb/cs/contactdisplay.asp?c=ipINKTOAJsG&b=3832751&sid=ewJXIjPWJfLYKd
P1KzG&r=1 
 
Mark Krieger, M.D. is Division Chief of Pediatric Neurosurgery and Director of the Neurosurgery 
Fellowship Program at CHLA.  Dr. Krieger is a highly-experienced pediatric neurosurgeon at one of the top 
ranked pediatric hospitals in the nation.  He will oversee the protocol compliant collection and dissemination of 
tumor materials suitable for vaccine preparation at the CHLA site and in his duties as Division Chief will ensure 
the proper pre- and post operative management of subjects enrolled on this protocol.  Dr. Krieger will also ensure 
coordination of information with the Neurosurgical Chair of the protocol, Dr. Gerald Grant at Stanford University.   
http://www.chla.org/site/apps/kb/cs/contactdisplay.asp?c=ipINKTOAJsG&b=3832751&sid=dvKTKhPVIiI5If
MQJrF&r=1 
 
 
Clinical Research Staff: 
ANJELIKA M. DECHKOVSKAIA, M.D., Senior Biological Scientist, UF Brain Tumor Immunotherapy 
Program, Department of Neurosurgery, University of Florida 
CATHERINE FLORES, Ph.D., Assistant Professor, UF Brain Tumor Immunotherapy Program, Department of 
Neurosurgery, University of Florida 
4. STUDY LOCATION(S)   
UNIVERSITY OF FLORIDA HEALTH 
The sites for the routine and experimental care for patients enrolled on this study will be as follows: 
• Neurosurgical Care:  Resections performed at UFHealth Shands Hospital, Pediatric Neurosurgeons  
• Consolidation chemotherapy and peripheral blood stem cell mobilization: UFHealth Shands Children’s 
Hospital, Supervising Physicians: William Slayton, MD, and John R. Wingard, MD  
• Leukapheresis and Stem Cell Harvest:  UFHealth Bone Marrow and Stem Cell Transplantation Clinics, 
Supervising Physician: John R. Wingard, M.D. 
• Dendritic cell generation, tumor RNA isolation and amplification, autologous T cell expansions: UF Brain 
Tumor Immunotherapy Program, Supervising Physician: Duane A. Mitchell, M.D., Ph.D. 
• High-dose chemotherapy and peripheral blood stem cell transplantation: UFHealth Shands Children’s 
Hospital Bone and Stem Cell Transplantation Unit, Supervising Physicians: John R. Wingard M.D., and 
William Slayton, MD   
• Autologous lymphocyte transfer and dendritic cell vaccination (inpatient): UFHealth Shands Children’s 
Hospital Bone and Stem Cell Transplantation Unit, Supervising Physicians: John R. Wingard, M.D., and 
William Slayton, MD  
• Dendritic cell vaccination and follow-up visits (outpatient):  UFHealth Pediatric Hematology/Oncology 
Clinic, Supervising Physicians: Duane A. Mitchell, M.D., Ph.D., William Slayton, MD, and John R. 
Wingard, MD 
• Immunologic monitoring and correlative assays:  UF Brain Tumor Immunotherapy Program, Principal 
Investigator:  Duane A. Mitchell, M.D., Ph.D.  
 
EXTERNAL SITES 
• Children’s National Medical Center 

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• Children’s Hospital Los Angeles 
5. TIME REQUIRED TO COMPLETE THE STUDY  
This protocol will be conducted under an FDA approved IND (IND BB-14058) covering the use of amplified 
tumor RNA pulsed DCs and adoptive lymphocyte transfer in patients with malignant brain tumors.  University of 
Florida IRB and Institutional Biosafety Committee (IBC) reviews are completed and full-regulatory approval by 
these agencies is finalized.  National Recombinant DNA Advisory Committee (RAC) review has been completed 
and a letter of approval/permission to proceed has been received.  The projected time frame for the phase I/II 
study is December 1, 2010 through March 31, 2019.  
6. BACKGROUND  
6.1 Significance and Overall Rationale 
Malignant brain tumors now represent the second most frequent cause of cancer death in children.  
Despite aggressive and highly toxic multi-modality therapy including surgery, craniospinal radiation, and HDC 
+ PBSCT, almost half of the children diagnosed with medulloblastoma and primitive neuroectodermal 
tumors (MB/PNETs), still die from recurrent disease.  Furthermore, survivors are often left with severe and 
lifelong treatment-associated cognitive and motor deficits. The development of more effective and less toxic 
tumor-specific therapies is paramount in improving clinical outcomes for children affected by MB/PNETs.  
Immunotherapy targeting tumor-specific antigens expressed within brain tumors is a treatment modality 
potentially capable of meeting this clear and urgent need. 
Despite considerable advancements and promising clinical results observed in immunotherapy trials at 
our center and others directed against adult malignant brain tumors, efforts in the immunologic treatment of 
pediatric brain tumors have been limited to relatively few notable studies. This is often due, at least in part, to the 
limited amount of viable tumor tissue available for tumor cell-based vaccine preparations, and the lack of 
identification of consistently expressed tumor-specific antigens within these cancers. 
The use of total tumor RNA-loaded dendritic cells (DCs) was pioneered by Drs. Nair and Gilboa at Duke 
University, as a novel platform for inducing potent immunologic responses against the variety of uncharacterized 
and patient-specific antigens present within malignant tumor cells.  We have demonstrated that sufficient RNA 
for clinical vaccine preparations can be amplified with high fidelity using existing molecular technologies 
from as few as 500 isolated pediatric and adult brain tumor cells, thus allowing vaccine preparation from 
surgical biopsies and even microdissected archival tumor specimens. We are currently exploring adoptive cellular 
therapy using amplified tumor RNA-pulsed DCs and autologous lymphocyte transfer (DC + xALT therapy) in 
adult patients with recurrent GBM (FDA IND BB-13630; Duke IRB protocol 6677; PI: Duane A. Mitchell, M.D., 
Ph.D.). In this proposal, we aim to extend evaluation of this novel platform to the treatment of recurrent 
MB/PNETs (reMB/PNETs) during hematopoietic recovery from HDC + PBSCT and NMA salvage 
chemotherapy. 
Immunotherapy administered during recovery from HDC and NMA salvage therapy may have 
tremendous advantages, as adoptive cellular therapy following lymphodepletive conditioning regimens has 
emerged as the most effective treatment strategy for advanced and refractory melanoma. Remarkable objective 
clinical responses in up to 75% of treated refractory melanoma patients have been observed, including durable 
complete regressions of metastatic lesions within the CNS. Although the mechanisms by which 
lymphodepletion enhances immunotherapy in humans are not well elucidated, elegant studies in murine tumor 
models have highlighted some key catalysts for induction of potent anti-tumor immunity. Depletion of 
immunosuppressive Tregs, increased bioavailability of inflammatory cytokines and homeostatic 
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compete with transferred tumor-specific T cells, and increased toll-receptor agonistic signals during 
myeloablative therapy play significant roles.   
Our HYPOTHESIS is that DC + xALT therapy targeting reMB/PNETs during recovery from 
myeloablative (MA) and non-myeloablative (NMA) chemotherapy will induce potent tumor-specific immune 
responses that mediate the safe eradication of invasive malignant disease. In this effort, we aim to leverage the 
myelosuppressive toxicity of standard-of-care HDC and NMA salvage therapy in order to enhance the potential 
efficacy of a novel immunotherapy employing the use of amplified tumor RNA-pulsed DCs.  Toward that end, 
our SPECIFIC AIMS are to: 
1. Conduct a Phase II clinical trial of DC + xALT therapy during hematopoietic recovery from NMA salvage 
chemotherapy and HDC + PBSCT in pediatric patients with reMB/PNETs with the following sub-aims:  
a. Determine the impact of DC +xALT therapy on progression-free survival (PFS) and overall survival 
(OS) of pediatric patients with reMB/PNETs compared to historical cohort;  
b. Investigate the correlation between clinical outcome and the frequency and persistence of tumor-
specific T cells in the peripheral blood of treated patients; 
c. Determine the impact of induction therapy and HDC + PBSCT (Group A) or salvage chemotherapy 
(Group B) on circulating levels of homeostatic and inflammatory cytokines, toll-like receptor activation 
status, and on the functional recovery of lymphocyte and NK cellular subsets in children with re-
MB/PNETs receiving DC + xALT therapy;  
d. Characterize the frequency of expression of the TAA-40 identified in common malignancies in first and 
second recurrent MB/PNETs in order to identify potential candidates for subsequent evaluation in 
antigen-specific immunotherapy approaches. 
6.2 Immunotherapy for Pediatric Brain Tumors 
Despite brain tumors being the leading cause of cancer deaths in children and the considerable 
advances in immunologic targeting of adult brain tumors, studies examining immunotherapy for 
MB/PNETs are markedly lacking except for a few notable reports.  Efforts in targeting pediatric brain tumors 
are hindered somewhat by the relatively small number of clinical cases compared to adult cancers, the lack of 
syngeneic murine models of common pediatric brain tumors in which immunotherapy efforts can be evaluated in 
preclinical studies, and the significant regulatory hurdles in conducting experimental therapies in the pediatric 
setting.  Despite these limitations, the use of HDC + PBSCT and NMA chemotherapy in pediatric patients with 
reMB/PNETs affords an ideal setting in which to leverage the recent findings by our laboratory and others in the 
benefits of treatment-induced lymphopenia in enhancing immune responses to tumor immunotherapy.  
Three notable studies have demonstrated the safety and potential efficacy of immunotherapy in children 
with malignant brain tumors.  
Ashley and colleagues conducted a phase I study of 9 pediatric patients with recurrent brain tumors using 
monocyte-derived DCs pulsed with tumor RNA isolated from resected tumor specimens[1]. DCs were derived 
from monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-
CSF), incubated with RNA for 45 minutes in serum-free media, washed and then cyropreserved until 
administration.  DC vaccines were administered intradermally and intravenously in treated patients. The 
feasibility and safety of tumor RNA pulsed DC vaccines was demonstrated in this study with 7 of the 9 enrolled 
patients receiving RNA-pulsed DC vaccines.  1 patient demonstrated a partial response to therapy as assessed by 
MRI and 2 patients showed disease stabilization.  Tumor-specific immune responses were demonstrated after 
vaccination in 2 of 7 patients.   
A subsequent study by the same group in 11 pediatric patients with newly-diagnosed, Stage 4 
neuroblastoma, evaluated tumor RNA-pulsed DC vaccines after HDC+PBSCT[2].  The patients received two 
courses of carboplatin induction therapy followed by standard chemotherapy, surgery, radiation, and HDC + stem 
cell rescue. DC vaccines were administered intravenously and intradermally beginning six weeks after stem cell 
transplantation and were prepared as described in the previous study.  The investigators noted immunologic 

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impairment in recall responses and proliferative responses in patients at 6 weeks post HDC+PBCT.  7 of 11 
enrolled patients were successfully treated during this study. The safety and feasibility of the total tumor RNA 
DC vaccines after HDC + PBSCT was demonstrated by this study but no clinical or radiographic responses were 
observed.   
Importantly, Ashley and colleagues demonstrated the safety and feasibility of total tumor RNA-pulsed 
DCs in pediatric patients with recurrent and primary brain tumors in these studies.  Recent advances, however, in 
our understanding of DC biology and their use in anti-tumor immunotherapy have made even the limited clinical 
responses observed in the first study somewhat encouraging.  These significant differences in the previously 
published reports and the methods we will use in this study are as follows: 
• Ashley and colleagues used immature DCs in their study which have now been shown to be vastly 
inferior in the induction of immunologic responses.  Our DCs are matured with a combination of IL-
1β, TNFα, and IL-6. 
• Route of injection comparisons have shown that intravenous injection of DCs in humans is in many 
cases tolerigenic and the preferred route for induction of immunity is intradermal. Our vaccines will 
be administered through intradermal injection only. 
• We have shown electroporation of RNA into DCs to be 100 to 1000 times more efficient than co-
incubation of DCs with “naked RNA”.  The labile nature of RNA results in degradation with a half-
life of seconds to minutes, thus electroporation to deliver RNA directly into DCs is far superior in 
mediating gene expression and anti-tumor immunity.   
• We and others have shown that the early recovery period after lymphodepletion is the most effective 
period for enhancing immunity to vaccination and adoptive T cell transfer and thus we will administer 
DC+ALT therapy during the peri-transplant period (24 hrs after PBSCT) as has been done in studies 
at the NCI using myeloablative therapy and adoptive cellular therapy in patients with melanoma.   
• Ashley and colleagues administered 3 to5 vaccines to their patients, while we will continually 
vaccinate patients throughout the recovery period of lymphopenia and normalization of T cell function 
(up to 1 year post HDC + PBSCT) as we have shown capacity to increase immunologic responses 
dramatically over time in vaccinated patients with newly-diagnosed GBM.  In fact, significant anti-
tumor immune responses have often occurred in our patients only after repetitive monthly vaccinations 
(Figs. 5-6).  
 We believe these advances will significantly enhance the potential clinical impact of our proposed 
therapeutic approach.  Admittedly, as more potent vaccination platforms are advanced, the risks of inducing 
intolerable autoimmunity will also likely increase, and thus careful evaluation of the safety of these potent 
vaccination platforms will be necessary.  Our proposed phase I study will establish the safety of DC + xALT 
therapy using amplified total tumor RNA pulsed DC vaccines to expand tumor-specific lymphocytes in vitro for 
adoptive transfer and maintenance in vivo with DC vaccination.  
6.3 Rationale for Current Study 
Adoptive cellular therapy after lymphodepletive regimens has emerged as a potent and effective means of 
inducing durable remissions of advanced stage refractory melanoma and therefore holds significant promise in 
the treatment of other solid tumors.  Recurrent MB/PNETs are the most common pediatric brain tumors and brain 
cancer is currently the leading cause of cancer deaths in children.  The use of HDC + PBSCT and NMA 
chemotherapy as standard therapy in patients with reMB/PNETs provides an ideal opportunity to administer 
adoptive cellular therapy during the hematopoietic recovery phase from HDC and NMA chemotherapy.  We have 
developed the use of total tumor RNA loaded DCs as an effective platform for induction of tumor-specific 
lymphocytes and will use TTRNA-pulsed DCs to expand lymphocytes specific for reMB/PNETs from children 
undergoing secondary resection and HDC + PBSCT (Group A) or NMA salvage chemotherapy (Group B).  In 
order to maintain T cell expansion and functional administration concurrent and monthly vaccinations with 
TTRNA-pulsed autologous DCs will be administered.   

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6.4 Re-MATCH Phase I Study 
21 subjects were enrolled on the protocol using a screening consent for tumor collection.  Eleven of these subjects 
were removed from the study (ineligible histology, tumor progression, inability to obtain sufficient PBMCs for 
DC/xALT generation) prior to immunotherapy.  Ten subjects were treated with DC+ALT therapy and nine were 
evaluable for the maximal tolerated dose (MTD) and dose-limiting toxicities (DLTs). One patient’s T cells did 
not grow and was treated with DC vaccination only and thus not evaluable for phase I safety endpoints.  
 
Therefore, ten were treated with DCs/xALT with nine of these patients evaluable for DLTs and MTD.  
For Group A, we treated a single subject that reached the safety endpoint at dose cohort #1 (3x106 T cells/Kg).  
For Group B, we treated three subjects that reached the safety endpoint at dose cohort #1, and 5 subjects at dose 
cohort #2 (3x107 T cells/Kg).  A maximal achievable dose of T cells was obtained at 3x107 T cells/Kg. Of the 
nine patients who were evaluable for DLTs and MTD (Group A, N=1; Group B, N=8), no DLTs were associated 
with adoptive cellular therapy as defined at two weeks after the third dendritic cell (DC) vaccination.  The phase 
I study was closed with a defined safe dose of 3x107 T cells/Kg i.v. and 1x107 DCs i.d.     
7. OBJECTIVES/SPECIFIC AIMS/STUDY QUESTIONS 
7.1 Hypotheses 
• Our MAIN HYPOTHESIS  is that: 
o Adoptive transfer of tumor-specific lymphocytes coupled with TTRNA-pulsed DC 
vaccinations that target reMB/PNETs will lead to the safe eradication of residual tumor 
cells during hematopoietic recovery from myeloablative and non-myeloablative 
chemotherapy and autologous PBSCT. 
• SECONDARY HYPOTHESES that will be explored in this study are that: 
o Treatment of pediatric patients with reMB/PNETs using TTRNA-xALT and TTRNA-
DCs will enhance polyfunctional anti-tumor T cell responses 
o Treatment of pediatric patients with reMB/PNETs using TTRNA-xALT and TTRNA-
DCs extends progression free survival (PFS) compared to a historical cohort. 
o A correlation exists between persistence of anti-tumor immunity and clinical outcome 
in patients with reMB/PNETs 
o Myeloablative and NMA chemotherapy will lead to increases in homeostatic and 
inflammatory cytokines, decreases in circulating CD4+CD25+FOXP3+ Tregs, as well 
as increases in TLR activation in patients with reMB/PNETs 
7.2 Study Objectives 
• PRIMARY OBJECTIVES for the PHASE II Trial: 
o To determine if DC + xALT therapy extends progression-free survival compared  to 
historical benchmarks during recovery from HDC + PBSCT (Group A) or salvage 
chemotherapy (Group B) in pediatric patients with reMB/PNETs  
• SECONDARY OBJECTIVES 
o To determine the objective radiographic response rate of MA and NMA chemotherapy 
coupled with DC + xALT therapy in patients with residual disease 
o To determine if magnitude and persistence of anti-tumor humoral or cellular immunity 
correlates with clinical outcome 
o To evaluate changes in cytokine profile and Toll-Like Receptor (TLR) activation status 
in pediatric patients with reMB/PNETs after HDC (Group A) or salvage chemotherapy 
(Group B) and during DC + xALT therapy 

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o To characterize the immunologic phenotype of lymphocyte subsets (naïve, effector, 
memory, regulatory) and NK cells in patients with reMB/PNETs at diagnosis and 
during experimental therapy 
o To identify potential tumor specific antigens as vaccine candidates through 
characterizing the frequency of expression of the top 40 tumor associated antigens 
(TAA40) identified in common malignancies in recurrent MB/PNETs 
o To determine the progression-free survival and overall survival rate in pediatric patients 
with recurrent MB/PNETs receiving DC + xALT therapy after HDC plus PBSCT 
(Group A) compared to a historical benchmark 
o To determine the progression-free survival and overall survival rate in pediatric patients 
with recurrent MB/PNETs receiving DC + xALT therapy after salvage chemotherapy 
(Group B) compared to a historical benchmark 
8. STUDY DESIGN 
This will be a dual-arm prospective multi-institutional Phase II clinical trial where the 12-month 
progression-free survival rate in each group will be compared to a historical benchmark. 
Using guidance provided by the FDA for tumor collection and transfer on an existing protocol (FDA IND 
13630, Duke IRB 6677; PI: Duane A. Mitchell, M.D., Ph.D.), we have received IRB and FDA approval to use 
identical processes for the transfer of tumor materials for the Re-MATCH protocol. To date, we have successfully 
transferred 3 specimens from outside institutions for RNA amplification. All attempts to amplify RNA sterilely 
have been successful whether tumor specimens were collected locally or transferred via overnight shipping. 
Additionally, we have received strong letters of support and commitment from collaborating institutions to open 
the phase 2 trial as a multi-institutional study. This would greatly facilitate the enrollment of the targeted number 
of evaluable subjects in a timely manner.  Guidelines from the FDA have been obtained on centralized cellular 
manufacturing for the treatment of subjects at outside institutions.  
As no study drug is administered during either the Induction phase or the Salvage chemotherapy phase of 
the trial, the regimens for both Group A and Group B patients and the mobilization and collection of PBSCs may 
be administered at UF or other Foundation for the Accreditation of Cellular Therapy (FACT)-accredited medical 
institutions under the care of a board-certified/board-eligible pediatric oncologist. PBSC products collected and 
cryopreserved at FACT-accredited institutions shall be shipped in a dry shipper to the UF Stem Cell Laboratory 
per SOPs prior to Consolidation (Group A) or NMA conditioning with cyclophosphamide and fludarabine (Group 
B).  Dr. Sri Gururangan (Neuro-oncology Chair) will be responsible for providing a roadmap of the induction and 
salvage chemotherapy regimens to outside oncologists and acquiring documentation of all prescribed medications 
and any chemotherapy or procedure related toxicities during these periods (see attached cover letter and check 
sheet). Standard medication regimens may need to be adjusted due to hematologic or other toxicities and may be 
managed at the discretion of the treating pediatric oncologist.  Focal boost radiotherapy may be delivered prior to 
immunotherapy if required for local control.  All deviations from intended regimens during induction or salvage 
therapy will be documented, but not considered a protocol deviation, as is within routine standard of practice for 
this patient population  
 
Phase II: 
This study will assess the clinical impact of DC + xALT therapy in patients with first localized 
reMB/PNETs.  Up to 42 patients will be enrolled to treat 35 patients with reMB/PNET with DC + xALT 
therapy.  Following surgical resection, biopsy, or cytology examination with confirmatory pathologic diagnosis, 
patients will be enrolled into HDC (Group A) or NMA salvage chemotherapy (Group B) based on eligibility 
for HDC.  Patients with localized relapse and have not failed HDC+PBSCT previously will be enrolled into 
Group A as HDC+PBSCT is considered standard-of-care in the relapsed disease setting. Patients with 

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disseminated disease, have previously failed HDC+PBSCT, or are otherwise considered poor candidates for 
HDC based on overall health status but otherwise meet eligibility criteria will be enrolled into Group B and will 
receive a salvage chemotherapy regimen followed by non-myeloablative cyclophosphamide/fludarabine 
lymphodepletive conditioning with PBSCT prior to DC + xALT therapy. For purposes of this protocol, 
localized relapse will be defined as recurrence in the same CNS location as the original tumor or a single 
location outside of the primary site. Disseminated disease will be defined as new lesions with little evidence 
of being contiguous with prior resection cavity, or intraventricular spread, or dissemination along any 
anatomically definable subcortical white matter tracts. 
The primary efficacy endpoint will be 12-month progression-free survival (PFS) from HDC + PBSCT or 
NMA salvage chemotherapy, after treatment with TTRNA-xALT and TTRNA-DCs. In Group A, the progression-
free survival experience among patients who initiated HDC after having previously received definitive 
radiotherapy is reported by Gururangan et al., (2008).  The 12-month PFS (PFS-12) rate is 33% (95% confidence 
interval: 10%, 59%).  The population of patients that will be treated in the current protocol is similar to the subset 
of patients treated on the myeloablative regimen reported by Gururangan et al., but will also include recurrent 
central PNETs in addition to MB.  For patients receiving NMA chemotherapy, there is no good historical 
benchmark.  Considering that patients in Group B tend to have poorer prognoses than Group A, we will 
conservatively use the benchmark from Group A for Group B.  
Adoptive cellular therapy during recovery from myeloablative therapy has shown extraordinary promise 
in treatment of refractory melanoma (greater than 70% objective response rate)[3], but is a complex and labor 
intense individualized cancer therapy requiring a high-level of technical expertise and infrastructural support.  
Therefore, we would continue to refine this regimen until strong suggestion of significant improvement in 
treatment outcome were observed before proceeding to large-scale confirmatory trials. With this rationale in mind, 
in the current study, if the true proportion of patients with reMB/PNETs who have failed prior definitive 
radiotherapy experienced a PFS-12 with TTRNA-xALT and TTRNA-DCs treatment of 55% or more there would 
be definite interest in continuing  the treatment regimen without further modification in larger confirmatory phase 
II or III studies.  If the true PFS-12 associated with DC + xALT therapy is 33%, there would be limited interest 
in further investigation of this treatment approach without significant modification.  Therefore, the study is 
designed to differentiate between a PFS-12 rate of 33% (null hypothesis) and 55% (alternative hypothesis).  With 
35 patients treated in the Phase II study; this assessment has 90% power assuming a type I error rate of 0.10.  
There is also 97% power to differentiate between PFS-12 rates of 33% and 60%.  
The PFS and OS of patients with rePNETs following definitive radiotherapy does not differ significantly 
from reMBs following definitive RT [4,5] and therefore all patients will be analyzed collectively for primary and 
secondary endpoint evaluations in this study. Though this study is not powered for histologic tumor subgroup 
analyses, we will analyze PFS of patients with reMBs and rePNETs separately as a hypothesis driven investigation 
only to test the notion that no appreciable difference in treatment outcome for patients with reMB and other 
PNETs after DC + xALT therapy will be observed.  Analysis of patients with reMB separately will also allow us 
to confirm that any comparisons with the historical control cohort made with analysis of all patients are consistent 
when analyzing patients with MB. 
Patients will be followed bi-monthly (+/- one month) for the first year post-immunotherapy, then every 3 
months (+/- one month) until tumor progression and death due to any cause.  As part of standard care for these 
patients, upon tumor progression, participants may undergo stereotactic biopsy or resection.  As this is not a 
research procedure consent will be obtained separately. However, if tissue is obtained, it will be used to confirm 
tumor progression histologically and to assess immunologic cell infiltration and antigen expression profile in 
secondary recurrent tumors compared to original recurrent tumor RNA used in TTRNA-DC preparation by gene 
expression microarray. 
 
Children and young adults with reMB/PNETs will be identified from the patient population referred for 
treatment of recurrent disease.  Our Centers are major referral centers for the treatment of pediatric brain tumors 
for the United States and abroad.  Additionally, patients will be identified through referral by network resources 

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such as the Pediatric Brain Tumor Consortium (PBTC) (see letter of support from Dr. Larry Kun, Director PBTC) 
and the Pediatric Brain Tumor Foundation of the United States (PBTFUS) (see letter of support from Mike 
Traynor, President, PBTFUS).  
Group A Phase II: 
Patients in Group A with reMB/PNETs will start Induction therapy with attempted gross total resection 
for tumor debulking and to provide tumor tissue that is required for histologic diagnosis and the extraction of total 
tumor RNA. Approximately two weeks later, subjects will undergo a non-mobilized leukapheresis for peripheral 
blood mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation and then start induction 
chemotherapy that consists of three to four 28-day cycles as presented below: 
 
Leukapheresis after each induction cycle until collection of a minimum 2x106 CD34+ cells/kg 
Cycle 1 & 2 
Drug 
Dosage 
Route 
Days Given 
Cyclophosphamide 2g/m2/day 
IV over 1 hour 
1, 2 
Mesna 
2g/m2/day 
IV 
1, 2 
Filgrastim 
10mcg/kg/day 
SQ or IV 
3 - 28* 
Cycle 3 & 4 
Temozolomide 
150mg/m2/day 
By mouth 
1 - 5 
Etoposide 
30mg/m2/day 
By mouth 
1 - 14 
*administered until bone marrow recovery and leukapheresis complete 
 
Patients will undergo a non-mobilized leukapheresis prior to induction for harvest of peripheral blood 
mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation. The target PBMC count based on 
the desired dose of TTRNA-xALT and sufficient TTRNA-DCs for T cell expansion and in vivo vaccination will 
be collected.  Afterwards, mobilized Peripheral blood stem cells (PBSC) will be collected after each induction 
cycle until the target CD34(+) PBSC yield needed for Consolidation (2x106 CD34+ cells per Kg at a minimum) 
is obtained.  Absolute nucleated cell count collected will be adjusted as needed on a patient specific basis. Upon 
recovery from the 3rd or 4th cycle of induction chemotherapy, patients will undergo disease restaging and organ 
function evaluation.  Patients will be replaced if they have disease progression by radiographic or histological 
findings or inadequate organ function.   Patients without tumor progression and suitable organ function (defined 
below in Section 10) will be admitted to the PBMT unit to begin Consolidation as presented below: 
 
Drug Name 
Route  
Dose  
Schedule 
Instructions for 
administration 
Carboplatin 
IV 
The lesser of 
500mg/m2 or 
dosing = AUC 7 
mg/ml-min per 
Calvert Formula; 
dilute  to 4 mg/ml 
in Normal Saline 
Days  
-8, -7,-6 
IV over 4 hours through 
central venous catheter 

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Etoposide 
IV 
250mg/m2; dilute 
to 0.3 mg/ml in 
Normal Saline  
Days 
-5,-4,-3 
IV over 3 hours through 
central venous catheter 
Thiotepa 
IV 
300mg/m2; dilute 
to 1 mg/ml in 
Normal Saline 
 
Days 
-5,-4,-3 
IV over 3 hours through 
central venous catheter 
Peripheral Blood Stem 
Cells 
IV 
Minimum:  
2x106 CD34+ 
cells/kg 
 
Day 0 
IV through central venous 
catheter per institutional 
guidelines 
TTRNA-xALT 
IV 
3x107/kg 
Day 1 
IV over 10-30 minutes through 
central venous catheter. 
Pre-medicate 30-60 minutes 
prior to infusion with 
acetaminophen (up to 10-15 
mg/kg/dose) and Benadryl (up 
to 1 mg/kg). Vital signs will be 
assessed prior to and post 
infusion then every 15 minutes 
for 1 hour.   
TTRNA-DCs 
Intradermal 1x107 cells 
 
 
Days  
1, 15, 29 
Each immunization will be 
divided equally to both 
inguinal regions.  A total 
volume of 200 µL per side will 
be delivered intradermally 
after preparation of skin with 
EMLA anesthetic cream. 
Sargramostim 
(GM-CSF) 
 
Intradermal 
150 ug 
 1, 15, 29 
 
 Embedded with DC Vaccine 
Filgrastim 
(G-CSF) 
SQ or IV 
5 micrograms/ 
kg/day   
 
Beginning 
no later 
than Day 6 
post-
transplant- 
count 
recovery 
Per institutional guidelines 
 
Three days after completion of the myeloablative therapy (Day 0), patients will be given their autologous 
PBSC transplant.  Immunotherapy will commence 24 hours after autologous PBSC transplant with infusion of 
TTRNA-xALT via an intravenous catheter.  The equally-divided TTRNA-DC vaccine embedded with GM-CSF 
will be injected intradermally into the groin bilaterally which drain to the inguinal lymph nodes (upper medial 
thigh).    Peripheral blood will be drawn prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day 
post Vaccine #1, 4 (+/- 1) days post Vaccine #1, weekly post Vaccine #1 for six weeks, and bimonthly, if feasible, 
until progression for T cell kinetics.   Blood will be processed in accordance with SOP-UFBTIP-126.  The 
subsequent DC vaccines #2 and #3 will occur at 2 week intervals following the first vaccine.  Patients will receive 

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at least 3 biweekly vaccines as long as clinically stable. Patients will receive G-CSF at 5 microgram/kg/day 
beginning no later than day 6 post-transplant until ANC recovers to >1000 cells/µL.   
NOTE:  Patients who are no longer candidates for HDC will be eligible to transfer from Group A to 
Group B.   
 
Group B Phase II: 
Patients on Group B will receive salvage chemotherapy consisting of cycles of oral etoposide for 14 days 
plus oral temozolomide (TMZ) for 5 days monthly until preparation of immunotherapeutic vaccines has been 
completed as presented below: 
 
 
Patients will undergo a non-mobilized leukapheresis prior to salvage chemotherapy for harvest of 
peripheral blood mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation. Afterwards, 
mobilized leukapheresis will be attempted after each salvage chemotherapy cycle until enough peripheral blood 
stem cells (PBSCs) are harvested for autologous stem cell infusion (goal of 2x106 CD34+ PBSCs/kg). Subjects 
who do not mobilize any peripheral blood stem cells or  do not undergo leukapheresis, will continue with 
immunotherapy without NMA chemotherapy. If either DCs and/or xALT do not meet release criteria or targeted 
dose, then the patient may remain on study and receive the qualified product but will be replaced for the purposes 
of safety assessment. If only DCs are to be administered, then lymphodepleting conditioning with 
cyclophosphamide/fludarabine will be withheld and DCs administered when the patient has recovered detectable 
peripheral blood lymphocyte counts as the rationale for lymphodepletion is for enhancing the expansion of 
adoptively transferred T cells (xALT). Patients who progress prior to immunotherapy may remain on study as 
long as they continue to meet the other eligibility requirements.  Patients may receive the first 3 vaccines as long 
as they are stable and remain eligible.  Subsequently, for the purpose of this study, progression will be defined as 
a new lesion confirmed by biopsy or resection, positive cerebrospinal fluid (CSF) cytology (when previously 
negative), or radiographic progression as defined by protocol criteria.  Following surgery and leukapheresis, 
adequate organ function testing will be repeated prior to initiation of cyclophosphamide and fludarabine 
conditioning.  Drug administration and dosage for the lymphodepletive conditioning may be adjusted based upon 
hematologic performance and organ function testing results.   
After completion of salvage chemotherapy and starting 11 days before immunotherapy, patients will 
receive NMA chemotherapy which includes 2 days of cyclophosphamide IV followed by 5 days of fludarabine 
IV.  Approximately 72 hours following fludarabine, PBSCs, if available, will be infused.  Approximately 96 hours 
following the final dose of fludarabine, Immunotherapy begins with infusion of TTRNA-xALT (3x107/kg) and 
injection of the first TTRNA-DC (1x107cells) vaccine. The NMA recovery will incorporate G-CSF at 5 
microgram/kg/day beginning no later than Day 16 until ANC recovers to >1000 cells as presented below: 
 
Drug Name 
Route  
 
Dose  
 
Schedule 
 
Temozolomide 
PO 
150  mg/m2/day 
Days  1-5 
 
Etoposide 
PO 
30  mg/m2/day 
Days 1-14 
 
Filgrastim (G-CSF) 
SQ or 
IV 
10 micrograms/ 
kg/day 
Starting Day 15 
*administered each cycle until enough 
CD34 cells are harvested (goal of 
2x106/kg) for infusion 

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Drug Name 
Route  
 
Dose  
 
Schedule 
 
Instructions for administration 
Cyclophosphamide 
IV 
1000 mg/m2/day 
Days 
1 & 2 
Dose reduce or omit based on cardiac 
and/or pulmonary function 
Fludarabine 
IV 
25 mg/m2/day 
Days 3-7 
Dose reduce or omit based on creatinine 
clearance 
Peripheral Blood Stem 
Cells, if available 
IV 
A minimum of  
2x106 CD34+ 
cells/kg or all 
available cells if 
< 2x106 CD34+ 
cells/kg 
Day 10 
IV through central venous catheter per 
institutional guidelines 
TTRNA-xALT 
IV 
3x107/kg 
Day 11 
IV over 10-30 minutes through central 
venous catheter. Pre-medicate 30-60 
minutes prior to infusion with 
acetaminophen (up to 10-15 
mg/kg/dose) and Benadryl (up to 1 
mg/kg) to reduce infusion-related 
reactions.  Vital signs will be assessed 
prior to and post infusion then every 15 
minutes for 1 hour.   
TTRNA-DCs 
 
Intra-
dermal 
1x107 cells 
 
Days  
11, 25, 39 
Each immunization will be divided 
equally to both inguinal regions.  A total 
volume of 200 µL per side will be 
delivered intradermally after preparation 
of skin with EMLA anesthetic cream. 
Sargramostim 
(GM-CSF) 
Intrade
rmal 
 
150 ug 
Days 11, 25, 
39 
 Embedded in DC vaccine 
Filgrastim 
(G-CSF) 
SQ or 
IV 
5 micrograms/ 
kg/day   
 
Beginning no 
later than day  
16- until 
count 
recovery 
Per institutional guidelines 
 
Based on prior chemotherapy history, patients enrolled on Group B receiving salvage chemotherapy may 
need to have adjustment in their chemotherapy regimen at the discretion of the treating physician.  Focal boost 
radiotherapy may be delivered prior to immunotherapy if required for local control. As no salvage chemotherapy 
regimens in the recurrent setting have been found to be curative or achieve significantly prolonged survival, we 
do not anticipate any clinical impact of adjustments to the planned regimen. All chemotherapy regimens will be 
recorded and any deviation from the prescribed regimen above noted.     
9. STUDY POPULATION 
The target population for this study is children and young adults (age 0-30 years) with recurrent MB, 
pineoblastoma, and cerebral PNETs who suffer first disease recurrence following standard radiotherapy +/- 
craniospinal irradiation and who are candidates for HDC plus autologous stem cell rescue or NMA salvage 
chemotherapy. Patients with disease recurrence prior to completion of standard radiotherapy +/- craniospinal 
irradiation will remain eligible as long as are first recurrence since completion of radiotherapy. Patients who are 

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unable to receive radiotherapy due to genetic syndromes that put them at significant risk for secondary 
malignancies (i.e. Gorlin’s syndrome or NF1 mutation) are eligible at first recurrence/progression as these patients 
have failed definitive treatment.   
10. INCLUSION CRITERA 
10.1 Inclusion Criteria 
Age: 
 
 
The patient must be ≤ 30 years of age at the time of enrollment. 
 
Disease Status: 
The patient must have a histologically confirmed first recurrence/progression of reMB/PNET (as 
confirmed by the study pathologist or his designate) after completion of definitive focal +/- 
craniospinal irradiation, or must be a patient with first recurrence/disease progression who is 
unable to receive radiation therapy due to genetic disorders that put them at significant risk for 
radiation-induced secondary malignancies (ie. Gorlin’s syndrome or NF1 mutation). 
 
Performance Status: 
The patient must have a KPS of > 50% (KPS for > 16 years of age) or Lansky performance Score 
(LPS) of ≥ 50 (LPS for ≤ 16  years of age) assessed within 2 weeks prior to registration and 
documented in the medical record or on SDW-UFBTIP-004. Patients who are unable to walk 
because of paralysis but who are up in a wheel chair will be considered ambulatory for the purposes 
of the performance score. 
 
Laboratory Analysis and Organ Function Requirements: 
 
 
Bone Marrow function: 
 
  
 
- Absolute neutrophil count ≥ 1000/µl (unsupported)* 
 
  
 
- Platelets ≥ 100,000/µl (unsupported)* 
 
  
 
- Hemoglobin > 8 g/dL (may be supported) 
*Patients on Group B with ANC <1000/µL and/or platelet count <100,000/µL prior to NMA will 
be allowed to get vaccine and ALT infusion; however, NMA conditioning will be withheld. 
 
Renal:  
 
 
-Serum creatinine ≤ upper limit of institutional normal.  
 
Hepatic:  
 
 
- Bilirubin ≤ 1.5 times upper limit of normal for age.  
 
 
- SGPT (ALT) ≤ 3 times institutional upper limit of normal for age.  
 
 
- SGOT (AST) ≤ 3 times institutional upper limit of normal for age. 
 
Ability to tolerate PBSC Collection: 
- No known contraindications to PBSC collection. Examples of contraindications might be a 
weight or size less than the collecting institution finds feasible, or a physical condition that would 
limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the 
apheresis procedure. 
 
Consent: 
The patient guardian or patient (if > 18 yrs of age) must consent to all elements of this protocol including surgical 
resection, the use of resected tumor specimens for RNA preparation, induction chemotherapy and PBSC 
collection during leukapheresis, high-dose chemotherapy with autologous stem cell rescue (Group A), NMA 
salvage chemotherapy with autologous stem cell rescue (Group B), and experimental immunotherapy consisting 
of DC + xALT therapy.  Signed informed consent according to institutional guidelines must be obtained prior to 

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registration. Patients who turn 18 while on the study will be re-consented at that time using an adult consent form.  
If subjects are referred from outside physicians and it is not feasible for the subject to travel to a participating site, 
Tissue Consent can be obtained by telephone from the subject/LAR in accordance with institutional policy, 
procedure, and/or directive. 
Additional Eligibility Requirements Prior to Initiation of Consolidation or NMA Chemotherapy: 
Renal: 
• GFR of at least 70 ml/min/1.73m2 (Group A only). 
Cardiac: 
• EKG without clinically significant arrhythmias (Group A only) 
• ECHO cardiogram with an ejection fraction of > 45% or MUGA scan within normal limits 
(Group A only).  Patients in Group B will be eligible if the ejection fraction is < or equal 
to 45% but will receive Fludarabine only during NMA conditioning prior to vaccine + ALT 
infusions. 
Pulmonary: 
• DLCO, FEV1, FEC (diffusion capacity) > 50% of predicted (corrected for hemoglobin and 
alveolar volume).  (Group A only) 
• Crying Vital Capacity if too young to perform pulmonary function tests. (Group A only) 
• Chest X-ray without significant abnormalities and a pulse oximetry reading of ≥ 93% in 
room air at rest and following a brisk 6-minute exercise resulting in a target heart rate of at 
least 100/min.  These two tests would be required for any patient in Group A who cannot 
co-operate for the DLCO test due to neurologic deficits and for all patients in Group B.  
Patients in Group B who do not meet this requirement will still be eligible but will receive 
Fludarabine only during NMA conditioning. 
 
10.2 Exclusion Criteria 
Disease Status: 
Patients with clinically significant increased intracranial pressure (e.g., impending 
herniation), uncontrolled seizures, or requirement for immediate palliative treatment will 
also be excluded from this study. 
Concurrent Therapy: 
Each patient will need to be scheduled for definitive resection or, in select cases, have had 
surgical resection and tumor tissue snap frozen and available for TTRNA to be eligible for 
enrollment. Patients receiving any other concurrent anticancer or investigational drug 
therapy will be excluded and replaced.  Focal boost radiotherapy may be delivered prior to 
immunotherapy if required for local control.   
Pregnancy: 
Females who are pregnant or need to breast feed during the study period will be excluded.  
A negative β-HCG test will be required within 2 weeks of enrollment.  Patients found to 
be pregnant will be excluded.  Male and female enrolled patients must be willing to use a 
medically acceptable form of birth control, which includes abstinence, while being treated 
on this study. 
Corticosteroids: 
Patients requiring an increase in corticosteroids, with the exception of nasal or inhaled 
steroid, such that at the time of first vaccination they require a dose above physiologic 
levels, may remain in the study but will be replaced for assessment of safety as increased 

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steroid usage may mask risks of autoimmune toxicity.  For the purposes of this study, 
physiologic dose will be defined as < 4 mg of dexamethasone/day.   
Medical Conditions: 
Patients with the following conditions will be excluded to avoid confounding results: 
• Patients with an active infection requiring treatment or an unexplained febrile 
(>101.5o F) illness. 
• Patients with known immunosuppressive disease, human immunodeficiency virus 
infection, or carriers of Hepatitis B or Hepatitis C virus. 
• Patients with active renal, cardiac (congestive cardiac failure, myocardial 
infarction, myocarditis), or pulmonary disease. 
• Patients receiving concomitant medications that may interfere with study outcome 
(e.g., immunosuppressive agents). 
• Patients with any clinically significant unrelated systemic illness (serious infections 
or significant cardiac, pulmonary, hepatic or other organ dysfunction) that would 
compromise the patient’s ability to tolerate protocol therapy or would likely 
interfere with the study procedures or results. 
Patients with the inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to 
therapy 
10.3 Inclusion of Women and Minorities 
Our brain tumor studies are open to patients of all ages, both sexes, and all minorities.  In addition, certain 
diseases that we treat occur preferentially in one gender or minority than another.  For example, carcinoma of the 
breast is a frequent cause of metastatic brain tumors and, of course, is much more common in women than in 
men.  Although the lung cancer incidence is rising in women, the incidence is still higher in men and it is also a 
frequent cause of metastatic brain tumors.  Primary brain tumors and metastatic brain tumors from some very 
common tumors such as melanoma are an infrequent disease in African-American populations.  Our accrual 
statistics reflect the lower incidence in the African-American population.  We will continue to actively recruit 
women and minorities into this study using methods that have shown previous success in recruiting the 
participation of these subgroups. 
We routinely send letters to our primary referring physicians notifying them of our interest in including 
minorities and women in all our brain tumor clinical trials.   
11. DESCRIPTION OF THE RECRUITMENT PROCESS 
11.1 Recruitment 
The following table shows the incidence rates by ICCC group and race/ethnicity for both sexes, 1992-1999 as 
provided by the Central Brain Tumor Registry of the United States.  A breakdown by sex was not available but the 
observation has been that in all race/ethnicity groups the incidence is slightly higher in males.   
  
 
 
 
 
 
*SEER Cancer Incidence Public-Use Data, 1992-1999. 
 
Number per 1,000,000 
WHITE 
28.7 
AFRICAN AMERICAN 
24.1 
NATIVE AMERICAN/ALASKA NATIVE 
14.1 
ASIAN/PAC ISLANDER 
22.0 
HISPANIC 
21.7 

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Our demographics of all brain tumor patients treated at the  Preston A. Wells, Jr., Center for Brain Tumor 
Therapy at the University of Florida does not differ significantly from the demographic break down of brain tumor 
incidences nationwide, demonstrating that a representative spectrum of patients affected by this disease are 
routinely seen at our Center. 
 
11.2 Screening and Enrollment 
Potentially eligible patients with reMB/PNET scheduled to undergo definitive surgical resection will be 
identified through direct referral to the multi-institutional sites.  In select cases, patients at outside institutions 
who have had surgical resection and tumor tissue snap frozen and available for TTRNA will be consider for 
enrollment.  PHI will be reviewed by the PI(s) and/or Study Coordinator but not recorded in order to pre-screen 
patients for eligibility for this trial.  The pre-screening PHI will consist of a review of the medical record to 
confirm presentation of first recurrence of an initial diagnosis of MB or central PNET after receipt of previous 
definitive focal +/- craniospinal irradiation for diagnosis of MB/PNET in patients < 30 years of age at time of 
enrollment.  Of note, patients with recurrent MB/PNET who have failed prior radiation therapy or are not able to 
receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary 
malignancies (ie. Gorlin’s syndrome or NF1 mutation) will still be eligible to receive treatment  The guardian(s) 
of pediatric patients or young adult patients potentially eligible for this trial will be approached by PI(s) and/or 
Study Coordinator about interest in the study and to give informed consent to participation in this clinical trial. 
At the time of consent the PI(s) of the various treatment teams will be available to answer questions and provide 
any clarification needed regarding the content of the consent document or clinical study details.  The Study 
Coordinator will also be present to obtain informed consent and provide a copy of the signed documentation to 
the guardian or adult patient.   
Given the history of safety for immunotherapy in adult patients we don’t anticipate significant toxicity 
with this treatment regimen.  All patients enrolled on the study, even if taken off study prior to treatment, will be 
included in the data analysis on an intent to treat basis.  We anticipate that a minimum of 80% of patients enrolled 
will proceed to HDC + PBSCT and receive DC + xALT therapy without prior tumor progression and therefore 
anticipate targeted enrollment using multi-institutional study sites. The target distribution for patients that will be 
treated with DC + xALT therapy based on the SEER Cancer Incidence Public-Use Data is shown in the following 
Table: 
 
 
 
Phase I 
Patient 
Numbers 
White 
African-
American 
Hispanic  
Asian 
Other 
 
Male 
Female Male Female Male Female Male Female Male Female 
9 
4 
3 
1 
0 
0 
0 
0 
0 
1 
0 
Phase 
II 
35 
17 
12 
1 
1 
1 
0 
0 
1 
1 
1 
TOTAL 
44 
21 
15 
2 
1 
1 
0 
0 
1 
2 
1 
Actual accrual will be actively reviewed by the PI (Dr. Duane A. Mitchell) and the Medical Monitor and 
compared with this table.  If the expected accrual diversity is not met or if accrual overall is slower than anticipated 
(assessed every 3 months), we will initiate a targeted recruitment program through techniques already established 
within our multi-institutional sites, including the placement of advertisements in newspapers or on radio stations 
to increase public awareness overall and specifically catering to the underrepresented population(s) and providing 
educational seminars for patients and staff at community institutions such as churches and medical clinics that 
preferentially serve the underrepresented population(s).  The PRTBTC has a strong referral network and we will 

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also utilize resources such as the Pediatric Brain Tumor Consortium and the Pediatric Brain Tumor Foundation 
of the United States to increase publicity and recruitment for this trial should accrual fall below expectation.   
12.  SAMPLE SIZE JUSTIFICATION 
Progression-free survival in Group A will be measured from the initiation of HDC for comparison to our 
historical experience of HDC + PBSCT in this patient population.  The progression-free survival experience 
among patients with recurrent disease who initiated HDC after having previously received definitive radiotherapy 
is reported by Gururangan (2008).  The 12-month PFS rate is 33% (95% confidence interval: 10%, 59%) with a 
two-year PFS of 0%.   
Due to the complexity and expense of adoptive cellular therapy treatment, if the true PFS-12 associated with 
DC + xALT therapy is 33%, there would be limited interest in further investigation of this treatment regimen 
without significant modification to improve efficacy.  However, if the true PFS-12 were 55% or greater, there 
would be interest in studying this treatment regimen within the context of larger confirmatory Phase II or III 
clinical trials.  Therefore, the study is designed to differentiate between a PFS-12 rate of 33% (null hypothesis) 
and 55% (alternative hypothesis).  With 35 patients enrolled in the Phase II trial, this assessment has 90% power 
assuming a type I error rate of 0.10.  There is also 97% power to differentiate between PFS-12 rates of 33% and 
60%. 
In Group B, progression-free survival will be measured from the time of proximal tumor recurrence before 
adoptive cellular therapy.  Patients with progression prior to immunotherapy may remain on study as long as they 
continue to meet other eligibility requirements.  Currently, no good historical benchmark exists for this patient 
population.  The Group A benchmark described above will be used conservatively for patients in Group B given 
that they are generally considered to have poorer prognosis than Group A.  Given this assumption, the sample 
size justification described above is also applicable to Group B. 
13. DESCRIPTION OF INFORMED CONSENT PROCESS 
Study site personnel will identify potentially eligible subjects who are scheduled for craniotomy due to 
recurrent MB/PNET and initially screen eligibility and interest in possible protocol participation. In select cases, 
patients at outside institutions who have had surgical resection and tumor tissue snap frozen and available for 
TTRNA will be screened for eligibility and possible protocol participation.  Dr. Mitchell (or his designee) of the 
UF Brain Tumor Immunotherapy Program and Department of Neurosurgery will discuss study participation with 
potential adult subjects or parents of potential minor subjects for education regarding this research study.  The 
investigational nature and objectives of the trial, the procedures and treatments involved and their attendant risks 
and discomforts, and potential alternative therapies will be carefully explained to the patient or the patient’s 
parents or guardian if the patient is a child, and a signed informed consent and assent will be obtained according 
to institutional guidelines.  Those patients that turn 18 while on study will be re-consented using an adult consent 
form.  
14. VOLUNTEER SCREENING PROCEDURES 
 Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be 
done after obtaining written informed consent.  Documentation of the informed consent for screening will be 
maintained in the patient’s research chart. Studies or procedures that were performed for clinical indications (not 
exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed 
consent was obtained.   

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15. STUDY PROCEDURES/STUDY INTERVENTIONS 
15.1 Overview 
In this Phase II trial, 35 to 42 children and young adults with reMB/PNETs will be treated with DC + xALT 
therapy at the MTD (3x107 T cells/kg) determined from the Phase I trial in order to estimate the clinical efficacy 
of this treatment.  Patients unable to undergo surgical resection, dependent on corticosteroid supplements above 
physiologic levels at time of first vaccine (> 4 mg decadron per day), whose final pathology is not recurrent MB 
or PNET, unable to generate mRNA from resected tumor specimen, fail induction chemotherapy regimen due to 
tumor progression, or are unable to tolerate HDC after induction therapy will be replaced.  If either DCs and/or 
xALT do not meet release criteria or targeted dose then the patient may remain on study and receive the qualified 
product but will be replaced for the purposes of safety assessment.  
A study schema outlining the stages of this clinical protocol covering both Groups is provided in Sections 
2.2, 2.3, and 2.4.   
 
15.2 Chemotherapy for Group A 
15.2.1 INDUCTION THERAPY 
During Induction therapy, surgery and anti-cancer drugs (chemotherapy) are used to remove and to kill as 
much tumor as possible.  Also, peripheral blood stem cells (PBSCs) are collected during the Induction phase of 
therapy by leukapheresis as described below.    
Surgery: Maximal debulking surgery will be performed to minimize tumor burden and confirm diagnosis 
of recurrent tumor.  All tumors will be confirmed as recurrent MB/PNET by a board-eligible/board-certified 
neuropathologist.  Tumor tissue in excess of what is needed to confirm pathologic diagnosis will be transported 
under aseptic precautions to Dr. Mitchell’s laboratory for tumor RNA preparation.  Tumor tissue may also be 
obtained through biopsy or CSF (cytology). 
Patients will undergo a non-mobilized leukapheresis prior to induction for harvest of peripheral blood 
mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation. The target PBMC count based on 
the desired dose of TTRNA-xALT and sufficient TTRNA-DCs for T cell expansion and in vivo vaccination will 
be collected.  
Approximately two weeks but no more than four weeks post-surgical resection, patients will continue 
induction treatment with 3-4 cycles of chemotherapy at 28-day intervals. Cycles 1 & 2 will consist of intravenous 
cyclophosphamide.  Cycles 3 & 4 will consist of oral etoposide plus oral temozolomide (TMZ).  After each 
induction cycle, patients will receive G-CSF in order to mobilize PBSCs for later stem cell support following 
high-dose chemotherapy. G-CSF will be given daily starting 24 hours following the last dose of chemotherapy 
and until completion of the leukapheresis procedure. Peripheral blood stem cells (PBSC) will be collected after 
each induction cycle until the target CD34(+) PBSC yield needed for Consolidation (2x106 CD34+ cells per Kg 
at a minimum) is obtained.  Absolute nucleated cell count collected will be adjusted as needed on a patient specific 
basis. The drugs will be given on the following schedule: 
 
 
Leukapheresis after each induction cycle until collection of a minimum 2x106 CD34+ cells/kg 
Cycle 1 & 2 
Drug 
Dosage 
Route 
Days Given 
Cyclophosphamide 2g/m2/day 
IV over 1 hour 
1, 2 
Mesna 
2g/m2/day 
IV 
1, 2 

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Filgrastim 
10mcg/kg/day 
SQ or IV 
3 - 28* 
Cycle 3 & 4 
Temozolomide 
150mg/m2/day 
By mouth 
1 - 5 
Etoposide 
30mg/m2/day 
By mouth 
1 - 14 
 
Upon recovery from the 3rd or 4th cycle of induction chemotherapy (ANC > 1000 cells/µL), patients will 
undergo disease restaging and organ function evaluation.  Patients dependent on steroid supplements above 
physiologic levels at time of Vaccine #1 (> 4 mg decadron per day), have radiographic or histologic evidence of 
progression will be replaced.  If either DCs and/or xALT do not meet release criteria or targeted dose then the 
patient may remain on study and receive the qualified product but will be replaced for the purposes of safety 
assessment. For the purpose of this study, progression will be defined as a new lesion confirmed by biopsy or 
resection, positive cerebrospinal fluid (CSF) cytology, or a new metastatic lesion (if previously negative). 
15.2.2 LEUKAPHERESIS FOR PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) 
• Intravenous Access: PBMCs will be obtained by placing two large gauge catheters into the antecubital 
veins bilaterally or by using a dialysis-type central venous catheter that will allow for large volume 
apheresis. 
• PBMC Mobilization: Patients will not receive mobilization prior to leukapheresis. 
• Apheresis Machine: The choice of apheresis machine is at the discretion of the institution. 
• Blood Priming: Blood priming of the apheresis machine is at the discretion of the institution. 
• Apheresis Procedure: The apheresis machine settings, procedure duration, and volume of whole blood 
processed shall be in accordance with SOP-UFBTIP-131. 
• PBMC Collection Goal: The collection goal for TTRNA-xALT and TTRNA-pulsed Dendritic Cell 
vaccine is a minimum of 5x109 mononuclear cells.  
• Product Testing: An aliquot of cryopreserved TTRNA-xALT and TTRNA-pulsed Dendritic Cells will 
be thawed and prepared for QC testing and must meet batch release criteria. 
 
15.2.3 PBSC MOBILIZATION AND LEUKAPHERESIS 
• Leukapheresis products previously collected and cryopreserved may be used for this protocol as long as 
the cells meet all standard release criteria and transfer agreements for use of the products, if applicable, 
are executed.  
• Intravenous Access: PBSCs will be collected using a dialysis-type catheter that will allow for large 
volume apheresis.  
• PBSC Mobilization: Patients will begin G-CSF (5mcg/kg/day) 24-36 hours after completion of 
chemotherapy.  When the WBC count starts recovering (WBC > 1,000 post nadir or in accordance with 
institutional standards), increase the G-CSF dose to 10mcg/kg/day.  PBSC collection will begin when the 
circulating CD34 
•  cell count is > 10 cells/μL or in accordance with institutional standards. G-CSF will continue until PBSC 
collection is complete. It is recommended that G-CSF be administered at night (approximately 2200) on 
the days(s) prior to scheduled leukapheresis.  If the post-G-CSF WBC is > 60,000, decrease the G-CSF 
dose to 5mcg/kg.  
• Apheresis Machine: The choice of apheresis machine is at the discretion of the institution. 
• Blood Priming: Blood priming of the apheresis machine is at the discretion of the institution. 
• Apheresis Procedure: The apheresis procedure will be performed in accordance with institutional 
standards. 
• PBSC Collection Goal:  The PBSC collection goal is 2x106 CD34+ cells per Kg at a minimum.    

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• PBSC Product Testing:  Each PBSC collection will be cultured for bacterial and fungal contamination, 
nucleated cell count and differential, and CD34+ cell enumeration. 
 
15.2.4 GUIDELINES FOR INDUCTION THERAPY AND PBSC COLLECTION 
As no study drug is administered during the Induction phase of the trial, the Induction regimen for Group 
A patients and mobilization and collection of PBSCs for stem cell rescue may be administered at UF or other 
Foundation for the Accreditation of Cellular Therapy (FACT)-accredited medical institutions under the care of a 
board-eligible/board-certified pediatric oncologist, with the exception of the first leukapheresis for collection of 
PBMCs for DC and xALT generation, which must occur at the main institution.  Subsequent PBSC mobilization 
and leukapheresis may be conducted according to institutional guidelines. PBSC products collected and 
cryopreserved at FACT-accredited institutions shall be shipped in a dry shipper to the main institution prior to 
Consolidation.  Dr. Sri Gururangan (Neuro-Oncology Chair) will be responsible for providing a roadmap of the 
induction and salvage chemotherapy regimens to outside oncologists and acquiring documentation of all 
prescribed medications and any chemotherapy or procedure related toxicities during these periods. Standard 
medication regimens may need to be adjusted due to hematologic or other toxicities and may be managed at the 
discretion of the treating pediatric oncologist.  Focal boost radiotherapy may be delivered prior to immunotherapy 
if required for local control.  All deviations from intended regimens during induction or salvage therapy will be 
documented, but not considered a protocol deviation, as is within routine standard of practice for this patient 
population.   All patients must return to the main institution for high-dose Consolidation therapy (Group A) and 
subsequent immunotherapy.   
15.3 Consolidation 
15.3.1 PRE-TRANSPLANT EVALUATION 
• Adequate collection of autologous PBSCs for transplant 
• Successful production of vaccine 
• Medical history 
• Physical examination 
• Bone Marrow function: 
- Absolute neutrophil count > 1000/µl (unsupported). 
- Platelets > 100,000/µl (unsupported). 
- Hemoglobin > 8 g/dL (may be supported). 
• Renal:  
- Serum creatinine ≤ upper limit of institutional normal  
- GFR of at least 70 ml/min/1.73m2. 
• Hepatic:  
 
 
- Bilirubin ≤ 1.5 times upper limit of normal for age.  
 
 
- SGPT (ALT) ≤ 3 times institutional upper limit of normal for age.  
 
 
- SGOT (AST) ≤ 3 times institutional upper limit of normal for age. 
• Adequate cardiac function defined as: 
- ECHO Cardiogram with ejection fraction of > 45% by radionuclide angiogram or MUGA scan 
within normal limits  
- EKG without clinically significant arrhythmias.  
• Pulmonary:  
- DLCO, FEV1, FEC (diffusion capacity) > 50% of predicted (corrected for hemoglobin and 
alveolar volume)  
- Crying Vital Capacity if too young to perform pulmonary function tests  

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- Chest X-ray and pulse oximetry reading of > 93% in room air at rest and following a brisk 6-
minute exercise resulting in a target heart rate of at least 100/min if patient cannot perform well 
on pulmonary function test due to neurologic deficits.  
• Negative serum pregnancy test for females of child-bearing potential. 
 
Eligible patients will be admitted to the Pediatric Blood and Marrow Unit (BMTU) to receive the 
myeloablative regimen of carboplatin, etoposide, and thiotepa, with autologous PBSC rescue.   
(Gururangan S, et al. Neuro-Oncol 2008; 10(5):745-751).  
 
 

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Drug Name 
Route  
Dose  
Schedule 
Instructions for administration 
Carboplatin 
IV 
The lesser of 500mg/m2 
or dosing = AUC 7 
mg/ml-min per Calvert 
Formula; dilute  to 4 
mg/ml in Normal Saline 
Days  
-8, -7,-6 
IV over 4 hours through central 
venous catheter 
Etoposide 
IV 
250mg/m2; dilute to 0.3 
mg/ml in Normal Saline
 
 
Days 
-5,-4,-3 
IV over 3 hours through central 
venous catheter 
Thiotepa 
IV 
300mg/m2; dilute to 1 
mg/ml in Normal Saline 
 
Days 
-5,-4,-3 
IV over 3 hours through central 
venous catheter 
Peripheral Blood 
Stem Cells 
IV 
Minimum:  2x106 
CD34+ cells/kg 
 
Day 0 
IV through central venous catheter 
per institutional guidelines 
TTRNA-xALT 
IV 
3x107/kg 
Day 1 
IV over 10-30 minutes through 
central venous catheter. 
Pre-medicate 30-60 minutes prior 
to infusion with acetaminophen 
(up to 10-15 mg/kg/dose) and 
Benadryl (up to 1 mg/kg) to 
reduce infusion-related reactions.  
. Vital signs will be assessed prior 
to and post infusion then every 15 
minutes for 1 hour.   
TTRNA-DCs 
intradermal 1x107 cells 
 
 
Days  
1, 15, 29 
Each immunization will be divided 
equally to both inguinal regions.  
A total volume of 200 µL per side 
will be delivered intradermally 
after preparation of skin with 
EMLA anesthetic cream. 
Sargramostim 
 (GM-CSF) 
Intradermal 
 
150 ug 
Days 
 1,15, 29 
Per institutional guidelines 
Filgrastim 
(G-CSF) 
SQ or IV 
5 micrograms/ 
kg/day   
 
Beginning 
no later 
than Day 
6 post-
transplant- 
count 
recovery 
Per institutional guidelines 
Note: The modified Calvert Formula calculates the ACTUAL mg of carboplatin to be given 
Carboplatin Dosing per modified Calvert formula[6] and using AUC of 7:  dose in mg/m2= 7 [0.93 
x GFR (ml/min/m2) + 15]   
 

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15.3.2 NMA SALVAGE CHEMOTHERAPY FOR GROUP B 
During NMA salvage chemotherapy, surgery and anti-cancer drugs (chemotherapy) are used to remove 
and to kill as much tumor as possible.  Also, peripheral blood stem cells (PBSCs) are collected during the salvage 
phase of therapy by leukapheresis as described below.    
Surgery: Maximal debulking surgery will be performed to minimize tumor burden and confirm diagnosis 
of recurrent tumor.  All tumors will be confirmed as recurrent MB/PNET by a board-eligible/board-certified 
neuropathologist. Tumor tissue in excess of what is needed to confirm pathologic diagnosis will be transported 
under aseptic precautions to Dr. Mitchell’s laboratory for tumor RNA preparation.  Tumor tissue may also be 
obtained through biopsy or CSF (cytology). 
Patients will undergo a non-mobilized leukapheresis prior to salvage chemotherapy for harvest of 
peripheral blood mononuclear cells (PBMCs) for TTRNA-xALT and TTRNA-DC generation. The target PBMC 
count based on the desired dose of TTRNA-xALT and sufficient TTRNA-DCs for T cell expansion and in vivo 
vaccination will be collected. 
Following standard salvage chemotherapy adequate organ function testing will be repeated prior to 
initiation of NMA chemotherapy (cyclophosphamide and fludarabine conditioning) as described below:  
• Bone Marrow function: 
- Absolute neutrophil count > 1000/µl (unsupported)* 
- Platelets > 100,000/µl (unsupported)* 
- Hemoglobin > 8 g/dL (may be supported) 
* Patients on Group B with ANC <1000/µL and/or platelet count <100,000/µL prior to NMA will 
be allowed to get vaccine and ALT infusion; however, NMA conditioning will be withheld. 
• Renal:  
- Serum creatinine ≤ upper limit of institutional normal and/or GFR > 70 ml/min/1.73m2 
- If GFR < 70 ml/min/1.73 m2, Fludarabine dose adjusted for GFR < 70 ml/min/1.73m2 per 
drug guidelines  
• Hepatic:  
 
 
- Bilirubin ≤ 1.5 times upper limit of normal for age.  
 
 
- SGPT (ALT) ≤ 3 times institutional upper limit of normal for age.  
 
 
- SGOT (AST) ≤ 3 times institutional upper limit of normal for age. 
• Adequate cardiac function defined as: 
- ECHO cardiogram with an ejection fraction of > 45% or MUGA scan within normal limits   
- Patients in Group B will be eligible if the ejection fraction is < 45% but will receive 
Fludarabine only during NMA conditioning prior to vaccine + ALT infusion. 
• Pulmonary: 
-- DLCO, FEV1, FEC (diffusion capacity) > 50% of predicted (corrected for hemoglobin and 
alveolar volume) or 
- Chest X-ray and pulse oximetry reading of > 93% in room air at rest and following a brisk  
            6-minute exercise resulting in a target heart rate of at least 100/min.   
- Patients in Group B who do not meet this requirement will still be eligible but will receive 
Fludarabine only during NMA conditioning. 
• Negative serum pregnancy test for females of child-bearing potential. 
 
Of note, cyclophosphamide will be withheld if a patient does not meet the cardiac performance criteria and 
lymphodepletive conditioning will proceed with fludarabine only.  Additionally, the fludarabine dose may be 
modified for GFR < 70 ml/min/1.73m2.  Refer to Section 18.8 Fludarabine Phosphate for dose modification 
guidelines. 

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NMA salvage chemotherapy will consist of 28-day cycles until Immunotherapy preparation is complete.  
The drugs will be given on the following schedule: 
 
 

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After completion of NMA salvage chemotherapy and starting 11 days before Immunotherapy, patients 
will receive 2 days of cyclophosphamide IV at 1 g/m2, followed by 5 days of fludarabine IV at 25 mg/m2 (dose 
may be modified for GFR < 70 ml/min/1.73m2.  Refer to Section 18.8 for dose modification guidelines).  
Approximately 72 hours following fludarabine, PBSCs, if available, will be infused.  Approximately 96 hours 
following the final dose of fludarabine, Immunotherapy will begin with infusion of the TTRNA-xALT and 
injection of the first TTRNA-DC vaccine.  Patients will receive 3 biweekly vaccines as long as clinically stable. 
 
 
Drug Name 
Route  
 
Dose  
 
Schedule 
 
Temozolomide 
PO 
150  mg/m2/day 
Days  1-5 
 
Etoposide 
PO 
30  mg/m2/day 
Days 1-14 
 
Filgrastim (G-CSF) 
IV or 
SQ 
10 micrograms/ 
kg/day 
Starting Day 15 
*administered each cycle until 
enough CD34 cells are 
harvested (goal of 2x106/kg) for 
infusion 

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Drug Name 
Route  
 
Dose  
 
Schedule 
 
Instructions for administration 
Cyclophosphamide 
IV 
1000 mg/m2/day 
Days 
1 & 2 
Dose reduce or omit based on cardiac 
and/or pulmonary function 
Fludarabine 
IV 
25 mg/m2/day 
Days 3-7 
Dose reduce or omit based on creatinine 
clearance 
Peripheral Blood Stem 
Cells, if available 
IV 
A minimum of  
2x106 CD34+ 
cells/kg or all 
available cells if 
< 2x106 CD34+ 
cells/kg 
Day 10 
IV through central venous catheter per 
institutional guidelines 
TTRNA-xALT 
IV 
3x107cells/kg or 
all available cells 
Day 11 
IV over 10-30 minutes through central 
venous catheter. Pre-medicate 30-60 
minutes prior to infusion with 
acetaminophen (up to 10-15 
mg/kg/dose) and Benadryl (up to 1 
mg/kg) to reduce infusion-related 
reactions.  Vital signs will be assessed 
prior to and post infusion then every 15 
minutes for 1 hour.   
TTRNA-DCs 
 
Intra-
dermal 
1x107 cells 
 
Days  
11, 25, 39 
Each immunization will be divided 
equally to both inguinal regions.  A total 
volume of 200 µL per side will be 
delivered intradermally after preparation 
of skin with EMLA anesthetic cream. 
Sargramostim 
(GM-CSF) 
Intrade
rmal 
 
 
150 ug 
Days 
 11, 25, 39 
Embedded in DC vaccine 
Filgrastim 
(G-CSF) 
SQ or 
IV 
5 micrograms/ 
kg/day   
 
Beginning no 
later than 
Day 16- 
count 
recovery 
Per institutional guidelines 
 
If either DCs and/or xALT do not meet release criteria or targeted dose then the patient may remain on 
study and receive the qualified product but will be replaced for the purposes of safety assessment.    
 
15.3.3 LEUKAPHERESIS FOR PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) 
• Intravenous Access: PBMCs will be obtained by placing two large gauge catheters into the antecubital 
veins bilaterally or by using a dialysis-type central venous catheter that will allow for large volume 
apheresis. 
• PBMC Mobilization: Patients will not receive mobilization prior to leukapheresis. 
• Apheresis Machine: The choice of apheresis machine is at the discretion of the institution. 
• Blood Priming: Blood priming of the apheresis machine is at the discretion of the institution. 

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• Apheresis Procedure: The apheresis machine settings, procedure duration, and volume of whole blood 
processed shall be in accordance with SOP-UFBTIP-131. 
• PBMC Collection Goal: The collection goal for TTRNA-xALT and TTRNA-pulsed Dendritic Cell 
vaccine is a minimum of 5x109 mononuclear cells.  
• Product Testing: An aliquot of cryopreserved TTRNA-xALT and TTRNA-pulsed Dendritic Cells will 
be thawed and prepared for QC testing and must meet batch release criteria. 
 
15.3.4 PBSC MOBILIZATION AND LEUKAPHERESIS 
• Leukapheresis products previously collected and cryopreserved may be used for this protocol as long as 
the cells meet all standard release criteria and transfer agreements for use of the products, if applicable, 
are executed.  
• Intravenous Access: PBSCs will be collected using a dialysis-type catheter that will allow for large 
volume apheresis.  
• PBSC Mobilization: Patients will begin G-CSF (5mcg/kg/day) 24-36 hours after completion of 
chemotherapy.  When the WBC count starts recovering (WBC > 1,000 post nadir or in accordance with 
institutional standards), increase the G-CSF dose to 10mcg/kg/day.  PBSC collection will begin when the 
circulating CD34 cell count is > 10 cells/μL or in accordance with institutional standards. G-CSF will 
continue until PBSC collection is complete. It is recommended that G-CSF be administered at night 
(approximately 2200) on the days(s) prior to scheduled leukapheresis.  If the post-G-CSF WBC is > 
60,000, decrease the G-CSF dose to 5mcg/kg.  
• Apheresis Machine: The choice of apheresis machine is at the discretion of the institution. 
• Blood Priming: Blood priming of the apheresis machine is at the discretion of the institution. 
• Apheresis Procedure: The apheresis procedure will be performed in accordance with institutional 
standards. 
• PBSC Collection Goal:  The PBSC collection goal is 2 x106 CD 34+ cells/kg.     
• PBSC Product Testing:  Each PBSC collection will be cultured for bacterial and fungal contamination, 
nucleated cell count and differential, and CD34+ cell enumeration. 
 
15.3.5 GUIDELINES  FOR  SALVAGE CHEMOTHERAPY AND PBSC COLLECTION 
As no study drug is administered during the salvage chemotherapy phase of the trial and administration 
of salvage chemotherapy is a standard-of-care for patients not amenable to HDC, the salvage regimen for Group 
B patients and mobilization and collection of PBSCs may be administered at UF or other Foundation for the 
Accreditation of Cellular Therapy (FACT)-accredited medical institutions under the care of a board-
eligible/board-certified pediatric oncologist, with the exception of the first leukapheresis for collection of PBMCs 
for DC and xALT generation, which must occur at the main institution.  Subsequent PBSC mobilization and 
leukapheresis may be conducted according to institutional guidelines. PBSC products collected and cryopreserved 
at FACT-accredited institutions shall be shipped in a dry shipper to the Stem Cell Laboratory under per SOPs 
prior to NMA conditioning with cyclophosphamide and fludarabine.  Dr. Sri Gururangan (Neuro-Oncology Chair) 
will be responsible for providing a roadmap of the induction and salvage chemotherapy regimens to outside 
oncologists and acquiring documentation of all prescribed medications and any chemotherapy or procedure 
related toxicities during these periods. Standard medication regimens may need to be adjusted due to hematologic 
or other toxicities and may be managed at the discretion of the treating pediatric oncologist.  Focal boost 
radiotherapy may be delivered prior to immunotherapy if required for local control.  All deviations from intended 
regimens during induction or salvage therapy will be documented, but not considered a protocol deviation, as is 
within routine standard of practice for this patient population. All patients must return to the main institution for 
NMA conditioning regimen with cyclophosphamide and fludarabine (Group B) with PBSCT, and subsequent 
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15.4 Post-transplant Immunotherapy  
All patients will receive TTRNA-xALT and TTRNA-DCs as Vaccine #1.  Peripheral blood will be drawn 
prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine 
#1, weekly post Vaccine #1 for six weeks, and bimonthly, if feasible, until progression for T-cell kinetics.  Blood 
will be processed in accordance with SOP-UFBTIP-126. DCs will be given intradermally and divided equally to 
both inguinal regions. Vaccines #2 and #3 will occur at 2-week intervals following the first dose.  Patients will 
receive at 3 biweekly vaccines as long as clinically stable.  Studies in patients receiving myeloablative and NMA 
chemotherapy have shown that T cell function normalizes (without intervening immunotherapy) between 6-12 
months in most patients.  
Patients will be followed bi-monthly (+/- one month) for first year post immunotherapy, then every 3 
months (+/- one month) until death due to any cause.  As part of standard care for these patients, upon tumor 
progression, participants may undergo stereotactic biopsy or resection.  As this is not a research procedure consent 
will be obtained separately. However, if tissue is obtained, it will be used to confirm tumor progression 
histologically and to assess immunologic cell infiltration and antigenic profile changes from the initially resected 
tumor specimen used in vaccine preparation.  
16. EXPERIMENTAL STUDY PROCEDURES (DC + XALT THERAPY) 
16.1 DC Vaccination 
Following myeloablative (Group A) and NMA chemotherapy (Group B), patients will receive intravenous 
TTRNA-xALT at 3x107cells/kg and intradermal TTRNA-DCs as vaccine #1.  Peripheral blood will be drawn 
prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine 
#1, weekly post Vaccine #1 for six weeks,  and bimonthly, if feasible, until progression for T cell kinetics.  Blood 
will be processed in accordance with SOP-UFBTIP-126.  DCs will be given intradermally and divided equally to 
both inguinal regions in accordance with SOP-UFBTIP-128. Vaccines #2 and #3 will occur at 2 week intervals 
following the first dose.  Each immunization will be divided equally to both inguinal regions.  A total volume of 
200 µL per side will be delivered intradermally after preparation of skin with EMLA anesthetic cream.  Details 
of the procedure will be recorded on SDW-UFBTIP-002.  Patients will be monitored in the clinic for thirty 
minutes post-immunization for the development of any adverse effects.  The immunizations will be supervised 
by a nurse or physician that has completed a Pediatric Advanced Life Support (PALS) course.  A cardiac 
resuscitation cart will be available in the immediate vicinity when performing these immunizations in case of 
severe allergic reactions.  The three vaccines will each be given 2 + 1 week(s) apart. 
Subjects who will not receive xALT either due to failure of the product to meet release criteria or inability 
to manufacture a viable product, may receive additional DC vaccination(s) if more than 3 doses were initially 
generated.  Subsequent DC vaccination will begin 4 weeks (+/- 5 days) after vaccine number 3 and continue every 
4 weeks (+/- 5 days) until all doses have been exhausted, the subject meets a withdrawal endpoint, or the treating 
physician elects to stop further vaccination.  These subjects will be evaluated for toxicity and laboratory immune 
measures; however, they will be replaced for the purposes of efficacy assessments. 
Patients will be monitored clinically with routine physical and neurologic examinations at every visit and 
with a contrasted-enhanced CT or MRI every 8 + 4 weeks.  Peripheral blood will be obtained bimonthly, if 
feasible, until progression as well as outlined in the study flow sheet below for immunologic monitoring. 
 
16.2  TTRNA-xALT Administration 
Patients will receive a single dose of TTRNA-xALT consisting of autologous lymphocytes enriched for 
tumor-specific lymphocytes after in vitro stimulation with TTRNA-pulsed DCs on the same day as the first DC 
vaccination.  No further TTRNA-xALT administrations will be given.  TTRNA-xALT infusions will be 

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administered at the main site and the patients will be monitored by an RN during and for 1 hour following the 
procedure.  If any patient develops signs of infection or is febrile prior to the infusion it will be postponed pending 
clinical work-up.  The TTRNA-xALT product will be prepared, delivered, and administered according to 
Standard Operating Procedures. Subject identifiers will be double-verified prior to TTRNA-xALT administration 
as is standard BMT transfusion procedure. 
The patient will be pre-medicated 30-60 minutes prior to infusion with acetaminophen (up to 10-15 
mg/kg/dose) and Benadryl (up to 1 mg/kg) to reduce infusion-related reactions.  All patients will have an 
intravenous catheter placed during PBSCT or one will be placed for the procedure.  The TTRNA-xALT will be 
infused in accordance with SOP-UFBTIP-132.  Vital signs will be assessed prior to and post infusion then every 
15 minutes for 1 hour.  The infusion will last 10-30 minutes depending on volume to be infused. The Infusion 
and any adverse experiences will be documented on SDW-UFBTIP-003.  All other institutional transfusion and 
cell infusion policies will be followed. 
17. SAFETY, TOXICITY, AND ADVERSE EVENTS 
17.1 Toxicity associated with Standard Therapy (HDC + PBSCT) 
HDC + PBSCT is an aggressive chemotherapeutic regimen that is standard therapy in this patient 
population at our Center and worldwide.   The significant toxicities associated with this treatment are universal, 
with 99% of all patients experiencing Grade 3 or greater treatment related toxicity within the first 100 days post 
HDC. In order to assess any potential toxicity’s associated with DC + xALT therapy we have classified toxicity 
evaluation into three possible categories:   
 
1) 
Non-overlapping toxicities 
2) 
Immunotherapy related mortality 
3) 
Chemotherapy related toxicity 
 
 
For ease of surveying common toxicities associated with this treatment regimen (or similar high-dose 
chemotherapy regimens) in patients with reMB/PNETs a table of toxicities experienced in three representative 
Toxicity ( Grade 3, 4) 
Gururangan 
et 
al.  
1998 
Broniscer et al. 
2004 
Sung et al. 
2007 
 
n = 20 
n = 17 
n = 25 
Microbiologically documented Infections 
4(20%) 
9 (53%) 
4 (16%) 
Presence of high fever (≥ 38.5oC) 
20(100%) 
NR 
14 (56%) 
Vomiting 
NR 
NR 
10 (40%) 
Oropharyngeal mucositis 
20 (100%) 
17 (100%) 
10 (40%) 
Diarrhea 
NR 
NR 
12(48%) 
Elevation of liver enzyme 
NR 
NR 
8(32%) 
Veno-occlusive disease 
NR 
NR 
2(8%) 
Hyponatremia 
NR 
NR 
5(20%) 
Hypokalemia 
NR 
NR 
5(20%) 
Treatment related mortality 
2(10%) 
2(12%) 
4(16%) 
Intracerebral hemorrhage 
1(5%) 
NR 
NR 
Subgaleal hematoma 
1(5%) 
NR 
NR 
Hepatotoxicity 
NR 
5(29%) 
NR 
Nephrotoxicity 
NR 
2(12%) 
NR 
Seizures  
NR 
2(12%) 
NR 

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clinical trials including one of our own is included above.  Toxicities external to this list will be considered non-
overlapping toxicity.  
 
17.2 Immunotherapy Related Dose-limiting Toxicity 
17.2.1 PHASE II TOXICITY MONITORING 
The stopping rules described below for monitoring dose-limiting toxicity and treatment-related mortality 
during the Phase II trial are guidelines for determining whether accrual should be formally suspended and the 
data carefully reviewed. 
17.2.2 MONITORING OF NON-OVERLAPPING VACCINE RELATED TOXICITY  
 Dose-limiting toxicity rates of 5% or less are considered desirable while rates of 20% or greater are 
considered undesirable. The statistical hypothesis that will be tested will differentiate between a 5% (alternative 
hypothesis) and 20% (null hypothesis) rate of unacceptable toxicity.  Stopping rules based upon boundaries 
proposed by Pocock will be used to monitor this study.  If the following thresholds for DLT ratios are satisfied 
(≥3/5, ≥4/15, ≥4/25, ≥5/35), then the study will be suspended and the data reviewed carefully.  The type I and 
type II errors associated with this testing/monitoring are 0.025 and 0.019, respectively.   
17.2.3 MONITORING OF VACCINE RELATED MORTALITY     
Accrual will be automatically terminated in the following situations:  (1) The occurrence of any vaccine-
related death, or (2) The occurrence of any death more than 100 days post-transplant that is not due to tumor 
progression (or other readily identifiable unrelated cause of death (i.e., motor vehicle accident).  A review by the 
DSMB and IRB along with discussion with the PI will ensue to determine whether accrual to this trial would 
continue.  
17.2.4 MONITORING OF CHEMOTHERAPY-RELATED MORTALITY 
 During the 100 day period post-transplant, there is concern that the administration of vaccines will 
exacerbate chemotherapy-related mortality.  Based upon our experience, a mortality rate of 3-5% is expected with 
the administration of HDC followed by transplantation without vaccination.  If the true rate of chemotherapy-
related mortality with the novel treatment regimen during the 100 day period was 10% or greater the regimen 
would be considered unacceptable for further clinical development due to excessive toxicity unless significant 
modifications were made to mitigate the rate of chemotherapy-related mortality.  If that percentage were 2.5% or 
less, the treatment regimen would have an acceptable toxicity mortality rate.  Monitoring and decision rules have 
been developed to differentiate between a 2.5% (alternative hypothesis) and 10% (null hypothesis) rate of 
chemotherapy-related mortality.  Boundaries defined by Pocock will be used to monitor this study.  If the 
following thresholds are satisfied (≥2/5, ≥2/15, ≥2/25, ≥2/35), the study will be terminated due to excessive 
toxicity.  The type I error or probability of concluding that the treatment regimen is safe from the perspective of 
chemotherapy-related mortality when it is truly unsafe is 0.05. The type II error rate, or probability of concluding 
that there is excessive treatment-related mortality when the treatment is safe, is 0.12.   
These monitoring rules were generated using S+ SeqTrial (S+ SeqTrial 2 User’s Manual, Insightful 
Corporation, Seattle, WA) using the alternative variance method. 
 
17.3 Management of Toxicities 
 
A DLT will be defined as a drug-related Grade IV toxicity or any non-neurologic toxicity ≥ Grade III of 
any duration.  A Grade III neurologic toxicity will only be declared a DLT if not reversible within 48 hours.  Only 
patients receiving at least 3 vaccines without toxicity will be considered as safe for MTD assessment.  Patients 
receiving less than 3 vaccines without toxicity will be replaced for safety assessments.  If toxicity is encountered 
before the 3rd vaccine, this will still be considered a DLT.  Although not considered a DLT, any patient with ≥ 
Grade II urticaria will not receive further vaccines and will be withdrawn from the study.  Any Grade IV toxicity 

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or any life-threatening event not attributable to a concomitant medication, co-morbid event, or disease 
progression, even if reversible, will be considered a DLT.  If biopsy cannot be obtained, any new radiographic or 
clinical changes not attributable to tumor progression that produce a Grade IV or life-threatening toxicity will be 
considered at DLT.  Life-threatening events, as described above, even if considered a Grade III toxicity, will still 
be considered a DLT even if reversible and in such cases no further vaccinations will be given. 
If a Grade III NCI CTC toxicity is seen that is not attributable to a concomitant medication, co-morbid 
event, or disease progression that has been documented radiographically or clinically, the next immunization for 
that patient will be withheld for up to 2 months or until the NCI CTC toxicity improves to a Grade II or until the 
KPS score returns to within 10 points of baseline.  Grade III neurologic toxicities will be declared irreversible if 
they cannot be reversed within 48 hours of their onset.  If the event cannot be reversed within 48 hours of its 
onset, a DLT will be declared for that patient and no further vaccinations or study-related procedures will be 
performed.  If the event is reversed, but Grade III NCI CTC toxicity is again seen with subsequent vaccinations, 
all further vaccinations and study-related procedures will be withheld and a DLT will be declared.  Medical 
therapy may be used to reverse any toxicity if necessary, but any episode of a toxicity requiring surgical 
intervention will still be considered a DLT even if reversible by surgery. This study will be halted if a total of 2 
patients experience a study-related DLT. 
Grade III or greater toxicities associated with DC-based immunotherapy have been rare.  Adoptive T cell 
therapy using tumor-infiltrating lymphocytes and high-dose IL-2 in patients with melanoma and treatment with 
anti-CLTA-4 monoclonal antibody blockade have been the immunotherapy regimens most often associated with 
treatment related toxicities.  To take the most conservative approach to assessing possible toxicities associated 
with this treatment, we will be vigilant for any similar toxicity associated with this therapy, in addition to 
autoimmune toxicity specific to the CNS. Possible immune-mediated disorders that have been observed in 
patients who have received immunotherapy in early phase trials have involved the skin (vitiligo and cutaneous 
leukocytoclastic vasculitis), the thyroid gland (autoimmune thyroiditis), the liver (autoimmune hepatitis) and the 
pituitary (hypophysitis). Abnormal lab results, which may be immune-mediated, include elevations of serum 
lipase and amylase and liver function tests. If a patient has an AE that is thought to be possibly related to 
autoimmune antibodies (eg, thyroiditis, hepatitis, thrombocytopenia) the PI will send a blood sample for 
appropriate autoimmune antibody testing. If specific autoantibodies are present, the serum sample taken for 
storage at baseline will be tested for the presence of those autoantibodies. Further immunotherapy treatment in 
that patient will be held until the etiology of the event is established. Continuation of DC + xALT therapy in the 
presence of Grade III or greater immune-mediated events should be done by the PI only after discussion with the 
patient, medical monitor, and DSMB on a case-by-case basis with consideration to risk-benefit analysis.  The IRB 
will be notified promptly and will review the event and determine whether the problem does or does not represent 
an unanticipated risk to the study participants. If review determines that unanticipated increased risk did occur a 
revised consent form stating such a risk will be drafted, approved by the IRB and prior to continued therapy will 
require the patient to be re-consented with the revised consent.  
In the case of hypersensitivity reactions, treatment measures deemed medically appropriate will be 
initiated and the PI notified of the event.  The following treatment recommendations may be applicable and can 
be adopted at the judgment of the supervising pediatrician: 
CTCAE (Common Terminology Criteria for Adverse Events) v.4.0 Grade I allergic reaction (transient flushing 
or rash, drug fever <38°C; intervention not indicated): 
-Supervise at the bedside. 
CTCAE v.4.0 Grade II allergic reaction (intervention or infusion interruption indicated; responds promptly to 
symptomatic treatment; prophylactic medications indicated for < 24 hours): 
-Interrupt the infusion of xALT and disconnect infusion tubing from patient. Do not inject any    
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-Administer IV antihistamines (diphenhydramine 1mg/kg and ranitidine 3 mg/kg). 
-After recovery of symptoms, resume the infusion at half the initial infusion rate. If no further symptoms  
-appear, complete the administration of the xALT. If symptoms reappear, stop infusion and discontinue 
patient from the study. 
 
CTCAE v.4.0 Grade III or IV allergic reaction (prolonged; recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae; life-threatening consequences; urgent intervention 
indicated): 
-Stop the infusion of xALT and disconnect infusion tubing from patient.  Do not inject any remaining    
 DCs 
-Administer epinephrine (1:10,000) in 3.5 to 5 mL IV boluses (no more than 6 doses). 
-Administer IV antihistamine (diphenhydramine 1mg/kg (up to 50 mg) IV push). 
-If wheezing persists: 0.35 mL of inhaled albuterol or other bronchodilators. 
-Consider methylprednisolone (1-2mg/kg or 30-60 mg IV push), which may prevent recurrent or  
 ongoing reactions. 
-Anaphylaxis will be treated promptly with standard of care treatment procedures.  
-Patient must be taken off study. 
 
All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (version 4.0). 
17.4 Adverse Event Reporting and Documentation 
17.4.1 ADVERSE EVENTS 
An “AE” will be defined as any adverse change from the subject’s pre-treatment baseline condition, including 
any clinical or laboratory test abnormality that occurs during the course of research after treatment has started.  
AEs will be categorized and graded in accordance with the NCI CTC (Version 4.0). 
17.4.2 SERIOUS ADVERSE EVENTS 
A “SAE” will be defined as an undesirable sign, symptom or medical condition which results in any of 
the following outcomes: 1) fatal or life threatening; 2) inpatient hospitalization or a prolongation of existing 
hospitalization; 3) a persistent or significant disability/incapacity; 4) a congenital anomaly or a birth defect and/or; 
5) medically significant event such that it may jeopardize the subject, and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
SAEs which are serious should be reported immediately to the PI, Dr. Duane A. Mitchell, M.D., Ph.D. or his 
designee and to the local IRB per standard reporting procedures.  Fatal or life-threatening, unexpected AEs where 
there is evidence to suggest a causal relationship between the drug and the adverse event will be reported by the 
sponsor to the FDA by telephone, facsimile, or in writing as soon as possible, but no later than 7 calendar days 
after first knowledge by the sponsor followed by as complete a report as possible within 8 additional calendar 
days.  Serious, unexpected AEs that are related or possibly related to the drug but are not fatal or life-threatening 
will be reported to the FDA by telephone, facsimile, or in writing as soon as possible, but no later than 15 calendar 
days after first knowledge by the sponsor.  Site Investigators will be notified in accordance with 21 CFR 312.32.  
SAEs that are considered serious, unexpected, and related or possibly related to the research (as defined by 
21CRF312.32[a]) will be discussed with the Medical Monitor.  At the time of the annual progress report to the 
UF IRB, a summary of the overall toxicity experience will be provided. 
17.4.3 ADVERSE EVENT DOCUMENTATION 
This study will include two adverse event collection periods: non-mobilized leukapheresis and Consolidation or 
NMA Chemotherapy. The non-mobilized leukapheresis collection period will begin at initiation of leukapheresis 

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and continue until 24 hours after the completion of the procedure.  The Consolidation or NMA Chemotherapy 
period will begin at initiation of chemotherapy and continue until 100 days after either the infusion of peripheral 
blood stem cells or completion of chemotherapy for subjects who did not receive PBSCs.  All AEs thought to be 
related to vaccine therapy (any grade) and all grade 2 or greater AEs will be collected.  After the 100 day reporting 
period, AEs that are stable and not related to vaccine therapy will not be followed until resolution.   If the subject 
has progression of disease and /or begins another line of therapy or another therapeutic trial the adverse events 
collection will be discontinued.   Events occurring outside the reporting windows that have a possible relationship 
to vaccine therapy must also be reported.  All AEs must be recorded in the subject’s medical record and case 
report form, if applicable. 
 
A summary of recorded AEs (not just those considered related to the DC + xALT therapy) will be kept which 
will categorize the event by organ system, relationship to treatment, its grade of severity, and resolution.  The PI 
will periodically review the collective AEs with the intention of identifying any trends or patterns in toxicity.  If 
any such trends are identified, depending on their severity and frequency, a protocol amendment will be 
considered. 
 
17.5 Concomitant Medication 
The following medications will be recorded in the data management system: 
• Steroids; 
• Anticonvulsants; 
• Any medication used it the treatment of a VACCINE/STUDY DRUG related AE/SAE; and 
• Any medication deemed to possibly be interactive with vaccine or study drug by PI or designee. 
Start date, stop date, and indication (reporting windows are those of adverse events) will be documented. 
 
 

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18. DESCRIPTION OF PROTOCOL DRUGS OR DEVICES 
18.1 Preparation and Administration of Standard of Care Therapeutic Agents 
18.2 Cyclophosphamide 
Source and Pharmacology 
Cyclophosphamide ((Cytoxan) NSC #26271) is an alkylating agent related to nitrogen mustard. 
Cyclophosphamide is inactive until it is metabolized by P-450 isoenzymes (CYP2B6, CYP2C9 and CYP3A4) in 
the liver to active compounds.  The initial product is 4-hydroxycyclophosphamide (4-HC) which is in equilibrium 
with aldophosphamide which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent in vitro than 
is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those produced by 
mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug.  Cyclophosphamide is well absorbed orally with a 
bioavailability greater than 75%. The plasma half-life ranges from 4.1 to 16 hours after IV administration and 
1.3 to 6.8 hours after oral administration. 
Formulation and Stability 
Cyclophosphamide for Injection is available as powder for injection or lyophilized powder for injection 
in 500 mg, 1 gm and 2 gm vials. The powder for injection contains 82 mg sodium bicarbonate/100 mg 
cyclophosphamide and the lyophilized powder for injection contains 75 mg mannitol/100 mg cyclophosphamide. 
Storage at or below 25ºC (77ºF) is recommended. The product will withstand brief exposures to temperatures up 

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to 30º C (86ºF). 
Supplier 
Commercially available from various manufacturers. See package insert for more detailed information. 
18.3 Mesna  
Source and Pharmacology 
[(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex®) NSC #113891] was developed as a 
prophylactic agent to reduce the risk of hemorrhagic cystitis induced by ifosfamide. Mesna is rapidly oxidized to 
its major metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and 
is rapidly eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol compound, 
mesna, which reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) 
resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy 
ifosfamide forming a nonurotoxic 4- sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model studies, mesna in 
combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate 
interference with antitumor efficacy. After an 800 mg dose the half-life for Mesna and DiMesna are 0.36 hours 
and 1.17 hours, respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine 
in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was eliminated within 4 
hours. Mesna tablets have an oral bioavailability of 45-79% and a urinary bioavailability which ranged from 45-
79% of intravenously administered mesna. The oral bioavailability is unaffected by food. When compared to 
intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures (150%) 
and provides more sustained excretion of mesna in the urine over a 24-hour period 
 
 
 
Formulation and Stability 
Mesna for injection is available as 100mg/ml 10ml multidose vials which contain 0.25 
mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/ml of benzyl alcohol as a preservative. Store 
product at controlled room temperature 15-25°C (68-77ºF). Mesna is not light-sensitive, 
but is oxidized to DiMesna when exposed to oxygen. Mesna as benzyl alcohol-preserved 
vials may be stored and used for 8 days. 
Mesna non-preserved ampoules are no longer provided by Bristol-Myer Squibb 
Company. 
 
Supplier 

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Commercially available from various manufacturers. See package insert for further 
information. 
18.4 Etoposide 
Source and Pharmacology 
Etoposide ((VePesid®, Etopophos®,VP-16) NSC #141540 (112005)) is asemisynthetic derivative of 
podophyllotoxin that forms a complex with topoisomerase II and DNA which results in single and double strand 
DNA breaks.  Its main effect appears to be in the S and G2 phase of the cell cycle. The initial t1/2 is 1.5 hours 
and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately 
55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 
10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, 
therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of 
renal disease on plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of 
etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism 
accounts for most of the non renal clearance of etoposide. The maximum plasma concentration and area under 
the concentration time curve (AUC) exhibit a high degree of patient variability. Etoposide is highly bound to 
plasma proteins (~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide systemic 
exposure is related to toxicity.  Preliminary data suggests that systemic exposure for unbound etoposide correlates 
better than total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. Cmax and AUC 
values for orally administered etoposide capsules consistently fall in the same range as the Cmax and AUC values 
for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability 
is approximately 50% (range 25-75%).  Etoposide phosphate is a water soluble ester of etoposide which is rapidly 
and completely converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that 
etoposide phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses.  Etoposide 
for Injection is available in sterile multiple dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 
to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30mg benzyl alcohol, 80 mg modified polysorbate 
80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol.  Vial headspace contains nitrogen. 
Unopened vials of Etoposide are stable until expiration date on package at room temperature (25°C). Etoposide 
phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in single-dose vials 
containing etoposide phosphate equivalent to 100 mg etoposide, 
32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under refrigeration 2°-
8°C (36°- 46°F). Unopened vials of etoposide phosphate are stable until the expiration date on the package. 
3.6.2 Supplier 

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18.5 Temozolomide (Temodar®) 
Chemical Name 
3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide1 
TMZ is commercially available from Schering-Plough Research Institute under the trade name 
Temodar®. 
TMZ undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound,  Maximally 
Tolerated Inhibitory Concentration (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation 
of DNA. Alkylation (methylation) occurs primarily 
at the O6 and N7 positions of guanine.  TMZ is available in capsules that are white in color with colored 
imprints indicating the different doses: 5 mg (green imprint), 20 mg (brown imprint), 100 mg (blue imprint) and 
250 mg (black imprint).  Capsules should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59- 
86ºF). The commercial product has an expiration date on the bottle.  TMZ will be administered orally, 30 minutes 
following the completion of each O6-Benzylguanine infusion. If a patient has emesis within 10 minutes of 
receiving a dose, the dose should be repeated as soon as the patient is able to tolerate re-dosing. If a patient cannot 
tolerate re-dosing within 2 hours of completion of the O6-Benzylguanine infusion, or has repeated emesis, no 
further doses of TMZ will be given on that day. For patients unable to swallow intact capsules, capsules may be 
opened and mixed with apple juice or applesauce, or administered via Gastronomy Tube (G-Tube) or Nasogastric 
Tube (NG-tube.) If mixing capsule contents with apple juice or apple sauce is necessary, mix the contents 
immediately prior to administration. Care must be taken to avoid inhaling the powder or having the powder come 
in contact with skin or mucous membranes. If opening of capsules is necessary, it should be performed by hospital 
staff trained in handling chemotherapeutics.  Chemotherapy precautions should be utilized in preparation. Gloves 
should be worn and all mixing media must be discarded as chemotherapy waste.  TMZ is available from 
commercial sources by the treating hospital pharmacy. 
Known AEs of Temozolomide 
Allergy/Immunology: sinusitis 
Blood/Bone Marrow: decreased WBC, lymphopenia, neutropenia, thrombocytopenia, anemia  
Cardiovascular: peripheral edema 
Constitutional Symptoms: fatigue, asthenia, fever, weight gain 
Dermatology/Skin: rash, pruritis 
Endocrine: adrenal hypercorticism 
Gastrointestinal: nausea, vomiting, constipation, diarrhea, anorexia 
Infection: viral infection, urinary tract infection 
Musculoskeletal/Soft Tissue: myalgia 
Neurology: convulsions, hemiparesis, dizziness, abnormal coordination, amnesia, insomnia, paresthesia, 
somnolence, paresis, ataxia, dysphasia, abnormal gait, confusion, anxiety, depression 
Ocular/Visual: diplopia, blurred vision, visual deficit or changes 
Pain: headache, back pain, abdominal pain, breast pain (female) 
Pulmonary/Upper Respiratory: upper respiratory tract infection, pharyngitis, coughing 
Renal/Genitourinary: urinary incontinence, micturition increased frequency 
 
 

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18.6 Carboplatin 
Source and Pharmacology 
The mechanism of action of carboplatin (Paraplatin®) NSC #241240 (092006) would appear to be similar 
to that of cisplatin. It binds to replicating DNA causing single strand breaks and interstrand cross-links with DNA.  
Data suggests that other factors also contribute to cytotoxicity. The α t1/2 is 1.1 to 2 hours and the β t1/2 is 2.6 to 
5.9 hours. Carboplatin is not protein bound. The major route of elimination of carboplatin is renal excretion. 
Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine 
within 12 hours and 71% of the dose within 24 hours. In patients with creatinine clearances below 60 mL/min the 
total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages 
will require adjustment dependent on the glomerular filtration rate. 
 
Formulation and Stability 
Carboplatin is available in 50 mg, 150 mg, 450 mg and 600 mg vials. 
Aqueous Solution: Carboplatin aqueous solution is supplied as a sterile, pyrogenfree, 10mg/mL aqueous solution 
of carboplatin in multidose vials. Unopened vials of carboplatin aqueous solution are stable to the date indicated 
on the package when stored at 25° C (77° F); excursions permitted from 15°-30° C (59°-86° F).  Protect from 
light. Carboplatin aqueous solution multidose vials maintain microbial, chemical, and physical stability for up to 
14 days at 25º C following multiple needle entries. 
Powder for Injection: Carboplatin powder for injection is a sterile lyophilized white powder in single dose vials 
containing equal parts by weight of carboplatin and mannitol. Unopened vials of carboplatin are stable to the date 
indicated on the package when stored at 15°-30° C (59°-86° F). Protect from light. 
Supplier 
Commercially available from various manufacturers. See package insert for more detailed information. 

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18.7 Thiotepa 
Source and Pharmacology 
Thiotepa (Tespa, Thiophosphamide, Triethylenethiophosphoramide Tspa, WR- 45312) NSC #6396 
(032006) is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to nitrogen 
mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylenimine radicals 
which, like irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is initiated by alkylation 
of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates 
alkylated guanines. Thiotepa is desulfurated by cytochrome P-450 enzymes such as 2B1 and 2C11 which catalyze 
the conversion of thiotepa to tepa. Tepa is less toxic than thiotepa and has been demonstrated to produce alkali-
labile sites in DNA, rather than cross-links. These findings indicate that tepa reacts differently from thiotepa and 
produces monofunctional alkylation of DNA. A second metabolite of thiotepa, a mercapturic acid conjugate, is 
formed via glutathione conjugation.  Monochloro tepa is the third metabolite found in the urine. 
Following short intravenous infusion (less than 5 minutes), peak concentrations of thiotepa were measured 
within 5 minutes. At steady state, the volume of distribution was independent of dose and ranged from 0.3 to 1.6 
liters per kilogram (l/kg).  Approximately 4.2% of the original dose is eliminated in the urine within 24 hours as 
tepa. The elimination half-life of thiotepa ranges from 2.3 to 2.4 hours.  The half-life of tepa ranged from 3.0 to 
21.1 hours in one study. 
Formulation and Stability 
Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of nonpyrogenic, sterile 
lyophilized powder. Store in a refrigerator at 2° to 8°C (36° to 46°F).PROTECT FROM LIGHT AT ALL 
TIMES. 
Supplier 
Commercially available from various manufacturers. See package insert for further information. 
 
 
 

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18.8 Fludarabine phosphate 
Source and Pharmacology 
9-b-Barabinofuanosyl-2-fluoroadenine.   
Fludarabine (FAMP, Fludara®) is a synthetic purine nucleoside.  While the exact mechanism of action of 
fludarabine has not been fully elucidated, fludarabine appears to inhibit alpha-DNA polymerase, ribonucleotide 
reductase, and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting 
in inhibition of DNA synthesis.  Additionally, the drug may inhibit DNA chain elongation and interfere with RNA 
and protein synthesis by decreasing the incorporation of uridine and leucine.   
Pharmacokinetics - After administration, fludarabine phosphate is rapidly dephosphorylated to fludarabine 
triphosphate, the cytotoxic form of the drug.  Areas under the concentration-time curve for fludarabine appear to 
be dose related.  The elimination profile of fludarabine has been reported as either biphasic or triphasic, with 
terminal elimination half-lives for fludarabine and fludarabine triphosphate of 8-10 and 15 hours, respectively.  
Fludarabine appears to be eliminated through the kidneys.   
Formulation and Stability 
Fludarabine is supplied in a 50mg powder form, and reconstituted with 2mL of sterile water.  The 
appropriate dose of drug is then withdrawn and added to 100 or 125mL of D5W or 0.9% sodium chloride solution.  
Fludarabine contains no preservatives and should be used within 8 hours after reconstitution. 
Supplier 
Commercially available from various manufacturers. See package insert for further information. 
Dosage Modification Rules 
 
Patients with renal impairment dosing: 
CrCl > 70 ml/min: No dosage adjustment required. 
CrCl 30-70 ml/min: Reduce dose by 20%. 
CrCl < 30 ml/min: Fludarabine should not be administered intravenously to these patients. 
Toxicity 
Toxicity from fludarabine includes the following: 
(a) hematologic-myelosuppression with anemia, neutropenia and thrombocytopenia; 
(b) nervous system-weakness, pain, malaise, paresthesias, visual and hearing disturbances, encephalopathy; 
(c) gastrointestinal-nausea, vomiting, GI bleeding, mucositis, and anorexia; 
(d) integumentary-rash, and pruritis; 
(e) other-interstitial pneumonitis, cough, fever, myalgia, tumor lysis, and elevated LFTs. 
 

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19. PREPARATION, ADMINISTRATION, AND TRANSPORT OF EXPERIMENTAL 
THERAPEUTIC AGENTS (DC + XALT THERAPY) 
19.1 External Sites 
Study personnel at external sites will receive training on the transport of tumor tissue and leukapheresis 
product as well as the preparation and administration of experimental therapeutic agents.  Documentation of 
training will be maintained at the University of Florida. 
Tumor tissue and leukapheresis product will be collected, prepared, and shipped to the University of 
Florida in accordance with SOP-UFBTIP-120 or SOP-UFBTIP-130 and SOP-UFBTIP-127.  Samples will be 
labeled with, at a minimum, the subject’s name and study ID code.   External sites will be supplied with kits that 
will include all materials necessary to prepare and transport tumor tissue and leukapheresis product, including 
shipping labels. 
TRNA DC and TTRNA-xALT products prepared by the University of Florida will be shipped to external 
sites in a liquid nitrogen dry-shipper under controlled conditions in accordance with SOP-UFBTIP-129.  External 
sites will store products in accordance with standard operating procedures/written instructions until time of 
formulation.  When the subject is present and both the subject and site staff are ready for administration, products 
will be formulated in accordance with SOP-UFBTIP-124 and SOP-UFBTIP-125.  Products will be labeled with, 
at a minimum, the subject’s name and study ID code. 
Individuals transporting samples must be certified to ship biological products, diagnostic or infectious 
materials.  All packaging must comply with the Department of Transportation (DOT), the Federal Aviation 
Authority (FAA), and the International Air Transport Association (IATA) dangerous goods regulations.   
19.2 TTRNA isolation 
Surgically resected reMB/PNET specimens are collected aseptically and transferred from the operating room 
to the research laboratory in accordance with SOP-UFBTIP-116.  All specimens obtained at outside hospital 
facilities will be transferred aseptically under FDA guidelines (BB IND 13630 (Sampson), BB IND 14058 
(Mitchell)) in accordance with SOP-UFBTIP-120 or SOP-UFBTIP-130. The tumor is washed of excess blood 
and minced using sterile scissors.  Minced tumor fragments are then snap frozen and stored in liquid nitrogen 
until RNA extraction.  Because tissue thawing in the absence of ribonuclease inhibitors leads to RNA degradation, 
frozen tumor tissue is homogenized immediately prior to RNA extraction.   Total cellular RNA is then extracted 
using the RNeasy kit (Qiagen, Valencia, CA) following the manufacturer’s specifications.  Extracted RNA is 
quantified with a NanoDrop at 260 nm and subsequently used in amplification reactions in accordance with SOP-
UFBTIP-102.   
19.3 Amplification of RNA 
For larger samples the total RNA is isolated using RNeasy (Qiagen Cat# 74104).  For small tumor samples 
SuperScript III CellDirect cDNA Synthesis System (Invitrogen) is used to isolate total RNA from the tumor cells.  
Invitrogen’s CellDirect Resuspension/Lysis Enhancer Buffers (Invitrogen, Cat# 11739-010) are mixed 10:1 and 
added directly to the autologous tumor cells.  The extracted RNA mixture is heated for 10 minutes at 75OC.  An 
aliquot of the CellDirect lysate or extracted RNA is used for 1st-strand cDNA synthesis with using the primers 
5’-AAG CAG TGG TAT CAA CGC AGA GTA CTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT 
TTT TTT TTT TTT TTT TTT TTT TTT TTT TTV N-3’; (CDS Primer IIIA), and 5’-AAG CAG TGG TAT CAA 
CGC AGA GT/G GCC ATA TTG GCC rGrGrG/3AmMC6-3’(SMART III) at 70OC for 3 minutes, 42OC for 20 

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minutes and 70OC for 15 minutes.  The 1st-strand cDNA libraries were amplified with ClonTech’s Advantage 2 
Polymerase PCR kit (ClonTech Cat# 639201) or ClonTech’s polymerase mix (ClonTech Cat# 639201)  by 
primers (CDS Primer IIIA; and T7 –Smart: 5’-CCA TCC TAA TAC GAC TCA CTA TAG GTA TCA ACG 
CAG AGT GGC CAT ATT G-3’) at 95OC for 2 minutes, 30-50 cycles of 95OC for 25 seconds, 65OC for 45 
seconds, 68OC for 6 minutes and 68OC for 10 minutes. The integrity of the amplification is evaluated by Real-
Time PCR on a 7900HT Fast Real-Time PCR System (Applied Biosystems) or equivalent using gene expression 
levels of human housekeeping genes (ACTB, EGFR, GAPDH or HPRT).  PCR amplification conditions may be 
modified to optimize amplifications as assessed by housekeeping gene detection.  The detection of at least one 
housekeeping gene and a cDNA smear extended to 1Kb or greater is required to declare the template suitable for 
RNA synthesis.  The amplified cDNA PCR products are purified with QIAquick PCR Purification kit (QIAGEN 
Inc., Valencia, CA, Cat# 28104). In vitro mRNA transcription was done using the same products and procedures 
as those previously approved for INDs 12,839, 13,240 and 13,630.  The amplified mRNA is synthesized using 
T7 mMessage mMachine™ Transcription Kit (Ambion Inc., Austin, TX, Cat# 1344) from PCR amplified 
TTRNA cDNA library templates, and cleaned with RNeasy™ kit (QIAGEN, Cat# 74104) and quantified with a 
NanoDrop at 260 nm. The integrity of the amplified mRNA is verified as defined in the RNA Release Criteria. 
The RNA amplification process will be conducted in accordance with SOP-UFBTIP-103 through SOP-
UFBTIP-115 and released in accordance with SOP-UFBTIP-119 as outlined below.    
  
RNA Release Criteria 
Nucleic acid/protein (260/280) 
>1.8 
Size 
RNA product range > 1kB by agarose gel 
electrophoresis.  
Sterile 
Negative aerobic and anaerobic bacterial cultures 
and fungal cultures by Clongen. 
 
19.4 Procedure for TTRNA-DC and TTRNA-xALT Generation 
Blood will be obtained by leukapheresis and transported to the UF cGMP facility in accordance with SOP-
UFBTIP-121 for cells collected at the University of Florida or SOP-UFBTIP-127 for cells collected at external 
sites.  PBMCs will be isolated in accordance with BR-UFBTIP-001 and plated into flasks for in vitro generation 
of DCs.  Non-adherent cells will be frozen in accordance with BR-UFBTIP-004 and subsequently used for 
production of antigen-specific T cells.  Immature DCs will be generated from the PBMCs in vitro by 7-day culture 
with GM-CSF and IL-4. At the end of the 7 day incubation, the immature DCs will be harvested and electroporated 
with TTRNA.  The electroporated immature DCs are placed in a flask with AIM V media with HABS containing 
GM-CSF, IL-4, TNF-α + IL-6 + IL-1β at 37oC, 5% CO2 for 18-24 hours for maturation.  The cells are washed 
with PBS and frozen in 80% human AB serum, 10% Cryoserv, and 10% Dextrose in accordance with BR-
UFBTIP-002.  A portion of the DCs are frozen and stored in liquid nitrogen until needed for DC vaccination.  
Another portion of the mature DCs is used for an in vitro 21 day stimulation of antigen-specific T cells in 
accordance with BR-UFBTIP-003.  After freezing and prior to release, an aliquot of cryopreserved cells will be 
thawed, prepared, and sent to Clongen for QA/QC release testing in accordance with FDA IND BB-14058 and 
SOP-UFBTIP-122 and SOP-UFBTIP-123. Testing will include sterility (aerobic and anaerobic bacterial 
cultures, fungal cultures), endotoxin, and mycoplasma.  A separate aliquot will be prepared for viability and 
phenotypic analysis for release criteria in accordance with SOP-UFBTIP-100.   
For each vaccination, DCs will be rapidly thawed at 37oC, washed with PBS and counted.  The DC 
concentration will be adjusted to 1 x 107 cells per 400 µL of preservative free saline and placed into a sterile 
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formulated DC will be stored at 2-8°C for up to 6 hours. After this time the material will be disposed of if not 
given to the patient. 
Autologous ex vivo expanded TTRNA-specific lymphocytes (xALT) 
Non-adherent cells will be obtained from the initial leukapheresis and frozen in accordance with BR-
UFBTIP-004 and will consist of the cells remaining after the plastic adherence step described above for DC 
generation in accordance with BR-UFBTIP-002.  These non-adherent cells are stimulated in vitro for 21 days 
with mature DCs.  2x107 non-adherent cells are placed into T-25 flasks along with 2x106 matured TTRNA loaded 
DCs, in 10 mLs AIM V containing 5% HABS and 3,000IU/mL IL-2 and incubated at 37OC for 5 days. After 5 
days, the cells will be treated with 100IU/mL IL-2 every 3 days if needed based on observation of cell clusters 
and PH measurement of media. The cells are expanded into progressively larger flasks as needed.  At the end of 
21 days, the TTRNA stimulated T cells are harvested, washed in PBS, counted and viably frozen in 90% HABS 
+ 10% Cryoserv in accordance with BR-UFBTIP-003.  After freezing and prior to release, an aliquot of cells is 
thawed and sent for QA/QC release testing according to FDA IND BB-14058 and SOP-UFBTIP-123. This 
includes aerobic and anaerobic bacterial cultures (1x106 TTRNA-xALT), fungal cultures (1x106 TTRNA-xALT), 
and endotoxin testing.  Viability (>70%) and phenotypic analysis will also be conducted for release criteria in 
accordance with SOP-UFBTIP-100.   
In preparation for TTRNA-xALT, cells are rapidly thawed at 37oC, washed with saline + human albumin, 
and counted.  The cell concentration will be adjusted to 3 x 107 cells/kg (or all cells available if less than target 
dose) in preservative free saline with 1% human serum albumin and placed into a syringe in accordance with 
SOP-UFBTIP-125.  The final thawed and formulated TTRNA-xALT will be stored at 2-8°C for up to 6 hours. 
After this time the material will be disposed of if not given to the patient. 
20. LABORATORY EVALUATIONS 
20.1 Baseline and Eligibility 
To be enrolled, patients must be scheduled for definitive resection, biopsy, and/or cytology collection of 
reMB/PNET or, in select cases, be at an outside institution and have had surgical resection and tumor tissue snap 
frozen and available for TTRNA. Clinical and laboratory evaluations will be obtained within 2 weeks of 
enrollment for the purposes of meeting Inclusion and Exclusion Criteria as outlined above.  Final pathologic 
diagnosis of reMB/PNET will be made by the study pathologist, or by certified outside pathology report.  
Pathology slides consisting of 1 hematoxylin and eosin (H&E44) and 19 unstained slides for 
immunohistochemistry prepared on Fischer Plus glass or Histostix coated slides when available will be delivered 
to: 
Duane Mitchell, M.D., Ph.D. 
Department of Neurosurgery 
1149 Newell Drive, Room L1-151 
University of Florida 
Gainesville, Florida 32611 
 
Blood will also be sent for the following tests:  CBC (Complete Blood Count) with manual differential. 
Initial clinical evaluations will also include a complete physical and neurologic examination.   
A baseline brain and spine MRI and study eligibility MRI (with and without gadolinium enhancement 
taken post-surgical resection of recurrent disease) of the brain using standard 5 mm slices with 2.5 mm spacing 
for comparison to subsequent MRI images will also be obtained. 
20.2 Data and Specimens to be Accessioned 
Before undergoing surgical resection 

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- History and physical examination 
 
- CBC, PT, PTT, Comprehensive metabolic panel & Type and Screen if clinically indicated 
- Material in excess of that required for pathologic diagnosis will be transported to Dr. Mitchell’s 
laboratory for RNA isolation in accordance with SOP-UFBTIP-116 and autologous tumor cell targets 
for immunologic monitoring. 
Prior to leukapheresis 
• Tests as required by the Apheresis Center (total estimated blood volume required for these 
evaluations is 10-20 mLs based on patient weight per institutional guidelines)   
o β-HCG if female and greater than 12 years of age 
o Infectious disease testing to include, at a minimum, HIV, Hepatitis B, Hepatitis C and CMV 
o CBC with differential, Complete or Basic Metabolic panel (per institutional standard), T4/T8 
ratio 
o To prevent the development of hypocalcemia from the citrate used for leukapheresis, all 
patients over age 3 will be given oral Tums, 2 tablets, b.i.d for 2 days prior to the leukapheresis 
procedure if standard of care.  Patients who have lowered levels of Ca will be treated per 
Apheresis lab standard.   
Prior to DC + xALT Therapy 
• At the time of first vaccination, all patients will receive a standard 0.5 mlTd (2 Lf tetanus and 2 Lf 
diphtheria toxoids) booster intramuscularly.  The rationale for this vaccination is to enhance DC 
trafficking to vaccine-site draining lymph nodes (VDLNs).  
• Additionally, 24 hours prior to first immunization, blood will be drawn for the following purposes: 
o  CBC with differential, T4/T8 ratio, and research blood. Total estimated blood volume required 
for these evaluations is 12 mL. 
During and After Immunizations 
• Clinical evaluations with each vaccine will include a general physical examination, complete 
neurologic examination, and KPS or LPS rating. 
• Radiographic evaluations consisting of a contrast enhanced brain CT or MRI scan will be obtained 
every 8 + 4 weeks. 
Blood will be obtained for T4/T8 ratio, CBC with manual differential and for Immunologic Monitoring prior to 
non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine #1, 
weekly post Vaccine #1 for six weeks, and bimonthly, if feasible, until progression.  Weekly blood draws 
should be drawn prior to subsequent vaccination.  Blood will be processed in accordance with SOP-UFBTIP-
126.  Total estimated volume of blood required over the six week period for investigational purposes will be 80 
mLs. 

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STUDY ROAD MAP: 
Timepoint 
Date 
Study Requirements 
Baseline 
  
Inclusion & exclusion criteria 
 
 
Tissue consent 
 
 
Medical history, physical & neurological exam 
 
 
MRI brain & spine 
  
  
Performance Status: KPS or LPS 
  
  
CBC w/ differential, PT, PTT, comprehensive metabolic panel 
 
 
β-HCG pregnancy test 
 
 
Type & Screen if clinically indicated 
Surgery 
  
Resection, biopsy or cytology collection 
 
 
Tumor tissue for extraction of total tumor RNA 
 
 
Pathology slides for research: 1 H&E & 19 unstained slides  
 
 
MRI brain with & without gadolinium post-surgery 
Non-Mobilized Leukapheresis 
 
Treatment consent 
 
CBC w/ differential, comprehensive or basic metabolic panel 
(per institutional standard), T4/T8 ratio, research labs** 
 
β-HCG pregnancy test 
 
Infectious disease testing to include, at a minimum, 
HIV, Hepatitis B, Hepatitis C & CMV 
 
Oral tums if standard of care 
Induction or Salvage Chemo 
Cycle 1 (28 days)   
Group A: Cyclophosphamide, Mesna, GCSF 
Group B: Etoposide, Temozolomide, GCSF 
Cycle 2 (28 days)   
Group A: Cyclophosphamide, Mesna, GCSF 
Group B: Etoposide, Temozolomide, GCSF  
Cycle 3 (28 days)   
Group A: Etoposide, Temozolomide 
Group B: Etoposide , Temozolomide 
Cycle 4 (28 days)   
Group A: Etoposide ,Temozolomide 
Group B: Etoposide, Temozolomide  
Mobilized Leukapheresis 
 
CBC w/ differential, comprehensive or basic metabolic panel 
(per  institutional standard), T4/T8 ratio 
 
 
β-HCG pregnancy test 
 
 
Infectious disease testing to include, at a minimum, 
HIV, Hepatitis B, Hepatitis C & CMV 
 
 
Oral tums if standard of care 
 
 

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Timepoint 
Date 
Study Requirements 
Pre Consolidation or NMA Chemo 
  
Medical history, physical exam 
  
  
MRI brain (spine if indicated) 
 
 
CBC w/ differential, comprehensive metabolic panel, GFR 
 
 
β-HCG pregnancy test 
  
  
ECHO or MUGA 
  
  
EKG (Group A only) 
  
  
DLCO, FEV1 & FVC or Crying Vital Capacity (Group A only) 
 
 
CXR & Pulse Oximetry 
(Group B & Group A subjects who cannot complete PFTs) 
Consolidation or NMA Chemo 
 
Group A: Carboplatin, Etoposide, Thiotepa, PBSCs , G-CSF 
Group B: Cyclophosphamide, Fludarabine , PBSCs, G-CSF 
Prior to Immunotherapy 
  
Td booster 
( 4 to 24 hours prior) 
 
CBC w/ diff, T4/T8 ratio, research labs** 
Immunotherapy 
Vaccine #1 
Group A: Day +1 
 
Group B: 96 hours post Fludarabine 
  
Physical & neurological exam  
 
Performance Status: KPS or LPS  
 
Tylenol, Benadryl, Intravenous TTRNA-xALT 
 
EMLA, Intradermal TTRNA-DC  
 
 
1 day post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
4 (+/-1) days post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 1 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 2 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 3 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 4 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 5 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
 
Week 6 post: CBC w/ diff, T4/T8 ratio, research labs** 
 
Vaccine #2 
14 days post Vaccine #1 
 
Physical & neurological exam  
 
Performance Status: KPS or LPS  
 
EMLA, Intradermal TTRNA-DC 
 
Vaccine #3 
14 days post Vaccine #2 
 
Physical & neurological exam  
 
Performance Status: KPS or LPS  
 
EMLA, Intradermal TTRNA-DC 
Bi-Monthly follow-up 
  
Physical & neurological exam 
  
  
Contrast-enhanced Brain CT or MRI scan 
 
 
CBC w/ diff, T4/T8 ratio, research labs, if feasible** 
**2 yellow (ACD-A) & 1 red (non-SST) 
 
20.3 Laboratory and Clinical Evaluation Facilities 
UF Health Clinical Laboratories 

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UF Health Clinical Laboratories, comply with federal regulations defined in the Clinical Laboratory 
Improvement Amendments of 1988 (CLIA’88) and the national accreditation standards defined by the College of 
American Pathologists (CAP). 
UF Health Clinical Laboratories are accredited by the College of American Pathologist’s Laboratory 
Accreditation Program. 
UF Health Department of Radiology 
The Department of Radiology at UF Health Shands Hospital consists of a large imaging facility for both 
inpatients and outpatients. The Neuroradiology Department will review all the radiological procedures in this 
proposal and be available to discuss the interpretation of any MRI findings that may be confusing in the setting 
of combinatorial therapy.  
UF Health Brain Tumor Biorepository  
This Biorepository or “tissue bank” has successfully obtained and stored brain tumor tissue and matched 
peripheral somatic cells from individual brain tumor patients.  There are also peripheral somatic cells stored from 
non-brain tumor disease control patients and normal subjects.   
Personnel from the Brain Tumor Biorepository will sterilely divide material from the operating room and 
preserve according to IRB approved biorepository protocol and SOPs.  All patient information is entered into 
database at which time the program will generate a unique number for the specimen.  
Outside Laboratories 
Accredited outside laboratories used in patient assessment will be registered using Form FDA 1572 (21 CRF 
312.53(c)). 
21. DATA ANALYSIS 
Samples collected from subjects during the phase 1 trial (FDA IND BB 14058; Duke IRB Pro00018020; PI: 
Duane A. Mitchell) will be analyzed as described below.  Patients treated at the phase 2 established dose of T 
cells (3x107 cells/Kg) may be included in the statistical analysis summary.  Patients treated below the targeted 
dose will be included in a descriptive analysis only. 
21.1 Progression Free Survival (PFS) and Overall Survival (OS)  
The study statistician will be responsible for all statistical analysis.  Estimating the potential efficacy of 
adoptive transfer with TTRNA-xALT plus TTRNA-DCs will be the primary goal of this Phase I/II evaluation.   
Patients enrolled on this study who are confirmed to have a reMB/PNET will be followed for all parameters 
until death.  The Kaplan-Meier estimator will be used to describe the progression-free survival and OS experience 
of vaccinated patients from the initiation of HDC as this is within 24hrs of the frame of reference for our historical 
control  
 
comparison (PBSCT defined as Day 0 in historical control cohort).  We will define the PFS and OS from the 
time of proximal tumor recurrence as a clinical reference point for further comparison to other treatment regimens 
within the published literature.  We do not anticipate any appreciable data lost during this study due to premature 
patient drop out or lost to follow up.  
 
21.2 Radiographic Response and Progression Criteria for Patients with Residual 
Disease 
All radiographic responses will be based on MRI scans of the brain and spine obtained with and without 
contrast. Tumor size will be based on the product of the maximal diameters in 2 different planes. Response will 
be assessed as a percentage change in tumor size from baseline. Tumor measurements in the follow-up scans will 

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be compared to those of the pre-treatment (baseline) scan to document response. However, determination of 
progressive disease will be based on comparison of the current tumor dimensions with the smallest 
measurements of the tumor recorded since the start of treatment. The assessment of steroid dose as “stable 
or tapering” will be based on the dose the patient was receiving on the day of the follow-up scan with that on the 
day of the pre-treatment scan. Residual disease will be defined as contiguous contrast enhancement ≥ 1 cm2 
(product of measurement obtained in 2 perpendicular planes (i.e., axial and coronal)).  For residual disease present 
at the time of the last MRI prior to initiating vaccination, radiographic response will be evaluated based on the 
NCI-endorsed, World Health Organization RECIST criteria and using a modified version of the MacDonald 
criteria[7,8] which is outlined below.   
Complete Response 
Complete disappearance of enhancing tumor on consecutive CT or MRI images at least 8 weeks apart, and 
neurologically stable or improved and at a stable or a lower steroid dose.  If CSF cytology was previously positive, 
it should now be negative.  To be assigned a status of “Complete Response” as a best overall response, changes 
in tumor measurements must be confirmed by repeat assessments that should be performed no less than 8 weeks 
after the criteria for response is first met. 
Partial Response 
At least a 50% reduction in tumor size on consecutive MRI images at least 8 weeks apart, and neurologically 
stable or improved and at the same or a lower steroid dose.  If CSF cytology was previously positive, it should 
now be negative.  To be assigned a status of “Partial Response” as a best overall response, changes in tumor 
measurements must be confirmed by repeat assessments that should be performed no less than 8 weeks after the 
criteria for response is first met. 
Stable Disease 
Insufficient change to qualify for Partial Response or Progressive disease.  CSF cytology remains positive or 
becomes negative. 
Progressive Disease 
At least a 25% increase in the longest diameter on an axial image of any enhancing contiguous tumor on 
consecutive CT or MRI images.  CSF cytology may be positive or negative. 
Not Assessable 
Progression has not been documented and one or more sites have not been assessed. 
21.3 Radiographic Response and Progression Criteria for Patients with Complete 
Resection 
A complete resection will be defined as contiguous contrast enhancement < 1 cm in 2 perpendicular 
measurements in each of 2 perpendicular planes (i.e., axial and coronal).  Because neither the RECIST [8] nor 
MacDonald [7] criteria are completely appropriate for patients with minimal residual disease, a modified version 
of these criteria will be used as outlined below. 
Complete Response 
Complete disappearance of enhancing tumor on consecutive CT or MRI images at least 1 month apart, and 
neurologically stable or improved and at the same or a lower steroid dose.  To be assigned a status of “Complete 
Response” as a best overall response, changes in tumor measurements must be confirmed by repeat assessments 
that should be performed no less than 4 weeks after the criteria for response is first met. 
 
Partial Response 
At least a 30% reduction in longest diameter on an axial image of any contiguous enhancing tumor on 
consecutive CT or MRI images at least 1 month apart, and neurologically stable or improved and at the same or 
a lower steroid dose.  To be assigned a status of “Partial Response” as a best overall response, changes in tumor 

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measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response is first met. 
Stable Disease 
Insufficient change to qualify for Partial Response or Progressive disease. 
Progressive Disease 
At least a 20% increase in the longest diameter on an axial image of any enhancing tumor on consecutive CT 
or MRI images with a minimum of ≥ 5 mm of contiguous contrast enhancement in 2 perpendicular measurements 
in each of 2 perpendicular planes (i.e., axial and coronal). 
Not Assessable 
Progression has not been documented and one or more sites have not been assessed. 
 
21.4 Special Circumstances 
 If a scan is suspicious but not definitive for progressive disease (including indeterminate lesion size 
or enhancement that is not clearly disease progression) in the absence of clinical progression, an 
investigator may elect to confirm progression through alternate means, including biopsy, or repeat 
MRI at 4-8 weeks, symptomatic follow up or other modalities.  
o Protocol treatment will continue until the investigator considers progression documented. 
 Disease that was measurable at baseline and appeared to be one solid mass splits to become 2 or 
more smaller lesions 
o note that the lesion has split, to identify the separate lesions as unique and to record the 
measurements of each. 
o appearance of these individual split lesions will not automate a response assignment of PD; they 
will contribute to a determination of progression only if the sum of all lesions meets the criteria 
for PD.  
 2 or more lesions which were distinctly separate at baseline become confluent at subsequent visits 
o note the occurrence and capture the required measurement(s) of the confluent mass. 
 A required region of a baseline scan may be unavailable or technically inadequate, and 1 or more 
lesions are detected on a subsequent scans.  
o Such lesions are identified as additional evaluable lesions that do not contribute to determination 
of that visit’s response. 
o If at a successive time point disease progression is noted, the overall response per time point will 
be PD. 
o For those areas inadequate at baseline, the first scan available will become the reference scan by 
which later scans are compared for evaluable progression. 
 1 or more lesions are detected in regions unavailable or inadequate at baseline that were also not 
required 
o regarded as new lesions, resulting in an overall response of PD for that time point. 
 Regions are not available or adequate at post-baseline visit assessments that showed disease at 
baseline 
o an overall response of NA will be assigned to that visit unless other available data shows 
progression. 
 
 

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Overall 
Response 
Measurable 
Lesions 
Evaluable 
Lesions 
New 
Lesions 
Overall 
neurological 
status 
Steroid Use 
Additional notes 
PD 
PD 
PD 
Yes 
Unequivocal 
worsening 
Stable or 
increased use 
PD by any single 
component (not steroids 
by criteria) no sooner than 
1 month after the first 
course of treatment  
SD 
All other combinations, but please note the following particular combinations: 
CR, PR or 
SD 
CR or SD No 
NA 
Off steroids, 
stable dose 
Note that a lack of steroid 
or neurological 
information could prevent 
CR or PR from being 
recorded 
CR, PR or 
SD 
CR or SD No 
improved, 
unchanged, 
possible 
worsening 
NA 
Note that a lack of steroid 
or neurological 
information could prevent 
CR or PR from being 
recorded  
NA 
NA 
NA 
improved, 
unchanged, 
possible 
worsening 
Off steroids, 
stable use 
CR, PR or 
SD 
CR or SD No 
improved, 
unchanged, 
possible 
worsening 
Off steroids, 
stable dose 
A CR or PR overall 
response assignment is not 
possible with a 
neurological grading of -1. 
PR 
PR or CR 
CR or SD No 
unchanged 
or improved 
Off steroids, 
stable use 
All conditions need to 
apply and CR criteria do 
not apply. 
CR 
CR 
CR 
No 
unchanged 
or improved Off steroids All conditions need to 
apply. 
NA 
NA 
NA 
NA 
NA 
Off steroids, 
stable dose 
NA applies when NA is 
true of both radiology and 
neurological status.  
 
 
 

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21.5 Survival 
Survival is not an endpoint in this study but will be accessioned to derive hypotheses that may relate data 
obtained in this study with survival times. Survival will be calculated from the date diagnostic tissue confirming 
recurrence is first obtained and also from the time of Vaccine #1 for both Groups A and B. 
Identification of Covariates 
Descriptive statistics (e.g. frequencies and means/SD) will be used to summarize levels of polyfunctional T 
cells, cytotoxic T cell responses, tumor-specific antibodies, and serum cytokine levels in the peripheral blood 
measured bimonthly.  Specifically, we will address the hypothesis that polyfunctional tumor-specific T cell 
responses may be important for mediating clinical efficacy of DC + xALT therapy.  Hotelling’s t-statistic will be 
used to determine whether changes in the polyfunctional T cells occurred during the 3 initial vaccinations.  Cox 
proportional hazards model will be used to assess the effect of the pre-vaccination level of polyfunctional T cell 
on PFS-12 and OS with and without adjustment for known prognostic factors.  The change observed in 
polyfunctional T cells during the first 3 vaccinations will be computed and its relationship with PFS-12 and PFS 
beginning at the time of the third vaccination with and without adjustment for known prognostic factors.  Similar 
analyses may be conducted examining changes between pre-vaccination and other monthly follow-up 
assessments.  The use of time-dependent variables within the Cox model for PFS-12 and OS beginning pre-
vaccination will be explored.  Logistic regression will be used to predict PFS-12 and 2yr-OS as a function of 
baseline polyfunctional T cell counts and previously defined changes.  Given the large number of predictors that 
will be examined relative to the overall sample size, it is recognized that these analyses will be exploratory.  These 
analyses are conducted to generate hypotheses only and will need to be validated in additional patients or studies.  
Statistically, joint effects will also be explored, but are unlikely to have sufficient power to identify such 
interactions.  Assuming that half the sample size of 35 patients are positive for a particular measure (i.e. detection 
of tumor-specific antibodies at a particular post-vaccination time point) and that all have died, we will have 80% 
power for a log rank test conducted with α=0.05 to detect a survival hazard ratio of 2.6 comparing patients with 
a positive and negative measure.   
21.6  Statistical Analysis of Longitudinal Immunologic Measures 
All statistical analyses have been proposed and will be undertaken by the study statistician. Our laboratory 
have devoted considerable energy to co-developing and co-validating the high-throughput immunologic assays 
outlined above for monitoring TTRNA-specific CD8+ or CD4+ T cells in PBMCs from patients with GBM. The 
reproducibility of these assays in our hands ensures that they can be reliably used for monitoring of changes over 
time. 
Of interest in this study is 1) whether there exists a difference in the number of tumor specific T cells as 
measured by CFC (Cytokine Flow Chemistry) after TTRNA-xALT and TTRNA-DC vaccination and 2) whether 
there exists a change in a given immunologic measure over time with each patient serving as their own control.  
For (1) we will use simple two-sample t-tests for means derived from each group for each parameter.  Assuming 
35 patients will received DC + xALT therapy during the Phase II trial, we will have 80% power to detect a 
difference between groups equal to approximately 1.79 standard deviations of the immune response (i.e., 
coefficient of variation = 0.557) at the α=0.05 level (2-tailed). 
For (2), we assumed for the power calculations, that measurements of immune response parameters will be 
normally distributed and correlated (r=0.5). All samples will be run in triplicate and the mean of the triplicate will 
be used for analysis. All statistical tests will be conducted at the 0.05 level of significance. In all assays proposed 
above, a paired t-test will be conducted unless assumptions required for conducting a t-test are not satisfied. In 
such cases, a non-parametric Wilcoxon signed rank test will be conducted. The difference detectable with a paired 
t-test from the mean at baseline in this study for a given patient is shown below:

 
 
Coefficient 
of Variation 
Test 
Percent change from 
baseline mean detectable  
(80% Power) 
Percent change from 
baseline mean detectable 
(90% Power) 
<0.10 
Luminex, DTH, 
Serum Titers,  
2.56% 
6.14% 
<0.15 
CFC, 
Proliferation 
3.67% 
4.50% 
 
Immunological response evaluations for baseline values will be conducted on a blood sample draw 24 hours 
before administration of HDC and prior to DC + xALT therapy and on a subsequent blood draw obtained two 
weeks after the third immunization. Immunologic response evaluations will also be performed from peripheral 
blood obtained prior to each vaccination.  The total amount of blood required for this purpose will be 10 cc.  A 
comparison of pre-therapy lymphocyte functions to those at intervals after each immunization will be made.  
These tests may provide evidence for the development of immune responses following DC + xALT therapy and 
will play an important role in the design of future immunotherapy clinical trials. 
21.7 T cell Cytokine Production 
CD4+ and CD8+ T cells derived from patients prior to and after DC + xALT therapy will be cultured in 96-
well plates with 0, 5, or 10 μg of PHA, TTRNA pulsed DCs, and control (PBMC RNA) pulsed  DCs. After 16 
and 72 hours of culture, supernatants are harvested and processed in duplicate with a custom BioRad Bio-Plex 
12-plex (IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p70), IL-15, IFN-γ, TNF-α, IP10) Cytokine Reagent Kit 
(BioRad) to differentiate responses into TH1 and TH2 types. Briefly, supernatants are incubated with anti-cytokine 
conjugated beads, followed by incubation with biotinylated detection antibody. Reaction mixture is detected with 
streptavidin-PE and analyzed on a Luminex 100 machine (Luminex Corporation, Austin, Texas). Unknown 
cytokine concentrations are calculated by BioPlex Manager software using standard curves derived from a 
recombinant cytokine standard. 
A paired t-test will be used to compare cytokine differences between treatment groups as described above. A 
Bonferroni correction will be used to control for the multiple cytokines being evaluated such that P<0.007 will 
be required for statistical significance. 
21.8 Cytokine Flow Cytometry  
The CFC analysis will be done at the UF Brain Tumor Immunotherapy Program.  This process involves the 
rapid early detection and analysis of the production of CD107a, γ-IFN, TNFα, and IL-2 prior to cellular secretion 
following antigen-specific stimulation in vitro as determined by CFC.  The functional CD4+ and CD8+ immune 
response of the patients will be monitored using an 11 color CFC assay.  Evidence for intra- and inter-molecular 
epitope spreading and evidence for the induction of autoimmunity will also be sought.  For cellular immune 
responses a polyfunctional analysis [9-11] of T cell function will be performed as previously described [11].  
Subsets of naïve (CD45RO-CD27+), effector (CD45RO+CD57+), effector memory (CD45RO+CD27-), central 
memory (CD45RO+CD27+), and terminal effector (CD45RO-CD57+) cells will be analyzed for production of 
IFNγ, TNFα, and IL-2 as well as induction of the cytolytic granule marker CD107.   
Immediately preceding each vaccination, 90 mLs of peripheral blood will be drawn into vacutainer tubes 
containing ACD.  PBMCs will be separated by density gradient centrifugation on ficoll-Hypaque.  Cryopreserved 
PBMC samples are thawed and rested overnight at 370C/5% CO2 in RPMI media containing 10% fetal calf serum.  
Cells are adjusted to 2x106/well and incubated with 1 μg/mL of each of the co-stimulatory MAbs αCD28 and 
αCD49d with or without stimulation with autologous tumor, mRNA-pulsed DCs, and autologous normal brain 
mRNA (when available)(2 μg/mL) in the presence of Brefeldin A (5 μg/mL Sigma-Aldrich, St. Louis, MO) 
monensin (1µg/mL; Golgistop, BD Biosciences, San Diego, CA), and αCD107a PE-Cy5 for 5-6 hr at 370C and 
5% CO2.  Following stimulation, cells will be treated with EDTA for 15 minutes at ambient temperature (AT, 18-
22ºC).  The cells will be washed and stained with MAbs specific for CD4 PerCP-Cy5.5-PE, CD8 APC-Cy7, 

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CD45RO PE-TR, CD27 APC, CD57 FITC, CD14/CD19 (PacBlue) and a vital-dye reagent (LIVE/DEAD Fixable 
Violet Dead Cell Stain Kit for Flow Cytometry; Invitrogen Corp., CA) for 20 minutes at RT.  After two washes, 
1xBD FACS Lysing solution (BD Biosciences, San Jose, CA) will be added and samples will be incubated for 
10 minutes at RT.  After one wash, 1xBD FACS Permeabilizing Solution 2 (BD Biosciences, San Jose, CA) will 
be added and samples incubated for 10 minutes at AT.  After one wash, cells will be stained with αCD3 
(AmCyan), αIFN-γ (PE-Cy7), αTNF-α (A700), and αIL2 (PE) for 30 minutes on ice, washed, and fixed in PBS 
containing 1% formaldehyde (Sigma-Aldrich, St. Louis, MO).  In all experiments, a negative control 
(αCD28/49d), and a positive control (SEB, 10 μg/mL, Sigma-Aldrich) will be included.  The samples are acquired 
on a custom LSRII polychromatic flow cytometer (BD Immunocytometry System, San Jose, CA) equipped for 
detection of 17 fluorescent parameters.  We are planning to collect a minimum of 500,000 total lymphocytes from 
each sample, because we expect the frequency of responding cells to be between 0.05 and 1.0%.  This number of 
events is required based on calculations performed by Dr. Holden Maecker (BD Bioscience, personal 
communication) to detect a statistically significant number of positive events that can be used for the analysis of 
the data and the characterization of the different populations.   
Ideally, we would be able to select a validated surrogate immunologic response marker for clinical efficacy, 
but no such marker has been identified to date and studies to validate such a marker would need to be large and 
prospective and would be clearly beyond the scope of this protocol.  It would be our intent, however, to 
incorporate any additional knowledge that becomes available at the time of data analysis to evaluate the relative 
biologic significance of the immune response markers that we have chosen.   
Tetramer studies will not be routinely performed because the HLA restriction of all antigens present in the 
mRNA-pulsed DCs has not been determined.  Tetramer analysis will be used, however, in patients with 
appropriate genetic haplotypes to quantitate changes in immunologic response to tumor-associated antigens 
differentially expressed in malignant brain tumors before and after vaccination as follows: IL-13R2α345-354, Her-
2369-377, survivin96-104, gp100209-217, and TRP-2180-188.  
21.9 Statistical Analysis for Polyfunctional Response 
The analysis used here will be one that has been successful at distinguishing HIV progressors and non-
progressors based on T cell phenotype [9-11]. All data will be background subtracted. For each measure, a lower 
threshold corresponding to two standard deviations above background is set to 0 based on a Poisson model 
essentially allowing T cells to be designated as positive or negative for a certain phenotypic marker. The number 
of positive phenotypic markers post-vaccination will be calculated for each patient. Additional exploratory 
analyses will be conducted using an exact binomial test that will compare treatment groups with respect to the 
proportion of patients with 5 positive markers, and 4 or more positive markers. 
21.10 Serology 
Antibody levels to specific antigens will be determined by FACS analysis of antigen immobilized on beads.  
Cellular lysate autologous tumor cells will be immobilized separately on Dynal M280 magnetic beads according 
to manufactures directions.  Beads are reacted with patient serum for 30 minutes at AT.  Washed beads are then 
developed with a fluorochrome conjugated goat anti-human polyclonal for an additional 30 minutes at AT.  Beads 
are analyzed for fluorescent intensity on a BD FACSCalibur™.  Differential levels of antibody binding from pre 
and post DC + xALT therapy samples to immobilized tumor lysate will be reported as humoral response to the 
tumor antigens.  As a further test, pooled normal brain lysate (Zyagen, Inc.) will be used to demonstrate tumor-
specificity or preabsorb normal brain binding antibodies. As a means of demonstrating specificity, serums will be 
pre-incubated with the same immobilized lysates prior to reacting with beads to absorb reactive antibodies.  
21.11 Statistical Analysis 
All data will be background subtracted and compared using paired t-tests as described above. 
 

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21.12 Toll-Like Receptor Agonist Activity 
Release of endotoxin, a TLR4 agonist, from gut microbial release into the bloodstream during 
myeloablative therapy has been shown to enhance the activation and expansion of adoptively transferred tumor-
specific lymphocytes in murine models[12].  Endotoxin levels (LPS) in patients receiving HDC + PBCT and 
NMA salvage chemotherapy will be measured in the serum before induction of chemotherapy and serially 
afterwards during immune monitoring blood draws.  The quantitative chromogenic Limulus amebocyte lysaste 
assay (QCL-1000, Whittaker M.A. Bioproducts, Walkersville, MD) will be used to measure serum LPS levels.  
Blood will be drawn aseptically into LPS-free tubes. Samples are subsequently diluted with pyrogen-free water 
and heat inactivated for 100 C for 10 minutes.  Escherichia coli 055:B5 reference endotoxin will be used for 
standard curve analysis (Whittakeer M.A. Bioproducts) and LPS levels at varying time points of therapy will be 
determined compared to baseline with a paired t-test.  
Upregulation of TLR expression and TLR signaling pathway genes in serially collected PBMCs will be 
analyzed by Oligo GEArray® Human Toll-Like Receptor Signaling Pathway Microarray allowing the profiling 
of  113 genes related to TLR-mediated signal transduction including all identified members of the TLR family[13-
15].   
21.13 Statistical Analysis 
Data analysis will be conducted using Genespring (Silicon Genetics) and intensity dependent 
normalization will be performed on entire dataset.  Triplicate samples of RNA extracted from various portions of 
tumor tissue (where sufficient material available) will be used to control for sampling variability and a threshold 
of a 2-fold change in expression relative to baseline, and a p-value cutoff of 0.05 will be performed to determine 
changes in TLR-specific gene expression. Data will be confirmed by real-time RT-PCR for a subset of TLR 
signaling pathway genes that show statistically significant changes after therapy.  The primary analysis will focus 
on pre and post HDC + PBSCT and salvage chemotherapy time points.  
21.14 Tumor Associated Antigen (TAA) Profile in Recurrent Tumors 
The identification and validation of antigens in MB/PNETs that can serve as potent tumor rejection 
antigens may be important for the development of potent and specific immunotherapy against these tumors. RNA 
amplified from tumors used in vaccine preparation and from 2nd recurrences (where biopsy or resection is 
clinically indicated for confirmatory diagnosis and sufficient tissue obtained) will be analyzed for a panel of 
common TAAs to determine the frequency of expression of these antigens in reMB/PNETs and whether 
immunotherapy directed against total tumor RNA encoded antigens modulates the expression of these genes after 
treatment.  The top 40 uniformly overexpressed transcripts in common malignancies that were not expressed in 
complementary normal tissues were determined using database mining of publically available SAGE and 
microarray analyses[16]. An analysis of MB/PNETs was not included in this data set but we will investigate the 
frequency of expression of these 40 TAAs (TAA-40) using a custom microarray chip containing the published 
Tag sequences for identity of each of these proteins (Agilent Made-to-Order Arrays, Affymetrix, Inc., Santa Clara, 
CA).  
RNA (directly isolated where sufficient material or amplified) from first and second recurrent tumors will 
be analyzed by the TAA-40 expression chip.  Tumors will be considered positive for a TAA-40 is expressed at > 
33 copies per cell and at least twofold higher than reference normal brain RNA from three donors (Zyagen, Inc.).    
21.15 Statistical Analysis 
Data analysis will be conducted using Genespring (Silicon Genetics) and intensity dependent 
normalization will be performed on entire dataset.  Triplicate samples of RNA extracted from various portions of 
tumor tissue (where sufficient material available) will be used to control for sampling variability and a threshold 
of a 2-fold change in expression relative to control (normal brain), and a 2-way ANOVA with a p-value cutoff of 
0.05 will be performed to determine changes in TAA-40 specific gene expression. Data will be confirmed by real-
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22. DATA MANAGEMENT 
22.1 Data Management and Quality Control 
The Department of Neurosurgery will be responsible for the management of clinical data. 
22.2 Laboratory Data Transmission and Accountability 
In addition to the observational clinical data, other material is collected, such as blood, tissue, and images, 
which must be transmitted, tracked, and accounted for by linking it to the appropriate patient and follow-up 
sequence.  Also, expectations for the generation of these elements and the resultant data must be set and monitored 
closely to ensure their timely collection and movement through the system.  
In the case of sample management, tissue and tissue-related data is managed by the Brain Tissue Bank.  
23. DATA AND SAFETY MONITORING PLAN 
23.1 Data Safety Monitoring Board 
The University of Florida Health Cancer Center (UFHCC) is committed to the safety of patients participating 
in clinical trials at its institution. The UFHCC is also committed to data accuracy and protocol compliance. The 
UFHCC has established an institutional plan to assure data safety and monitoring for all clinical trials at the 
University of Florida Health Cancer Center. This plan is designed to comply with policies and guidelines 
regarding data and safety monitoring from the National Institutes of Health and the National Cancer Institute.  
Data and safety monitoring takes place within the established process of protocol review and monitoring by 
the UFHCC Protocol Review and Monitoring Committee (PRMC), the Institutional Review Board (IRB), and the 
UFHCC’s Data and Safety Monitoring Board (DSMB). The DSMB is the primary agent for assuring data and 
safety monitoring.  The DSMB includes two co-chairs and multidisciplinary representation from clinical 
researchers, physicians and biostatisticians.  The DSMB includes both voting and advisory members from the UF 
Health Cancer Center, UF Health Cancer Center-Orlando Health, and the UF Proton Therapy Institute – the three 
facilities it serves. 
The UFHCC DSMB meets bi-annually. If an emergent situation arises the committee will convene a 
meeting.  All studies identified by the PRMC as requiring review by the DSMB will be monitored.  The DSMB 
will report final recommendations to the PRMC who reviews and then forwards these recommendations, along 
with any additional recommendations, to the Principal Investigator. The Principal Investigator is responsible for 
forwarding PRMC’s recommendation to the Institutional Review Board. Final responsibility and authority for 
closing or amending of such trials will rest with the PRMC and Institutional Review Board. 
Requirements for periodic data and safety monitoring are commensurate to the clinical trial’s risk and 
complexity.  The IRB, PRMC, and/or DSMB may require more frequent and/or additional monitoring to assure 
patient safety and trial integrity.  Data safety and monitoring activities continue until all patients have completed 
their treatment and until all patients have been followed beyond the time point at which study-related adverse 
events would likely be encountered. 
Circumstances that would prompt communication with the DSMB include: 
• Any unexpected death 
• Any circumstance felt by the medical monitor to warrant DSMB notification and/or input 
• A frequency of DLTs that require suspension of enrollment 
23.2 Independent Medical Monitor 
For research involving more than minimal risk (as defined in 32 CFR 219.102(i)) to subjects, an independent 
medical monitor shall be appointed by name. The medical monitor will oversee the progress of this research 
protocol, especially issues of individual subject management and safety. The medical monitor shall be 
independent of the investigative team and shall possess sufficient educational and professional experience to serve 
as the subject advocate. The medical monitor shall promptly report discrepancies or problems to the PI. They 

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shall have the authority to stop a research study in progress, remove individual subjects from a study, and take 
whatever steps are necessary to protect the safety and well-being of research subjects until the PI can assess the 
medical monitor's report.  
The Medical Monitor will review the general progress of the study in regard to the safety for the subjects in 
a written report discussed with the PI biannually.  
23.3 Independent External Monitor 
An independent external monitor will conduct data and safety monitoring for this study. The monitor will 
compare source documents with completed case report forms to ensure accuracy and tabulation of adverse events. 
The monitor will report all findings to the sponsor-investigator, who will notify the IRB when significant safety 
concerns are identified.  
The independent external monitor will conduct monitoring visits to ensure subject safety and that the protocol 
is conducted, recorded and reported in accordance with the protocol, standard operating procedures (SOPs), Good 
Clinical Practice (GCP), and applicable regulatory requirements. The monitor also provides ongoing education 
and resources to investigators and study teams to enhance data quality. The frequency of monitoring will be based 
on accrual and additional monitoring may be prompted by findings from monitoring visits, unexpected frequency 
of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of an investigator or 
the IRB. 
23.4 Principal Investigator 
This clinical research study will also be monitored internally by the PI.  In terms of internal review, the PI 
will continuously monitor and tabulate adverse events.  Appropriate reporting to the UF IRB will be made.  If an 
unexpected frequency of grade III or IV events occur, depending on their nature, action appropriate to the nature 
and frequency of these adverse events will be taken.  This may require a protocol amendment, dose de-escalation, 
or potentially closure of the study.  The PI of this study will also continuously monitor the conduct, data, and 
safety of this study to ensure that: 
• Stopping rules for toxicity and/or response are met; 
• Risk/benefit ratio is not altered to the detriment of the subjects; 
• Appropriate internal monitoring of adverse events and outcomes is done; 
• Over-accrual does not occur; 
• Under-accrual is addressed with appropriate amendments or actions; 
• Data are being appropriately collected in a reasonably timely manner. 
 
24. RISKS/BENEFITS ASSESSMENT 
24.1 Potential Benefits 
Based on experience with immunotherapy and our previous clinical trials, DC-based immunotherapy may be 
of benefit to subjects with reMB/PNETs.  Of course, because individuals respond differently to therapy, no one 
can know in advance if it will be beneficial in an individual case.  The potential benefits may include reduction 
and/or remission of the subject’s brain cancer.  Because this procedure is experimental, it cannot be guaranteed 
that subjects will receive any benefit as a result of participating in this research study.  The information collected 
in this research may help scientists better understand the mechanisms involved in the immune system’s ability to 
fight cancer.  If such an understanding comes from this research, then it may benefit society by furthering the 
development of improved treatment methods for human malignant brain tumors in the future. 

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24.2 Potential Risks 
24.2.1 ALLERGIC REACTIONS TO DC IMMUNIZATION OR TTRNA-XALT 
Injection of antigen presenting cells may result in an allergic reaction, which could include redness and 
swelling at the injection site, itching, hives, low blood pressure, difficulty breathing, or in the most extreme 
circumstances, death.  In addition, if the immune system becomes overly activated, potential discomforts may 
include pain, redness and swelling at the injection site.  The risks associated with the injection of autologous 
lymphocytes for immunotherapy in humans are currently unknown.  The best current assessment of potential risks 
of TTRNA-xALT can be gathered from the extensive experience gained at our institution and others in autologous 
PBSCT using mobilized progenitors.   We have experienced no grade III or IV toxicities associated with infusion 
of autologous lymphocytes in patients who have received mobilized PBSCT.  A recent review describing 
management of toxicities associated with this procedure describes only complications associated with the 
consolidation and conditioning regimens utilized in stem cell transplantation, as well as the post-transplant period 
where patients exhibit profound neutropenia. Patients may experience an allergic reaction to preserved cells or 
other transfusion associated side effects such as pain at the injection site, mild swelling or edema, hypotension, 
or shortness of breath. 
24.2.2 CEREBRAL EDEMA 
Cerebral edema may be secondary to the disease process itself, the surgical procedure, necrosis from 
previous radiation, or inflammation due to immune infiltration of the brain or destruction of tumor cells.  
Symptoms may include, but are not limited to, severe headache, confusion, lethargy, unresponsiveness, coma, or 
focal neurological deficits.  Patients will be monitored throughout the course of the study and those patients with 
any signs or symptoms of cerebral edema may need their steroid doses increased, treatment with an osmotic 
diuretic, or surgical decompression.  Edema that fails to respond to aggressive therapy may lead to permanent 
neurological impairment.  The probability of this risk can be predicted to some degree based upon tumor size, 
location, pre-operative neurological impairment, and post-operative course prior to DC injections. Patients will 
be monitored throughout the course of the study.  
24.2.3 INFECTION 
The DC injections or the TTRNA-xALT may include the risk of infection due to potential contamination 
of the DCs or leukocyte product in the laboratory.  This may result in localized redness, swelling, or induration 
at the injection site.  In the most extreme situation, this may lead to systemic bacterial/fungal sepsis and possibly 
death.  The probability of this risk is relatively low, given the small injection volume (1 mL divided between >2 
intradermal locations) and the fact that the DCs will be strictly tested for sterility prior to each injection.  The risk 
of infection due to potential contamination of the DCs in the laboratory will be minimized by biosafety quality 
assurance and testing.  All cell cultures will be handled under sterile conditions in a core tissue culture facility 
dedicated to the processing of human cells.  Prior to injection into patients, DCs must pass sterility tests in 
thiglycolate broth, tryptic soy blood agar, and inhibitory Sabouraud agar.  Following injections, patients will be 
monitored throughout the course of the study for any signs and symptoms of infection. There have been no 
infections to date in the recent VICTORI (IRB #3108-05-9R4) or ACTIVATE (IRB #5421-05-1R1) clinical trials 
testing similar approaches in a similar patient population.  If an active infection is suspected, patients will be 
cultured and treated with appropriate antibiotics.  
24.2.4 DELAYED AUTOIMMUNE DISEASES 
It is possible that delayed autoimmune disease(s) may develop as a result of injection with DCs or TTRNA-
xALT.  This means that the immune system may be stimulated to attack natural tissue in the body.  Animal studies 
have reported the development of autoimmunity in the context of vaccination and recovery from lymphopenia.  
However, our current experience with DC vaccination in glioma patients has not demonstrated evidence of 
autoimmunity in treated patients.  It therefore, is unknown what the risk of delayed autoimmune disease is for 
this study.  

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24.2.5 PHLEBOTOMY 
Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or swelling in 
the area of the insertion, bleeding at the site of the needle puncture, light headedness, fainting and very rarely, 
local infection, which may be severe. These risks are reduced by the fact that the blood will be drawn by a qualified 
physician, nurse or phlebotomist (a professional trained to draw blood). 
24.2.6 LEUKAPHERESIS 
As with any donation of blood, a variety of minor reactions may occur with leukapheresis, which include 
fainting, dizziness, or nausea.  Uncommon but serious complications may also result, which include bleeding, 
infection, an adverse reaction to the anticoagulant or replacement fluids, hypocalcemia, hypotension, shock, 
convulsions, air emboli, heart failure, or the inability to transfuse blood back into the patient.  These risks are 
reduced by the fact that the procedure will be performed by qualified staff at a specialized clinical hemapheresis 
unit.  Patients will be carefully monitored throughout the procedure by trained nursing and medical staff.  Calcium 
gluconate (2 mg PO) will be given to minimize the risks of hypocalcemia, fluid supplementation will be given to 
minimize hypotension, and blood will be routinely screened for HIV, hepatitis, and syphilis to minimize the risk 
of transmitting infection. 
24.2.7 MRI 
The risks and/or discomforts associated with the performance of MRI include the anxiety produced from 
being in a tight, enclosed space (claustrophobia).  In addition, the machine operates using a large and powerful 
magnet.  The magnetism of the machine attracts certain metals: therefore, people with these metals in their bodies 
(specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods or plates) will be 
excluded from the study. Patients will also be checked to make sure that they do not bring any metal objects into 
the MRI facility.  Dental fillings are less affected by the magnetic fields generated and are therefore permitted.  It 
will be asked that patients let the physicians conducting this study know of any metal in their bodies other than 
dental fillings.   
24.3 Allergic Reactions to Contrast Agents 
During the MRI, patients will be given a contrast agent.  The agent is given routinely to obtain enhanced 
MRI scans of the brain.  The agent is administered through the vein and requires the placement of an IV catheter.  
The catheter placement is similar to drawing blood except that the catheter remains in the vein during the time 
the agent is actively delivered.  The risks of a blood draw and insertion of a catheter are similar.  There have been 
a few, rare cases of allergies to the agent used in MRI contrast enhanced scans. Patients with any known severe 
allergies to contrast agents will be excluded from the study.  Patients with mild allergies (i.e., rash only) will be 
pretreated with Tylenol and Benadryl prior to injection of the contrast agent. 
 
 

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24.4 GM-CSF and G-CSF Risks 
 
Risks and side effects related to the Filgrastim (G-CSF) include those which are: 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side effect 
that is expected to occur in 20% or 
fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
 
• Local irritation (skin) at 
injection site 
• Ache or pain inside the 
bones, increased levels of 
liver enzymes and uric acid 
in the blood, low number of 
platelets in the blood 
• Allergic reaction, low fever 
• Enlargement or rupture of 
the spleen  
• Worsening of pre-existing 
skin rashes 
• Temporary hair loss  
• Inflammation of a blood 
vessel in the skin 
 
Risks and side effects related to Sargramostim (GM-CSF) include those which are: 
Likely: 
Less Likely: 
Rare, but Serious: 
• Headache  
• Bone pain  
• Muscle and joint pains  
• Fever and Chills  
• Rash and itchiness  
• A feeling of discomfort or 
not feeling well and/or 
tiredness  
 
• Stomach or abdominal pain or 
cramps  
• Weakness  
• Loss of appetite  
• Nausea and/or vomiting  
• Diarrhea  
• Excessive sweating  
• Inflammation of a vein through 
which the drug was given  
• Redness and pain at the injection site  
• Weight gain  
•  Fewer platelets in the blood.   A low 
number of platelets causes you to 
bruise and bleed more easily  
• Increase in the blood of certain 
enzymes or bilirubin (a substance 
that comes from the liver breaking 
down waste products) which could 
indicate liver irritation or damage  
• Elevation in the blood of creatinine 
which normally is removed from the 
blood by the kidney and could 
indicate kidney damage  
• Fluid build-up in the tissues usually 
of the lower legs  
• Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, and a rapid heart beat  
• A severe reaction which can 
cause shortness of breath, a low 
blood pressure, a rapid heart 
rate, fever, a feeling of warmth 
and back pain which may occur 
only with the first dose and not 
with further doses  
• An abnormally rapid heat beat  
• Leakage of fluid into the lungs 
which may result in shortness of 
breath and difficulty breathing 
and/or leakage of fluid into body 
tissues with puffiness of legs, 
arms or abdomen, weight gain 
and a drop in blood pressure  
• Inflammation of the lungs which 
may lead to pain and shortness 
of breath  
• A build-up of fluid around the 
heart which may be painful 
 
 

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24.5 Unknown Risks 
The overall risk classification of this research is unknown.  Clinical trials using DC-based immunizations 
on brain tumor patients only recently published in the literature. From our experience with 40 patients in ongoing 
and previous trials we have not seen any toxicities or serious unexpected AEs.  
 
24.6 Confidentiality 
Participation in research investigations may result in a loss of confidentiality.  However, all data from 
preoperative and postoperative evaluations will be coded to protect the patient’s identity.  The coding and the 
results of these studies will be available only to the individuals involved with the study, the clinical staff 
administering the study, representatives of the National Institutes of Health, and representatives of the U.S. Food 
and Drug Administration.  Any publications resulting from this study will not use patient identifying data. 
 
24.7 Treatment Alternatives & Financial Reimbursement 
Alternative treatments for recurrent malignant brain tumors include additional surgery, radiation, and/or 
chemotherapy.  If the patient chooses not to participate in this trial, they certainly may seek alternative treatment.  
If the patient fails treatment through this trial, these alternatives may still be available to the patient.  There will 
be no financial reimbursement or compensation to subjects for study participation. 
25. KEY STUDY PERSONNEL 
Duane A. Mitchell, M.D., Ph.D. (Principal Investigator) is Associate Professor of Neurosurgery, 
Neuroscience, Pathology, and Immunology, Co-Director of the Preston A. Wells, Jr. Center for Brain 
Tumor Therapy, and Director of the University of Florida Brain Tumor Immunotherapy Program.  Dr. 
Mitchell has considerable translational research experience involving the immunologic treatment of cancer.  Dr. 
Mitchell is a graduate of the prestigious NIH-sponsored Medical Scientist Training Program (MD/PhD Program) 
and received his Ph.D. under the guidance of Dr. Eli Gilboa, a world-renowned tumor immunologist and pioneer 
of the RNA transfected DC platform that will serve as the antigen presentation platform in this investigation.   He 
has devoted his research efforts on the development of immunotherapeutic approaches to the treatment of 
malignant brain tumors, and has served as PI on seven FDA and IRB approved Phase I/II clinical trials 
investigating immunotherapy in patients with malignant brain tumors.  He is the Chair of the Immunotherapy 
Working Group for the NCI Pediatric Brain Tumor Consortium and a panel member of the Immunotherapy 
Working Group for the NCI Brain Malignancy Steering Committee. The study outlined in this proposal will be 
conducted under FDA IND-BB-14058 covering the use of adoptive T cell therapy and amplified total tumor RNA-
pulsed DCs in pediatric patients with recurrent MB/PNETs.   He will be responsible for supervising all aspects of 
the study; including writing and disseminating all study results and reports. He will also be ultimately responsible 
for ensuring the regulatory compliant execution of this trial and coordinating the multidisciplinary interactions of 
the investigators and administrators involved with this study.  Overall coordination of the multi-site phase II trial 
will be assisted by Dr. Gerald Grant, Stanford University (Neurosurgery Chair) and Sri Gururangan, University 
of Florida (Neuro-Oncology Chair).  A Leadership Plan for this collaboration with Dr. Mitchell functioning as 
lead PI and Immunotherapy Chair has been developed and is outlined below (Section 21.1 Leadership Plan). 
 
William Slayton, M.D. is Professor, Division Chief, and Program Director of Pediatric 
Hematology/Oncology at the University of Florida with over 20 years of experience in the care of pediatric 
patients.  Dr. Slayton has an active clinical protocol involving the use of high-dose chemotherapy followed by 
autologous stem cell rescue in children with CNS tumors and extensive experience in treating children with CNS 
tumors using intensive chemotherapy that will be utilized as the backbone for the clinical trial design investigating 
the safety and immunologic effects of adoptive lymphocyte transfer and DC vaccination during hematopoietic 

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recovery from high-dose chemotherapy.  http://hemonc.pediatrics.med.ufl.edu/faculty-and-staff/attending-
physicians/dr-william-slayton/ 
 
John R. Wingard, M.D. is the Price Eminent Scholar and Professor of Medicine, Deputy Director for 
Research of the UF Health Cancer Center, and Director of the Bone Marrow Transplant Program for the 
University of Florida.  Dr. Wingard is a renowned expert in bone and stem cell transplantation as well as active 
clinical researcher. He also oversees the pediatric and adult stem cell transplantation programs and in such 
capacity coordinates the care of patients receiving high-dose chemotherapy and stem cell transplantation at the 
University of Florida including children with CNS tumors.  Dr. Wingard has extensive experience in the collection 
and dissemination of autologous and allogeneic cellular products to patients at multiple FACT-accredited 
institutions and will assist Dr. Mitchell in the multi-site coordination of collection of leukapheresis specimens, 
peripheral blood stem cell products, bar-coded storage and dissemination of cellular products, and batch records 
for the cellular products generated on this protocol.  The UF stem and bone marrow transplant program maintains 
state-of-the-art facilities and technologies for autologous cell product delivery to pediatric and adult patients. 
http://hemonc.medicine.ufl.edu/about-us/meet-the-team/john-r-wingard-md/ 
  
David R. Nelson, M.D. is Professor of Medicine, Molecular Genetics and Microbiology, Director, UF 
Clinical and Translational Science Institute, and Associate Dean for Clinical Research.  He has met with Dr. 
Mitchell several times to outline the many facets of this protocol that can leverage the extensive clinical research 
infrastructure supported by the NIH-funded CTSI at the University of Florida.  Dr. Nelson will oversee the 
coordination of the multi-site collection and registration of clinical data into a clinical database, coordinate the 
availability of the clinical research hospital and infusion center for this protocol, as well as coordinate the 
interaction between clinical research sites.  Additionally, the CTSI maintains extensive biorepository and tissue 
distribution capabilities as one of only 12 CAP-certified biorepositories in the United States.  The CTSI-supported 
biorepository and distribution capabilities will be leveraged to coordinate the collection of tumor tissues and 
leukapheresis specimens from participating centers and disseminate autologous vaccine products to subjects 
enrolled at sites outside of the UF health network.   
https://www.ctsi.ufl.edu/ 
http://biorepository.pathology.ufl.edu/ 
http://gastroliver.medicine.ufl.edu/hepatology/faculty-staff/david-r-nelson-m-d/ 
 
Scott Rivkees, M.D. (Other Significant Contributor) is Professor and Chairman of Pediatrics and Chair of 
the Child Health Research Institute at the University of Florida. Dr. Rivkees has met several times with Dr. 
Mitchell to coordinate the Re-MATCH protocol within the extensive UF pediatric health system.  Dr. Rivkees 
currently oversees the active partnership between the UF and Orlando Regional Medical Center (ORMC) 
including Arnold Palmer Children’s Hospital. ORMC extends the patient network of the UF health system by 
over 2 million subjects, and Dr. Rivkees is attending physician at both UF/Shands medical center and Arnold 
Palmer Children’s with active on-site rotating work between both centers.  He will facilitate the interactions 
between Dr. Mitchell and his clinical research team with the pediatric oncology and clinical research teams both 
at UF and ORMC to enhance recruitment and enrollment of subjects served by the Florida health system.  He will 
also ensure that all physical and intellectual resources available within the Department of Pediatrics at the 
University of Florida are available to Dr. Mitchell in support of this protocol.  
http://research.pediatrics.med.ufl.edu/researchers/research-faculty/scott-rivkees/ 
 
Brian D. Cleaver, Ph.D. is Director of the Powell Gene Therapy Center (PGTC) and Human Applications 
Laboratory at the University of Florida.  Dr. Cleaver has extensive experience (>10 years) in the FDA-
regulated cGMP manufacturing of cellular and gene vector products for use in clinical trials.  He has directed 

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GMP manufacturing of products for use at single-site, multi-site, and even international clinical studies and is an 
expert in the regulatory compliant manufacturing of GMP materials.  Dr. Cleaver and his staff within the PGTC 
will be responsible for the generation of cellular products used in this protocol and the regulatory oversight, record 
keeping, and release of qualified cellular products for this study.   
http://www.gtc.ufl.edu/core/gtc-apps.htm 
http://urology.ufl.edu/about-us/faculty-staff-directory/brian-d-cleaver-phd/ 
 
 
Anthony T. Yachnis, M.D. is Professor of Pathology and Medical Director of Anatomical Pathology at the 
University of Florida.  He is a board-certified neuropathologist with over twenty years of clinical experience. In 
such capacity, he reviews and performs confirmatory diagnosis on all brain tumor specimens collected at 
University of Florida (>600 annually) and will ensure the pathologic eligibility criteria for patients enrolled in 
this study are met. He will also evaluate the histochemical analysis of lymphocytic infiltrates in tumor specimens, 
and perform all neurotoxicity evaluations.  Dr. Yachnis will interact with the study team in the coordination of 
collection of tumor materials collected at the UF site and will perform the confirmatory diagnostic evaluation of 
specimens collected from external sites. 
http://pathlabs.ufl.edu/team/pathologists/yachnis-a 
 
William A. Friedman, M.D. (Other Significant Contributor) is Professor and Chairman of Neurosurgery at 
the University of Florida and Co-Director of the Preston A. Wells, Jr. Center for Brain Tumor Therapy.  
Dr. Friedman is a highly experienced neurosurgeon specializing in the care of patients with malignant brain 
tumors. As Co-Director of the Preston Wells Center with Dr. Mitchell, his major interests are in the advancement 
of novel therapeutics for pediatric and adult patients with malignant brain tumors.  Dr. Friedman’s role will be to 
facilitate the utilization of the vast financial, physical, and environmental resources within the Department of 
Neurosurgery and Preston Wells Brain Tumor Center in support of this protocol.  He will meet regularly with Dr. 
Mitchell in the coordination of this study and ensure that all institutional resources are leveraged appropriately.  
Dr. Friedman is also actively overseeing the partnership with the Orlando Regional Medical Center’s 
neurosurgical practices and thus will be able to assist in the recruitment and enrollment of subjects from the 
ORMC network. Additionally, Dr. Friedman will ensure that the clinical research and regulatory staff of the 
department are available in support of this protocol including requisite CRC, regulatory, administrative, and 
nursing support.  Dr. Mitchell and Friedman are coordinately responsible for staffing any additional specialized 
needs in support of the research mission of the Preston A. Wells, Jr. Center for Brain Tumor Therapy.  In such 
capacity, up to $20M in unrestricted funds are available to Drs. Mitchell and Friedman to support clinical research 
activities.  The capacity to support unforeseen budget shortfalls from the clinical trial award supporting this 
protocol is an additional administrative role that Dr. Friedman would facilitate in collaboration with Dr. Mitchell.  
http://neurosurgery.ufl.edu/faculty-staff/our-faculty/william-a-friedman-md/ 
http://neurosurgery.ufl.edu/faculty-staff/clinical-research-staff/ 
http://news.medinfo.ufl.edu/articles/lead-story/10-million-wells-foundation-gift-will-enable-uf-to-speed-brain-
tumor-remedies/ 
 
Elias Sayour, M.D. is a pediatric oncologist who conducted his research fellowship on the immunotherapy 
of malignant brain tumors.  Dr. Sayour will function as an integrative co-investigator at the University of 
Florida. He will assist in the enrollment, evaluation, and medical management of patients enrolled, and in the 
evaluation of clinical data and laboratory analysis on acquired tissue and blood specimens.    
 
Jeffrey Drake is a research associate with considerable experience in molecular biology techniques and cell 
culture.  He will be responsible for working with the cGMP facility and staff in the generation of clinical-grade 
RNA and the generation of autologous dendritic cells and tumor-specific lymphocytes.   

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Marcia B. Hodik, RN, BSHS, CCRC is a registered nurse with over 20 years of pediatric nursing 
experience.  She has functioned as a study coordinator for Gastroenterology and Hepatology. She currently holds 
certification as a Certified Clinical Research Coordinator and is the president of the local ACRP Chapter.  She 
will be responsible for screening and enrolling patients, ensuring protocol compliance and collecting and 
recording study data.  
 
 
Paul Kubilis, MS is a biostatistician dedicated full-time to research efforts within the Department of 
Neurosurgery. He is committed to delivering understandable and useful results that help investigators achieve 
their research goals. He has extensive knowledge in study design, data analysis and presentation of data for 
publication.  He will collaborate with Dr. Mitchell on data analyses and manuscript preparation.  
 
25.1 Key Study Personnel External Sites 
CHILDREN’S NATIONAL MEDICAL CENTER, WASHINGTON, D.C.  
111 MICHIGAN AVE., N.W. 
WASHINGTON, D.C. 20010 
http://www.childrensnational.org/ 
 
Roger J. Packer, M.D.  is Professor of Neurology & Pediatrics, Senior Vice President of the Center for 
Neuroscience, and Director of the Brain Tumor Institute at Children’s National Medical Center in 
Washington, D.C.  Dr. Packer is a renowned pediatric neuro-oncologist that leads the brain tumor program at 
CNMC, one of the nation’s leading pediatric medical centers.  He has been a colleague and associate of Dr. 
Mitchell’s for several years through interactions within the NCI-funded Pediatric Brain Tumor Consortium 
(PBTC) and has a strong interest in the implementation of novel therapeutics for children with malignant brain 
tumors. He will supervise the implementation of the Re-MATCH protocol within CNMC and ensure that the vast 
expertise, infrastructure, and resources that the center maintains in support of the treatment of pediatric patients 
is appropriated in support of this protocol.  Dr. Packer will be available to assist Dr. Eugene Hwang in the routine 
care 
of 
patients 
enrolled 
on 
this 
protocol 
as 
well. 
http://www.childrensnational.org/research/faculty/bios/cnr/packer_r.aspx 
 
Anthony Sandler, M.D. is the Diane and Norman Bernstein Professor of Pediatric Surgery, Senior Vice 
President and Surgeon-in-Chief of the Joseph E. Robert Center for Surgical Care, and Principal 
Investigator of the Immunology Initiative in the Sheik Zayed Institute at Children’s National Medical 
Center.  Dr. Sandler’s primary interest is in the immunologic treatment of pediatric brain tumors.  The Shiek 
Zayad Institute at CNMC was established with a $150 million philanthropic gift to advance novel therapeutics 
for pediatric patients.  Dr. Sandler has hosted Dr. Mitchell as a visitor to the Shiek Zayad Institute to tour the 
outstanding basic and clinical research facilities established at CNMC.  In addition to his strong scientific and 
clinical interests in immunotherapy, Dr. Sandler is an experienced pediatric neurosurgeon.  He will oversee the 
surgical obtainment and transfer of tumor specimens of suitable quality for vaccine preparation.  He will also be 
responsible for the routine pre- and post-operative care of subjects enrolled on the Re-MATCH protocol.   
http://innovationinstitute.childrensnational.org/about-us/team/1001 
 
Eugene I. Hwang, M.D. is a pediatric neuro-oncologist and Director of the Pediatric Neuro-Oncology 
Fellowship Program at Children’s National Medical Center.  Dr. Hwang received his pediatric neuro-
oncology fellowship training at Duke University and worked with Dr. Mitchell during the development of the Re-
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novel initiatives within the Pediatric Brain Tumor Consortium.  Dr. Hwang will play an active role in the care of 
patients enrolled on this protocol and in the integration of the Re-MATCH protocol with the outstanding clinical 
research team at CNMC.  He will also oversee the collection and transport of leukapheresis products to the GMP 
facility at University of Florida for vaccine and T cell preparation and be directly responsible for vaccine 
administration for subjects enrolled at CNMC.  
http://www.childrensnational.org/findadoctor/profiles/eugene-hwang-4385.aspx 
 
CHILDREN’S HOSPITAL LOS ANGELES 
4650 SUNSET BLVD 
LOS ANGELES, CA 90027 
http://www.chla.org 
 
Girish Dhall, M.D. is Clinical Director of Neuro-Oncology at Children’s Hospital Los Angeles.  He is an 
experienced pediatric hematology/oncologist who will oversee the management of subjects enrolled on the 
protocol at CHLA.  Dr. Dhall will also direct the collection and dissemination of leukapheresis products for 
vaccine and T cell preparation to the University of Florida and the administration of vaccine products to subjects 
enrolled at CHLA.  
http://www.chla.org/site/apps/kb/cs/contactdisplay.asp?c=ipINKTOAJsG&b=3832751&sid=ewJXIjPWJfLYKd
P1KzG&r=1 
 
Mark Krieger, M.D. is Division Chief of Pediatric Neurosurgery and Director of the Neurosurgery 
Fellowship Program at CHLA.  Dr. Krieger is a highly-experienced pediatric neurosurgeon at one of the top 
ranked pediatric hospitals in the nation.  He will oversee the protocol compliant collection and dissemination of 
tumor materials suitable for vaccine preparation at the CHLA site and in his duties as Division Chief will ensure 
the proper pre- and post operative management of subjects enrolled on this protocol.  Dr. Krieger will also ensure 
coordination of information with the Neurosurgical Chair of the protocol, Dr. Gerald Grant at Stanford University.   
http://www.chla.org/site/apps/kb/cs/contactdisplay.asp?c=ipINKTOAJsG&b=3832751&sid=dvKTKhPVIiI5If
MQJrF&r=1 
 
25.2 Investigator Leadership Plan 
Drs. Mitchell, Grant, and Gururangan have been collaborators on several initiatives in experimental 
therapeutics for pediatric brain tumors for more than a year now, and are co-investigators on a grant award from 
the Pediatric Brain Tumor Foundation of the United States that has provided support during the preclinical phases 
of this investigation and clinical trial planning period.  These individuals have jointly developed the experimental 
strategy proposed in this application. This existing infrastructure and high-level expertise will be leveraged to 
integrate the novel immunotherapeutic platform that is the focus of this investigation.  Drs. Grant and Gururangan 
have in the past and will continue to jointly oversee the surgical and post-surgical clinical care of the patients 
enrolled on this protocol. 
This protocol will be carried out under an existing FDA-approved IND for use of amplified total tumor RNA 
loaded DCs in patients with malignant brain tumors (FDA IND-BB-14058) using standardized SOPs developed 
within Dr. Mitchell’s laboratory that are centralized within the UF BTIP.    
 Dr. Mitchell and the multi-site key personnel will be responsible for informed patient consent enrollment of 
subjects for this investigation. Dr. Gururangan will ensure the informed consent of procedures involving induction 
chemotherapy and HDC + PBCT, and Dr. Mitchell will ensure the informed consent of experimental 
immunotherapy consisting of DC + xALT therapy.  Dr. Mitchell and his group will be responsible for all 
experimental procedures involving generation, quality assurance and quality control assessment, and 
administration of DC + xALT therapy in patients with reMB/PNETs. Drs. Grant and Gururangan will be 

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responsible for the provision of neurosurgical and adjuvant chemotherapy respectively according to current 
practice guidelines.  No deviation from standard of care provision of therapy other than the addition of 
immunotherapy is mandated by enrollment on this protocol.  During admission to the BMT unit, HDC + 
PBSCT will be provided by the local primary team with Dr. Mitchell coordinating the interaction between these 
treating physicians and the research study team.  Dr. Mitchell will be responsible for ensuring that all study data 
is accurately documented within patient CRFs by the research nurse and study coordinator.  All AEs and serious 
adverse events (SAE) will be reviewed jointly by Drs. Mitchell, and Gururangan to assess whether deemed 
vaccine related and reporting to the DSMB when deemed necessary. 
Drs. Mitchell, Gururangan, and external site key personnel will have a standing monthly conference call where 
this protocol and other collaborative projects are thoroughly reviewed. All relevant protocol issues including 
amendments, accrual, and any treatment related events are discussed during this meeting.   
The detailed budget for this proposal has been allocated to cover the supply costs and personnel efforts 
required to meet the study objects.  Dr. Mitchell, as the PI, will function as the coordinating investigator for supply 
expenditures related to this study and will be responsible for timely submission of required study progress reports. 
New intellectual property relative to this project is not foreseen, and therefore it is unlikely that additional 
disclosures will result from this project. Publication decisions and authorship issues will be decided according to 
the relative contributions of the PIs.  
26. WITHDRAWAL FROM THE PROTOCOL  
In this protocol, children being treated for grave and often fatal illness will be treated. Reasons for withdrawal 
from the study are expected to fall into three general categories. First, being treated on this protocol will put the 
family of the treated child under social and financial hardship, since many of the children treated at UF are referred 
from a distance. This often means an interruption of income for one or both of the parents and difficulties in 
providing care for siblings, if there are any. Since the protocol spans over 1.5 years (beginning with surgical 
resection) it may become too difficult for some families to complete planned treatment. Second, a significant AE 
may convince the child’s family and the child not to continue with the study. Third, a failure to cooperate with 
the treatment team or treatment schedules may lead to an investigator’s need to remove a child from the study. 
Any data collected from cases where the subject is withdrawn will be retained and the collected information 
regarding this case will be included in the reports of the study along with a brief reason for withdrawal from the 
study. 
27. MODIFICATIONS TO THE PROTOCOL 
The investigator/sponsor shall submit a protocol amendment describing any change in the Phase II trial that 
affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. 
Changes in the protocol will be distributed to all investigators and persons responsible for the conduct of the 
study in advance of the announced date of change. Where necessary, training will be provided and records of the 
training kept if the change is significant enough to require it. 
28. CONTINUING REVIEW AND FINAL REPORT 
A. The protocol will undergo continuing review and approval, at least annually, with the UFIRB.  Once 
approved by the UFIRB, notification will be submitted to the USAMRMC Office of Research Protections 
(ORP) Human Research Protections Office (HRPO) for approval.  Following completion of the study, a 
final report will be submitted to the UF IRB and HRPO as soon as these documents become available. All 
investigators will remain current with the Collaborative Institutional Training Initiative (CITI). 
B. Case report forms will be used to collect data for each subject and a copy of these forms has been submitted 
as Section 28. (See below). All case report forms have been coded to protect confidentiality of the subject. 
Study records will be kept confidential as required by law. The subject will not be identified by name, 

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social security number, address, telephone number, or any other direct personal identifier in study records 
disclosed outside of UF. For records disclosed outside of UF, a unique code number will be assigned.  
C. Study team (PI, Co-PIs, co investigators, study coordinator) will adhere to the following requirements and 
responsibilities issued by the USAMRMC ORP HRPO: 
 
1) The protocol will be conducted in accordance with the protocol submitted and approved by the 
USAMRMC ORP HRPO and will not be initiated until written notification of approval of the 
research project is issued by the USAMRMC ORP HRPO. 
2) Accurate and complete study records will be maintained and made available to representatives of 
the US Army Medical Research and Material Command as part of their responsibility to protect 
human subjects in research. Research records will be stored in a confidential manner so as to 
protect the confidentiality of subject information. 
3) The knowledge of any pending compliance inspection/visit by the FDA, PHRP, or other 
government agency concerning clinical investigation research, the issuance of Inspection Reports, 
FDA From 483, warning letters, or actions taken by any Regulatory Agencies, including legal or 
medical actions, and any instances of serious or continuing noncompliance with the regulations or 
requirements will be reported immediately to USAMRMC ORP HRPO. 
29. REFERENCES 
1. Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, et al. (2004) Results of a phase 1 study 
utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults 
with brain cancer. Neuro-oncol 6: 236-246. 
2. Caruso DA, Orme LM, Amor GM, Neale AM, Radcliff FJ, et al. (2005) Results of a Phase I study 
utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 
neuroblastoma. Cancer 103: 1280-1291. 
3. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, et al. (2008) Adoptive cell therapy for patients 
with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative 
regimens. J Clin Oncol 26: 5233-5239. 
4. Gururangan S, Krauser J, Watral MA, Driscoll T, Larrier N, et al. (2008) Efficacy of high-dose 
chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma. Neuro 
Oncol 10: 745-751. 
5. Broniscer A, Ke W, Fuller CE, Wu J, Gajjar A, et al. (2004) Second neoplasms in pediatric patients 
with primary central nervous system tumors: the St. Jude Children's Research Hospital 
experience. Cancer 100: 2246-2252. 
6. Newell DR, Pearson AD, Balmanno K, Price L, Wyllie RA, et al. (1993) Carboplatin 
pharmacokinetics in children: the development of a pediatric dosing formula. The United 
Kingdom Children's Cancer Study Group. J Clin Oncol 11: 2314-2323. 
7. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG (1990) Response criteria for phase II 
studies of supratentorial malignant glioma. Journal of Clinical Oncology 8: 1277-1280. 
8. Galanis E, Buckner JC, Maurer MJ, Sykora R, Castillo R, et al. (2006) Validation of neuroradiologic 
response assessment in gliomas: measurement by RECIST, two-dimensional, computer-assisted 
tumor area, and computer-assisted tumor volume methods. Neuro-Oncology 8: 156-165. 
9. Betts MR, Gray CM, Cox JH, Ferrari G (2006) Antigen-specific T-cell-mediated immunity after HIV-
1 infection: implications for vaccine control of HIV development. Expert Review of Vaccines 5: 
505-516. 
10. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al. (2006) HIV nonprogressors 
preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781-4789. 

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11. Betts MR, Exley B, Price DA, Bansal A, Camacho ZT, et al. (2005) Characterization of functional 
and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection 
after HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of 
America 102: 4512-4517. 
12. Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, et al. (2007) Microbial translocation 
augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 
signaling. J Clin Invest 117: 2197-2204. 
13. Akira S, Sato S (2003) Toll-like receptors and their signaling mechanisms. Scand J Infect Dis 35: 
555-562. 
14. Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. 
Immunol Lett 85: 85-95. 
15. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21: 335-376. 
16. Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, et al. (1999) Analysis of human 
transcriptomes. Nat Genet 23: 387-388. 
 
 
 

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30. APPENDICES 
30.1 Referenced Documents  
 
UFBTIP 
IDENTIFIER 
DOCUMENT TITLE 
BR-UFBTIP-001 
Isolation of Peripheral Blood Mononuclear Cells (PBMC) Following Leukapheresis 
BR-UFBTIP-002 
Production of Total Tumor RNA Transfected Dendritic Cell Product 
BR-UFBTIP-003 
Procedure for the Production of Total Tumor RNA Specific T Cell Product 
BR-UFBTIP-004 
Non-Adherent Cell Freezing Procedure 
SDW-UFBTIP-002 
DC Vaccine Administration 
SDW-UFBTIP-003 
ALT Vaccine Administration 
SDW-UFBTIP-004 
Performance Status Assessment 
SOP-UFBTIP-100 
Assay for Dendritic Cell and T cell Phenotype 
SOP-UFBTIP-102 
RNA Extraction from total tumor sample in BSC 
SOP-UFBTIP-103 
Small Scale cDNA Production Using Total Tumor RNA From Patient Using Reverse 
Transcriptase  
SOP-UFBTIP-104 
Real Time PCR Assay to Determine the Presence of Housekeeping Genes in the 
cDNA From Total Tumor RNA 
SOP-UFBTIP-105 
Large Scale cDNA Production Using Total Tumor RNA From Patient Using Reverse 
Transcriptase 
SOP-UFBTIP-106 
Check of Large-Scale Reverse Transcription Reaction by PCR 
SOP-UFBTIP-107 
Large Scale PCR Amplification of cDNA from Total Tumor RNA 
SOP-UFBTIP-108 
Small Scale Amplified DNA Clean Up Using Qiaquick Purification Kit 
SOP-UFBTIP-109 
Small Scale IVT Reaction From Small Scale DNA Clean Up of the Large scale PCR 
Amplification using T7 mMessage mMachine Kit 
SOP-UFBTIP-110 
Clean Up of Small Scale IVT RNA with RNeasy kit from Qiagen 
SOP-UFBTIP-111 
cDNA Synthesis From Small Scale IVT RNA 
SOP-UFBTIP-112 
Real Time PCR Assay to Determine the Presence of Housekeeping Genes in the 
Small Scale IVT RNA 
SOP-UFBTIP-113 
Large Scale Clean Up of Large Scale PCR Amplification using Qiagen PCR 
Purification Kit 
SOP-UFBTIP-114 
Small Scale IVT Reaction From Small Scale DNA Clean Up of the Large scale PCR 
Amplification using T7 mMessage mMachine Kit 
SOP-UFBTIP-115 
Clean Up of Small Scale IVT RNA with RNeasy kit from Qiagen 
SOP-UFBTIP-116 
Procurement and Transport of the Tissue Sample From the Surgical Suite to the 
Laboratory 
SOP-UFBTIP-119 
RNA Release Criteria 
SOP-UFBTIP-120 
External Tissue Collection, Snap Frozen 
SOP-UFBTIP-121 
Leukapheresis Product Transport and Receipt Procedures 
SOP-UFBTIP-122 
Preparation of RNA Transfected DC Product for QC Testing 
SOP-UFBTIP-123 
Preparation of RNA Stimulated T Cell Product for QC Testing 
SOP-UFBTIP-124 
Procedure for DC Vaccine Preparation 
SOP-UFBTIP-125 
Procedure for Preparation of TTRNA-ALT for Adoptive Transfer 

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UFBTIP 
IDENTIFIER 
DOCUMENT TITLE 
SOP-UFBTIP-126 
Isolation and Cryopreservation of Peripheral Blood Mononuclear Cells (PBMC) and 
Plasma From Whole Blood for Immune Monitoring 
SOP-UFBTIP-127 
Leukapheresis Transport 
SOP-UFBTIP-128 
Administration of DC Vaccine    
SOP-UFBTIP-129 
Vaccine Transport 
SOP-UFBTIP-130 
External Tissue Collection, fresh tissue 
SOP-UFBTIP-131 
Leukapheresis for Peripheral Blood Mononuclear Cells (PBMCs) 
SOP-UFBTIP-132 
Administration of ALT (adoptive lymphocyte transfer) 
 
 
 

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31. ADDENDUM A 
31.1 Single Patient-Specific Protocol (UF Site Only)