Tumor Associated Antigen (TAA) Specific Cytotoxic T Lymphocytes Administered in Patients With Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Baylor College of Medicine

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TUMOR-ASSOCIATED ANTIGEN (TAA)-SPECIFIC CYTOTOXIC T LYMPHOCYTES 
ADMINISTERED IN PATIENTS WITH BREAST CANCER (TACTIC) 
 
 
 
PRINCIPAL INVESTIGATORS 
 
Ann M. Leen, PhD 
Mothaffar Rimawi, MD 
 
 
CO-INVESTIGATORS 
 
Kent Osborne, MD 
Ifigeneia Tzannou, MD 
Valentina Hoyos, MD 
Carlos Ramos, MD 
Premal Lulla, MD 
Bilal Omer, MD 
George Carrum, MD 
Helen Heslop, MD 
Julie Nangia, MD 
Matthew Ellis, MD PhD 
Angela Coscio, MD 
Maryam Shafaee, MD 
Adrian Gee, PhD 
Bambi Grilley, RPh 
 
 
STATISTICAL CO-INVESTIGATOR 
Tao Wang, PhD 
Susan Hilsenbeck, PhD 
 
Center for Cell and Gene Therapy 
Baylor College of Medicine 
 
Houston Methodist Hospital 
6565 Fannin St. 
Houston, TX  77030-2707 
 
Dan L. Duncan Comprehensive Cancer Center 
Baylor College of Medicine 
 
Conducted under Investigator-held IND BB-IND: 17586

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Contents 
1.0 
CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY 
INFORMATION ................................... 4 
2.0 
OBJECTIVES ...................................... 6 
  PRIMARY ENDPOINT ................................................................................ 6 
  SECONDARY ENDPOINT ........................................................................... 6 
3.0 
BACKGROUND AND RATIONALE ... 6 
3.1  T CELL THERAPY FOR NON-VIRAL TUMORS ............................................... 6 
3.2  CLINICAL EXPERIENCE TARGETING NON-VIRAL TAAS ................................ 7 
3.2.1 
Melanoma-targeted therapies ........................................................................ 7 
3.2.2 
T cell therapy to prevent leukemic relapse .................................................... 8 
3.3  TARGETING EBV NEGATIVE LYMPHOMAS USING ADOPTIVE T CELL 
TRANSFER ....................................................................................................... 9 
3.4  EXTENDING OUR APPROACH TO TREAT BREAST CANCER ........................... 9 
3.5  POTENTIAL ADVERSE EVENTS .................................................................. 9 
4.0 
PATIENT ELIGIBILITY ..................... 10 
4.1  PROCUREMENT INCLUSION CRITERIA .................................................... 10 
4.2  PROCUREMENT EXCLUSION CRITERIA ................................................... 10 
4.3  TREATMENT INCLUSION CRITERIA .......................................................... 10 
4.4  TREATMENT EXCLUSION CRITERIA ........................................................ 12 
5.0 
STUDY DESIGN ................................ 12 
5.1  BLOOD PROCUREMENT FOR CTL AND ANTIGEN-PRESENTING CELL 
(APC) GENERATION....................................................................................... 13 
5.2  ADMINISTRATION AND MONITORING ....................................................... 14 
6.0 
TREATMENT PLAN .......................... 14 
6.1  DOSE LEVELS ....................................................................................... 14 
6.2  DOSE SCHEDULE .................................................................................. 14 
6.3  PREMEDICATION ................................................................................... 15 
6.4  CELL ADMINISTRATION: ......................................................................... 15 
6.5  MONITORING ........................................................................................ 15 
6.6  SUPPORTIVE CARE ............................................................................... 15 
6.7  TREATMENT CENTER ............................................................................ 15 
6.8  OTHER TREATMENT .............................................................................. 15 
7.0 
PATIENT EVALUATION ................... 15 
7.1  FOLLOW UP INTERVAL ........................................................................... 15 
7.2  HISTORY AND PHYSICAL EXAMINATION .................................................. 16 
7.3  OTHER STUDIES ................................................................................... 16 
8.0 
RESPONSE CRITERIA ..................... 21 
8.1 
Definitions .................................................................................................... 21 

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9.0 
STATISTICAL CONSIDERATIONS .. 21 
9.1  STUDY DESIGN AND SAMPLE SIZE ......................................................... 22 
9.1.1 
Sample Size ................................................................................................ 22 
9.2  DATA ANALYSIS .................................................................................... 22 
9.3  ANALYSIS SET ...................................................................................... 23 
10.0  MODIFIED FOLLOW-UP AND OFF STUDY CRITERIA 
23 
10.1  CRITERIA FOR MODIFIED FOLLOW-UP .................................................. 23 
10.2  OFF STUDY ...................................................................................... 24 
11.0  RECORDS TO BE KEPT .................. 24 
12.0  REPORTING REQUIREMENTS ....... 24 
13.0  INFORMED CONSENT ..................... 25 
14.0  CLINICAL TRIAL OVERSIGHT AND MONITORING………25 
15.0  REFERENCE LIST ............................ 26 
16.0  APPENDIX I - GRADING OF CRS ... 32 
 
 
 

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1.0 CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY INFORMATION 
 
PATIENT ID   
 
 
 PATIENT NAME______________________ 
 
 
 
 
 
 
TACTIC PROTOCOL (Procurement) 
 
YES 
NO 
 
Any “NO” answers will make a patient ineligible for study participation. 
 
 
Any breast cancer patient with metastatic or locally recurrent 
unresectable breast cancer  
 
 
Life expectancy of  12 weeks 
 
 
Age > 18 and < 80 years old 
 
 
Hgb ≥ 7.0 (transfusion allowed) 
 
 
Informed Consent explained to, understood by and signed by 
patient. Patient given copy of informed consent. 
 
 
YES 
NO 
 
Any “YES” answers will make a patient ineligible for study participation. 
 
 
Severe intercurrent infection 
 
 
Active infection with HIV (can be pending at this time) 
 
 
Patients with a chronic uncontrolled medical condition that, in the 
opinion of the principal investigator, precludes them from 
participation.  
 
 
Signature of MD ______________________ 
Date ____________________ 
 
To check eligibility of a patient, telephone Dr. Rimawi at 713-798-1999. To register a 
patient, telephone the research coordinator, Claudette Foreman, at 713-798-7315. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TACTIC PROTOCOL (Treatment) 
 
PATIENT ID   
 
 
 PATIENT NAME _______________________ 
YES NO 
VALUE/DATE 
Any “NO” answers will make a patient ineligible for study participation. 
 
 
 
Any breast cancer patient with metastatic or locally recurrent 
unresectable breast cancer currently progressive after at least two 
prior lines of therapy in the advanced setting. Patients with HER2+ 
disease must have failed two or more different anti-HER2 agents.  
 
 
 
Patients must have measurable or evaluable disease per RECIST 
1.1 criteria.  
 
 
 
Life expectancy of  12 weeks. 
 
 
 
Age > 18 and < 80 years old 
 
 
 
Pulse oximetry of >95% on room air  
 
 
 
ECOG Performance Status of ≤ 2 or Karnofsky score of  50. 
 
 
 
Bilirubin < 2 x upper limit of normal 
 
 
 
Creatinine normal for age 
 
 
 
AST < 3x upper limit of normal 
 
 
 
Hgb ≥ 7.0 (transfusion allowed) 
 
 
 
Off investigational therapy for 1 month prior to receiving treatment 
on this study. 
 
 
 
Off conventional therapy for at least 1 week prior to receiving 
treatment on this study. 
 
 
 
Informed Consent explained to, understood by and signed by 
patient. Patient given copy of informed consent. 
 
 
 
Sexually active patients must be willing to utilize one of the more 
effective birth control methods for 6 months after the T cell infusion. 
 
YES 
NO 
VALUE/DATE 
Any “YES” answers will make a patient ineligible for study participation. 
 
 
Severe intercurrent infection 
 
 
Receiving systemic corticosteroids (patients off steroids for at least 48 
hours are eligible) 
 
 
Pregnant or lactating 
 
 
HIV positive 
 
 
Patients with a chronic uncontrolled medical condition that, in the 
opinion of the principal investigator, precludes them from participation. 
 
Signature of MD ______________________ 
Date ____________________ 
 
To check eligibility of a patient, telephone Dr. Rimawi at 713-798-1311. To register a 
patient, telephone the research coordinator, Claudette Foreman, at 713-798-7315. 
 
 
 
 
 
 

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2.0 OBJECTIVES  
 
 Primary endpoint  
To determine the clinical efficacy associated with the administration of multiTAA-specific T 
cells in breast cancer patients with metastatic or locally recurrent unresectable disease as 
measured by clinical benefit rate (defined as overall response plus stable disease for 10 
weeks or longer) according to the RECIST criteria (see Section 8.4.1). 
 
 Secondary endpoint 
To evaluate the progression-free and overall survival of patients after multiTAA-specific T 
cell infusion 
 
3.0 BACKGROUND AND RATIONALE 
 
3.1 T cell therapy for non-viral tumors 
From an immunotherapeutic perspective the model tumor antigen to target should be one 
that is exclusively and universally expressed on tumor cells in order to limit collateral damage, 
and ideally should be essential for the maintenance of the oncogenic phenotype of the tumor. 
However, the majority of antigens do not meet these criteria since they are not neo-antigens 
uniquely present in malignant cells but rather antigens that are also expressed in normal cells 
and against which peripheral blood T cells are tolerized or deleted. Tumor-specific antigens 
have nonetheless been identified, and these can be classified into 4 groups; 
(i) 
Unique antigens (eg. MUM1) result from single mutations that are tumor and 
patient specific and therefore are only expressed in neoplastic cells1-3. They are 
often considered ideal for immunotherapy since tumor cells can be specifically 
targeted without destroying nearby normal tissue, and they may also be relatively 
strong antigens1-4. However, because they are also usually patient-specific, the 
identification of the mutated gene and then the generation of an individualized 
CTL product targeting the identified antigen is highly labor and cost intensive.  
(ii) 
The shared lineage-restricted antigens, expressed on tumor cells as well as their 
normal tissue of origin, such as the melanoma associated antigens MART, gp100 
or Melan-A. These antigens are also strongly immunostimulatory, equivalent 
almost to “weak” viral antigens, enabling the efficient and relatively simple 
generation and expansion of tumor-specific T cells from healthy donors and 
patients with minimal in vitro manipulation5. However, T cell mediated destruction 
of normal melanocytes, for example, has resulted in vitiligo as well as ocular and 
systemic autoimmunity in patients treated with melanoma-specific CTL or TILs6. 
(iii) 
Shared tumor-specific TAA (e.g. the cancer testis antigens [CTA] - MAGE, BAGE, 
GAGE, NY-ESO-1, SSX, PRAME) are expressed in multiple tumors including 
breast cancer but not in healthy organs7-11, with the exception of germ line tissues 
that are immune privileged and therefore not susceptible to T cell attack. Most 
CTAs have heterogeneous expression in cancer tissues and are frequently 
expressed in high-grade or late tumor stages, with expression often correlated 
with a worse prognosis. Furthermore, tumors expressing one CTA are also often 
found to express multiple CTAs, and several have been found to be targets of 
spontaneous humoral or cell-mediated immune responses12-14. Thus, CTAs are 
particularly attractive as targets for tumor immunotherapy since reactive T cells 
can be produced on a large scale to provide broad-spectrum protection against a 
variety of tumors. CTAs have been targeted in both vaccine and T cell therapy 
protocols, with evidence of clinical efficacy15-21.  

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(iv) 
The last group of antigens are over expressed in many different tumors but 
expressed at low levels in healthy tissue (eg. hTERT, CEA and Survivin). T cells 
targeted to these antigens carry the risk of inducing collateral damage to normal 
tissues co-expressing the antigen (e.g. CEA and normal biliary epithelium), and 
there are limited clinical data available regarding the safety of targeting these 
antigens in vivo. However, Survivin- and CEA-specific T cells have been isolated 
from the peripheral blood of patients who have cleared their tumors, and 
increases in Survivin-specific T cells in patients receiving oncolytic viruses have 
been reported, suggesting that they can have efficacy without toxicity in patients22-
27.  
 
3.2  Clinical experience targeting non-viral TAAs 
 
3.2.1 Melanoma-targeted therapies 
T cell immunotherapies for non-viral tumor antigens have been described, with promising 
clinical results in some studies. Rosenberg and colleagues reported that infusion of 
melanoma-specific tumor-infiltrating lymphocytes (TILs) together with high-dose interleukin 
2 (IL-2) produced clinical responses in approx. 35% of patients with metastatic melanoma 28-
30. The specificity of the infused cells was not analyzed but it is likely that they targeted 
multiple epitopes/tumor associated antigens. More promising results were subsequently 
achieved using a modified treatment protocol which incorporated a lymphodepletion step 
prior to CTL infusion, in order to improve the expansion and persistence of adoptively-
transferred cells. Ninety three patients with metastatic melanoma refractory to standard 
therapies received immunodepleting chemotherapy -/+ total body irradiation followed by the 
adoptive transfer of highly selected, TIL-derived, tumor-reactive T cells and high-dose IL-2 
(720,000 IU/kg q 8h to tolerance). Fifty two of the 93 patients had objective clinical responses 
to treatment (39 PR, 12 CR), including regression of large bulky tumors31,32. However, the 
collection of autologous TILs is not possible for most tumors. Furthermore the in vitro 
expansion of large numbers of tumor-specific T cells (>1010 CTL) is a complex and expensive 
procedure.  
 
To extend applicability and generate a more defined tumor-specific product with respect to 
specificity and function, a number of groups have investigated the clinical use of tumor-
specific T cells isolated from peripheral blood and selectively activated and expanded ex 
vivo. Mitchell and colleagues used insect cells modified to express HLA-A2, CD80 and CD54 
and loaded with an HLA-A2-restricted epitope peptide derived from the melanoma-expressed 
tyrosinase antigen to repetitively stimulate and selectively expand tyrosinase peptide-specific 
T cells. Infusion of 5x108 cells (of which between 10-30% were tyrosinase-specific) to 10 
patients with tyrosinase-positive melanoma tumors was associated with clinical responses in 
two33. Other groups have used dendritic cells (DCs) to activate a tumor-directed product. For 
example, Yee and colleagues generated CD8+ T cell clones specific for HLA-A2 peptides 
derived from MART1 and gp100 using peptide-loaded autologous DCs as stimulators. Four 
infusions (3.3x109/m2/infusion) of the tumor-directed clones without and subsequently with 
low dose IL2 produced clinical benefit in 8 of 10 patients with metastatic melanoma and IL2 
was found to be crucial for in vivo persistence34. A follow-up study from the same group 
incorporating a pre-conditioning step with high dose cyclophosphamide +/- low or high dose 
IL2 was shown to further increase proliferation and persistence35. However, the toxicities 
associated with pre-conditioning followed by T cells with high dose IL2 were found to be 
substantial and recruitment on this arm of the study was halted. Finally, MART1 was also 
targeted by Mackensen et al, who prepared tumor-directed T cell lines using HLA-A2 peptide-

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loaded DCs to stimulate selected CD8+ T cells. Eleven patients received at least 3 and up to 
10 infusions of specific CTLs (median 2.11 x 108 cells/infusion) with low dose IL2, with 
evidence of T cell homing to tumor sites detected and favorable clinical responses reported 
in 3 (1 complete, 1 partial, and 1 mixed response)36. 
 
Thus, while the generation and adoptive transfer of CD8+ melanoma peptide-specific T cells 
from peripheral blood has proven to be feasible, as in the TIL setting clinical benefit appears 
to be tightly linked with in vivo persistence, which has proven challenging. One potential 
strategy to overcome this obstacle may be to infuse CD8+ peptide-directed T cells with 
antigen-specific CD4+ T cell populations, which not only mediate tumor killing directly against 
HLA class II positive targets37, but can support the survival and maintain the effector function 
of the transferred CD8+ T cells via the production of immunostimulatory cytokines and other 
signals upon antigen encounter. Perhaps a more general limitation of this peptide stimulation 
approach, however, is its limitation to individuals with a restricted HLA genotype due to the 
small number of class I-restricted epitopes used for T cell activation. Finally, one emerging 
concern is the potential for such a targeted therapy to evade the immune system as was 
reported by Mackensen et al who reported the evolution of MART1 negative tumors in 2 
patients infused with MART1-targeted CD8+ T cells36. 
 
3.2.2 T cell therapy to prevent leukemic relapse 
Adoptive immunotherapy has also proven to be an effective strategy in preventing leukemic 
relapse in the post allogeneic HSCT setting. The first adoptive T cell transfer protocols were 
based on the premise that donor peripheral blood contained T cells that were able to mediate 
antitumor activity in vivo. Accordingly, unmanipulated donor lymphocyte infusions (DLI) have 
been extensively used to provide anti-tumor immunity38. However, the efficacy of this 
approach is limited by the low frequency of tumor-specific T cells and the relatively high 
frequency of alloreactive T cells, resulting in frequent and severe GVHD. One strategy to 
enhance the “graft vs leukemia” effect without promoting GVHD is to selectively target tumor-
expressed antigens using selectively-expanded T cell populations and clinically the antigens 
which have been targeted fall into two categories: (i) minor histocompatibility antigens 
(mHAgs) expressed by leukemia progenitors, and (ii) TAAs overexpressed by the leukemic 
cells with limited expression on normal cells.  
 
mHAgs are HLA-binding peptides derived from endogenous proteins in cells of the stem cell 
transplant recipient that differ from those of the donor due to genetic polymorphisms, thus 
representing a unique class of antigens that can only be targeted after allogeneic HSCT to 
promote both GVL and GVHD effects in vivo.39 However, much of the current research in this 
area is focused on identifying and selectively targeting mHAgs expressed exclusively on 
malignant cells. Warren and colleagues recently evaluated the safety of adoptively 
transferring donor-derived CD8+ CTL clones recognizing minor histocompatibility antigens 
(mHAgs) preferentially expression on hematopoietic cells to patients with relapse of acute 
leukemia after myeloablative allogeneic HSCT40. The highest doses administered to each 
patient ranged from 2.25 x 109 - 6.6 x 109 cells. Pulmonary toxicity was seen in three of the 
seven treated patients, and was severe in one, and correlated with the level of expression of 
the mHAg-encoding genes in lung tissue. However, the administration of steroids coincided 
with a rapid reversal in pulmonary symptoms. Thus the associated toxicity could be rapidly 
and effectively controlled40. 
In both the autologous and donor-specific setting adoptive transfer approaches are being 
developed against a number of leukemia-associated antigens including Wilms Tumor Gene 
1 (WT1), Proteinase 3 (Pr3), human neutrophil elastase (NE), melanoma associated antigen 

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A3 (MAGE-A3) and preferentially expressed antigen in melanoma (PRAME)13,14. Of these 
WT1 is perhaps the most extensively characterized with several groups having defined CD4+ 
and CD8+ epitope peptides, thus confirming the immunogenicity of this target. Its clinical 
relevance is evidenced by the fact that disease control or remission in several vaccine studies 
has been associated with the induction of WT1-specific T cells, and an increased frequency 
of circulating WT1-specific T cells post HSCT has been associated with sustained disease 
remission. Based on these and other studies, O’Reilly and colleagues have recently initiated 
a clinical trial of donor-derived WT1 peptide-specific T cells, activated using DCs loaded with 
an overlapping peptide library (15mers overlapping by 11 amino acids) spanning the entire 
sequence of the antigen, and infused as treatment of persistent minimal residual disease or 
recurrence of WT1+ AML, ALL, or MDS following allogeneic HSCT. In preliminary reports, T 
cell infusions at the lowest dose levels were reported to be safe, well tolerated, and 
associated with clinical benefit41,42.  
 
3.3 Targeting EBV negative lymphomas using adoptive T cell transfer 
To target lymphoma we have developed a strategy to target multiple tumor expressed 
antigens including PRAME, SSX2, MAGE-A4, NY-ESO-1 and Survivin.  
To date we have infused a total of 18 patients: 9 with Hodgkin lymphoma, 8 with aggressive 
non-Hodgkin lymphoma, and 1 with a composite lymphoma. Patients have received 2 
infusions of cells ranging from 0.5-2x107 multiTAA-T cells/m2 without adverse events. Of 11 
patients who were infused as adjuvant therapy all but 1 remain in remission (range 1-24 
months post-infusion). Seven patients have received multiTAA-specific T cells to treat active 
disease. Of these, 1 had transient disease stabilization followed by disease progression, 3 
have stable disease 3-6 months post-multiTAA-specific T cells while the remaining 3 (all with 
HL) have had complete responses, as assessed by PET. Notably, since patients received no 
pre-infusion cytoreductive chemotherapy, these clinical responses can be attributed to the 
cells infused. Indeed, clinical benefit correlated with the detection of tumor-reactive T cells in 
patient peripheral blood post-infusion directed against both targeted antigens as well as non-
targeted TAAs including MAGEA2B and MAGE C1, indicating antigen spreading. Thus, 
infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-
ESO-1 and Survivin has been safe and provided clinical benefit to patients with lymphomas. 
 
Additionally, we have administered these multi-antigen-targeted T cell lines to patients with 
multiple myeloma (n=5) and a spectrum of solid tumors including squamous cell carcinoma, 
lung cancer and osteosarcoma (n=4).  
 
3.4 Extending our approach to treat breast cancer 
Given our demonstration that (i) targeting NY-ESO-1, PRAME, MAGE-A4, SSX2 and 
Survivin simultaneously is feasible and safe, and (ii) these antigens are expressed in different 
stages of breast cancer including triple-negative breast cancer7-11, we now propose to 
administer multiTAA-specific CTLs to patients with breast cancer. The CTL generation 
protocol will be identical to that used in our lymphoma study. In the current phase II study, 
we propose testing the safety and antitumor activity of these multiTAA-specific cells in 
patients with a breast cancer diagnosis at a fixed dose of 2x107 cells/m2.  
 
3.5 Potential adverse events  
Although no toxicity has been associated with CTL infusion in patients with Hodgkin and non-
Hodgkin lymphoma, we will actively look for evidence of potential side effects such as: 
 
Cytokine Release Syndrome: 

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There have been several reported SAEs associated with cytokine release syndrome (CRS) 
in patients who received T cells43 or bispecfic T-cell engagers44. The majority of CRS have 
been reported after the infusion of CAR T cells45-47, but CRS can also occur after the infusion 
of conventional antigen-specific T cells48 or tumor infiltrating lymphocytes49. Patients will be 
monitored closely as per study calendar and assessed for evidence of incipient CRS (onset 
of fever, malaise and dyspnea) and treated promptly. Management of CRS will follow 
published guidelines43,50, and is described in more detail in SOP F 05.11.XX and includes 
treatment options based on the clinical severity of the symptoms, such as 
oxygen, inotropic agents, IL-6 receptor antibody (4-8 mg/kg),TNF-α antibody (5-10 mg/kg), 
and/or steroids (1-2 mg/kg/day of methylprednisolone or equivalent). 
 
 
4.0  PATIENT ELIGIBILITY 
 
4.1 Procurement Inclusion Criteria 
 
4.1.1 Any breast cancer patient with metastatic or locally recurrent unresectable disease.  
 
4.1.2 Patients with life expectancy >12 weeks. 
 
4.1.3 Age > 18 and < 80 years old 
 
4.1.4 Hgb ≥7.0 (transfusions allowed -see Section 7.3). 
 
4.1.5 Informed Consent explained to, understood by and signed by patient. Patient given 
copy of informed consent. 
 
4.2 Procurement Exclusion Criteria 
 
4.2.1 Patients with severe intercurrent infection. 
 
4.2.2 Patients with active HIV infection at time of procurement 
 
4.2.3 Patients with a chronic uncontrolled medical condition that, in the opinion of the 
principal investigator, precludes them from participation.  
 
4.3 Treatment Inclusion Criteria 
 
4.3.1 Any breast cancer patient with metastatic or locally recurrent unresectable breast 
cancer currently progressive, after at least two prior lines of therapy in the advanced 
setting. Patients with HER2+ disease must have failed two or more different anti-
HER2 agents.  
 
4.3.2 Patients must have measurable or evaluable disease per RECIST 1.1 criteria.  
 
4.3.3 Patients with life expectancy > 12weeks 
 
4.3.4 Age > 18 and < 80 years old 
 
4.3.5 Pulse oximetry of >95% on room air  

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4.3.6 Patients with an ECOG score of ≤ 2 or Karnofsky score of ≥ 50 as described below: 
 
ECOG Performance Status 
 
 
 
Grade 
ECOG 
 
 
0 
Full active, able to carry on all pre-
disease performance without 
restriction 
 
 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature, e.g., light house 
work, office work 
 
 
2 
Ambulatory and capable of all 
selfcare but unable to carry out any 
work activities. Up and more than 
50% of waking hours 
 
 
3 
Capable of only limited selfcare, 
confined to bed or chair more than 
50% of waking hours 
 
 
4 
Completely disabled. Cannot carry 
on any selfcare. Totally confined to 
bed or chair 
 
 
5 
Dead 
 
 
 
 
 
Performance Status Criteria 
 
Karnofsky performance scores are intended to be multiples of 10 
Karnofsky 
 
Score 
Description 
 
 
100 
Normal, no complaints, no evidence 
of disease 
 
 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease 
 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
 
 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
 
 

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40 
Disabled, requires special care and 
assistance. 
 
 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
 
 
10 
Moribund, fatal processes 
progressing rapidly. 
 
 
 
 
4.3.7 Patients with bilirubin <2x upper limit of normal, AST <3x upper limit of normal, and 
Hgb ≥7.0 (transfusion allowed - see Section 7.3). 
 
4.3.8 Patients with a creatinine normal for age  
 
4.3.9 Patients should have been off other investigational therapy for one month  prior to 
receiving treatment on this study.  
 
4.3.10 Patients should have been off conventional therapy for at least 1 week prior to 
receiving treatment on this study. 
 
4.3.11 Sexually active patients must be willing to utilize one of the more effective birth 
control methods for 6 months after the T cell infusion. 
 
4.3.12 Informed Consent explained to, understood by and signed by patient. Patient given 
copy of informed consent. 
 
4.4 Treatment Exclusion Criteria 
 
4.4.1 Patients with severe intercurrent infection. 
 
4.4.2 Patients receiving systemic corticosteroids (Patients off steroids for at least 48 
hours are eligible) 
 
4.4.3 Pregnant or lactating   
 
4.4.4 Patients with a chronic uncontrolled medical condition that, in the opinion of the 
principal investigator, precludes them from participation. 
 
4.4.5 HIV positive 
 
 
5.0 STUDY DESIGN  
 
This protocol will be discussed with eligible patients and informed consent for participation in 
the study will be obtained for the generation of the cell lines. The protocol will be discussed 
with patients undergoing treatment at other medical Institutions at the time they are referred 
to Houston Methodist Hospital (HMH). 
 

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All cell culture manipulations will be carried out in the Center for Cell and Gene Therapy GMP 
facility using current standard operating procedures (SOPs). After quality assurance testing 
of the manufactured cell product is complete, a certificate of analysis will be issued. 
 
5.1 Blood procurement for CTL and antigen-presenting cell (APC) generation 
Generation of tumor-specific CTL lines requires the generation of several different 
components from peripheral blood mononuclear cells (PBMC). The CTL line will be derived 
from patient peripheral blood T cells, by stimulation with antigen-presenting cells (APCs) 
pulsed with pepmixes spanning the tumor-associated antigens SSX2, MAGEA4, Survivin, 
PRAME, and NY-ESO-1. The initial stimulation will be performed in the presence of the 
Th1/pro-proliferative cytokines interleukin (IL) 7, IL-12, IL-15, and IL6 and cells will be 
expanded in the presence of IL-2 or IL15. The APCs used to stimulate and expand the tumor-
specific T cells will be dendritic cells derived from patient mononuclear cells.  
 
For CTL generation, we will either use: 
* a mononuclear cell-apheresis collection procedure (for patients with ALCs <500) or  
* a maximum blood draw of 390 ml total, obtained in 1-3 draws over a 2 month period for 
CTL generation, testing for infectious viruses and HLA typing. PBMC will be separated from 
whole blood using ficoll gradients. T cells and monocyte-derived dendritic cells (DCs) can be 
prepared from fresh or cryopreserved PBMC. 
 
To initiate tumor-specific CTL lines we will make DCs by culture of PBMC-derived monocytes 
with cytokines (GM-CSF, IL-4) followed by maturation with a standard DC maturation cocktail 
(IL-1, IL6, TNF and PGE1). These mature DCs will be pulsed for 30-60 mins with a 
mastermix of pepmixes spanning the target antigens PRAME, SSX2, MAGEA4, NY-ESO-1 
and Survivin. For dilution 1ul of each pepmix (200ng/peptide) will be added to 200ul Cell 
Genix/RPMI media and 50-100ul will be used to pulse the DCs (≤5x10e6 DCs - 50ul; >5x10e6 
DCs - 100ul). Subsequently the DCs will be washed once and used to stimulate PBMC-
derived T cells in the presence of a T cell activating cocktail, IL7, IL15, IL12 and IL6 at a 
responder:stimulator ratio of at least 10:1. For initiation, DCs will be prepared from about 
100mL of blood and the T cells will be derived from the monocyte-depleted PBMC fraction. 
 
To expand the tumor-specific T cells we will use pepmix-pulsed DCs for the second and 
subsequent stimulations and cells will be cultured in the presence of IL-2 or IL-15. At least 
100 x 106 mononuclear cells are required to generate the second batch of DCs.  
 
At the end of the culture period, CTLs will be cryopreserved and aliquots tested for 
phenotype, function, specificity, identity and sterility. The frequency of tumor-specific CTLs 
will be determined using intracellular cytokine staining, ELIspot assay, and HLA-peptide 
tetramers if available. Effector memory phenotype and T cell subsets will be analyzed by flow 
cytometry.   
 
Products that meet study specific release criteria, as detailed on the CofA, will be infused as 
per Section 5.2. 
 
If a positive sterility testing result is reported after the product was infused, the FDA and other 
relevant parties would be notified as per manufacturing SOP B01.03.XX (Product Quality 
Assurance Program and Release and Return of Clinical GMP/GTP Products) and  clinical 
research SOP J02.06.XX (Serious Adverse Experience and Unanticipated Problem 

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Reporting). Our management of such a situation is further described in our SOP F05.09.XX 
(Management of Culture Positive Cell Therapy Products).  
 
We will use pepmixes produced by JPT Technologies as an antigen source. These pepmixes 
are overlapping peptide libraries (15 mers overlapping by 11 amino acids) spanning the entire 
sequence of each of the antigens of interest as per our lymphoma (TACTAL) study.  
 
5.2 Administration and Monitoring 
 
Patients will be evaluated in the clinic and 2 fixed doses of CTL will be administered 4 weeks 
apart. Patients will be monitored for clinical toxicity by the CTEP NCI Common Toxicity 
Criteria Scale (Version 4.X, See Section 13.3) with the exception of CRS toxicities that are 
related to T-cell infusions. CRS toxicities will be graded according to Appendix I. We will also 
analyze immunological parameters including phenotype and CTL frequencies by ELIspot and 
tetramer studies in patients who have HLA types for which tetramers are available. This 
information will be used to determine the in vivo persistence of the infused product and 
whether multiTAA-specific T cells will be able to recruit the patient’s endogenous immune 
system as measured by epitope spreading.  Functional analyses (antigen-specific cytotoxicity 
and 
cytokine 
release) 
will 
be 
performed 
by 
chromium 
release 
assays 
and 
ELIspot/intracellular cytokine staining, respectively. The levels of serum cytokines before and 
following infusion will be compared. If needed, we will compare the infused product with the 
patient’s peripheral blood using TCR deep-sequencing. A time period of 6 weeks post the 2nd 
infusion will constitute the time for clinical efficacy and safety monitoring. If patients have had 
a partial response or have stable disease they will be eligible to receive up to 6 further doses 
of CTLs, each of which will consist of the same cell dose or less (if there is not enough product 
available for the subject’s original dose) than their second infusion  
 
6.0 TREATMENT PLAN  
 
This study will evaluate the clinical efficacy of T cells specific for all 5 tumor associated 
antigens in a fixed dose study. 
 
6.1 Dose Levels  
 
The patients will be treated 2 times 4 weeks apart at a fixed dose of 2x107 cells/m2. 
 
6.2 Dose Schedule 
 
This protocol is designed as a phase II fixed-dose study.  
 
Each patient will receive 2 injections at a fixed dose, 28 days apart, according to the 
following dose schedule: The expected volume of infusion will be 1 to 10 cc. 
 
Dose schedule:   
 
Day 0 
2 x 107 cells/m2 
Day 28 
2 x 107 cells/m2 
 
If patients have stable disease or a partial response by the Response Evaluation Criteria in 
Solid Tumors (RECIST) criteria (see 8.4.1) at their 6 week evaluation after the 2nd cell 
dose, they will be eligible to receive up to 6 additional doses of CTLs, At least one month 

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should have passed before each additional dose.. Each additional infusion will consist of 
the same cell number or less (if there is not enough product available for the subject’s 
original dose) than their second infusion. Patients will not be able to receive additional 
doses until the initial safety profile is completed at 6 weeks following the second infusion.  
 
6.3 Premedication 
 
Patients may be premedicated with diphenhydramine (Benadryl) up to 1mg/kg IV (max 50mg) 
and acetaminophen (Tylenol) 10mg/kg po (max 650mg), though this is not mandatory. 
 
6.4 Cell Administration:  
 
Tumor-specific T cells will be given by intravenous injection over 1-10 minutes through 
either a peripheral or a central line. 
 
 
 
6.5 Monitoring 
Monitoring will be undertaken according to institutional standards for administration of blood 
products with the exception that the injection will be given by a physician. 
 
6.6 Supportive Care 
 
Patients will receive supportive care for acute or chronic toxicity, including blood 
components or antibiotics, and other intervention as appropriate. 
 
6.7 Treatment Center 
 
All treatments will be administered at the Center for Cell and Gene Therapy in Houston 
Methodist Hospital. Patient follow up and regular care will be at the Breast Center at Baylor 
Clinic or Smith Clinic.  
 
6.8 Other Treatment 
 
Patients should not receive other treatment for their cancer between the first and second 
CTL doses or for at least 6 weeks post 2nd CTL (for purposes of evaluation). If a patient 
receives other treatment for their cancer between the first and second CTL doses, that 
patient will be taken off treatment.  
 
7.0 PATIENT EVALUATION 
 
7.1 Follow up Interval 
Patients shall be seen in clinic prior to the first and second infusions and 
evaluated (seen in clinic or contacted by a research coordinator) at 1 -2 
week intervals for up to six weeks after the 2nd infusion and then at 3, 6, 9 
and 12 months (post 2nd infusion). We will then continue to follow patients 
clinically for up to 4 additional years (total of 5 years follow-up) to evaluate 
long-term disease responses. If persistence of cells is noted at the 12 month 
visit, additional follow-up will added. Additional visits will be obtained as 
clinically indicated or if the patient is having more than 2 infusions.  
 

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7.2 History and Physical Examination 
A complete history will be performed at pre-infusion, at week 2 post CTL #1, 
at Week 4/Day 0 (CTL infusion #2) and Weeks 1, 2, 4, 6 post CTL infusion 
#2, at 3, 6, 9 and 12 months, then annually for up to 4 additional years for a 
total of 5 years follow-up.  Physical examinations will be conducted at pre-
infusion for CTL #1 and on days of subsequent CTL infusions. 
 
7.3 Other Studies  
 
7.3.1 The following investigations will be obtained at pre-infusion for CTL #1 
and on days of subsequent CTL infusions 
 
CBC and differential and Complete Metabolic Panel (CMP). 
 
7.3.2 Pregnancy testing is required on female patients of childbearing 
potential prior to CTL infusion #1. Pregnancy testing is not required 
prior to CTL infusion #2 for patients treated. 
 
7.3.3 Diagnostic imaging (CT scans, MRI, nuclear imaging) and/or blood 
tests (serum cytokines) to document measurable disease and 
response to therapy at pre-infusion and 6 weeks following the second 
infusion. The time may vary by 1-2 weeks due to scheduling issues 
and may be done earlier if clinically indicated. The choice of imaging 
will depend on what studies have been most informative in following 
the patient’s disease. If diagnostic imaging studies are performed at 
other times either during or after treatment on this study, that data will 
be collected and information gained will be used for this study.  
 
7.3.4 The following investigations will be obtained pre-infusion, and at 1, 2, 
4 weeks after the first infusion and then at 1, 2, 4, 6 weeks and 3, 6, 9, 
and 12 months following the 2nd infusion. 20-40ml of peripheral blood 
will be collected in preservative-free heparin anticoagulant. This blood 
will be used for analysis of specificity of CTL response using HLA-
peptide tetramer analysis and immune function assays including 
ELIspot, intracellular cytokine staining and cytotoxicity assays. Serum 
will be batched for analysis of blood cytokine levels. These studies will 
be done on patients on whom the appropriate reagents are available.  
 
7.3.5 If the patient has additional injections of cells after the first 2 infusions, 
the tests listed in 7.2.1 and 7.2.4 will also be obtained pre each 
infusion, and at 1, 2, 4, and 6 weeks post each infusion. Follow up will 
then continue at 3, 6, 9 and 12 months after the last infusion. No study 
specific blood tests will be done after two years (if the patients have 
had additional injections) but we will continue to follow patients 
clinically once a year for up to 4 additional years (total of 5 years follow-
up) to evaluate long term disease responses. 
 
7.3.6 Other Tissues: Should the patient undergo a tumor biopsy at any time 
while they are on study, a sample of this will be used to assess the 
tumor antigen expression profile.  

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If a patients’ hemoglobin is less than 7.0g/dl at any of the evaluation 
times, the amount of blood drawn for the evaluation will be reduced 
and may be obtained over more than one venipuncture, if necessary. 
 
All pre-study exams must be done within 72 hours of eligibility. 

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7.4 Summary of Monitoring 
 
Study Calendar: A summary of monitoring studies is provided in the following table: 
Study Procedure 
Treatment 
Follow-up 
Pre-
infusion 
Day 
0 
Wk 
1 
Wk 
2 
Wk 
4/ 
Day 
0 
[#2} 
Wk 
1   
[#2]  
Wk 
2 
[#2]  
WK  
4 
[#2] 
Wk  
6 
[#2] 
M 3 
M 6 
M 9 
M 
12 
Y 2 
Y 3 
Y 4 
Y 5 
STUDY DRUG ADMINISTRATION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
mTAA CTL infusion 
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
DATA/TESTS/SPECIMENS TO BE OBTAINED 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood Procurementᵃ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PE 
 X 
 
  
 
X 
 
 
 
 
  
  
  
  
  
  
  
  
Hx 
 X 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testb 
 X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood Tests [Hematology, Comprehensive Metabolic 
Panel]ᶜ 
 X 
 
  
 
X 
 
 
 
 
 
 
 
 
  
  
  
  
Imaging studiesd 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
Immune function studiesᵉ 
 X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
TCR deep-sequencingf 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor Biopsyg 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DATA REVIEW 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Assessment for Procurement 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Assessment for Therapy 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Breast Cancer Information  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AE Assessment 
  
Xh 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Response Assessment 
  
  
  
  
  
  
  
  
Xi 
  
  
  
  
  
  
  
  
Follow-up 
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Cancer 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Follow-up Pregnancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Relapse and Progression Assessment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Death 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    a-  Blood will be collected for infectious disease testing, HLA typing, and mTAA CTL generation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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b- Pregnancy testing will be done pre-infusion in patients of childbearing potential. Either serum or urine is acceptable 
 
 
 
 
 
 
 
 
 
 
 
c-  Hematology labs for CBC with differential WBC count; Comprehensive Metabolic Panel includes BUN, creatinine, bilirubin, SGOT, SGPT, alkaline phosphatase, sodium, potassium, chloride, carbon dioxide, albumin. 
       d-  Imaging studies required per section 7.3.3; imaging studies will be performed on a case by case basis to assess disease status at the discretion of the treating physician. 
 
 
 
 
 
   e- Blood will be used for immune function assays including ELISPOT and cytotoxicity assays per section 7.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
   f-  If required, TCR deep-sequencing will be performed  to compare the infused product with the patient’s peripheral blood per section 5.2 
 
 
 
 
 
 
 
 
 
   g- Should the patient undergo a tumor biopsy at any time on the study, a sample will be used to determine the tumor antigen expression profile per section 7.2.6 
 
 
 
 
 
 
   h- Adverse events are assessed throughout the clinical safety monitoring timeframe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   i-   Time point for evaluation clinical efficacy, and eligibility for additional doses per section 5.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Additional Treatment 
Study Procedure 
Treatment 
Follow-Up 
 
 
Day 
0 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
M 3 
M 6 
M 9 
M 12 
 Y 2 
Y 3 
Y 4 
Y 5 
 
 
STUDY DRUG ADMINSITRATION 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
mTAA CTL infusion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
DATA/TESTS/SPECIMENS TO BE OBTAINED 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Concomitant Medications 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
PE 
X 
  
 
 
 
  
  
  
  
  
  
  
  
 
 
Hx 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Blood Tests [Hematology, Comprehensive Metabolic Panel]ᵃ 
X 
  
 
 
 
 
 
 
 
  
  
  
  
 
 
Imaging studiesᵇ 
  
  
  
  
X 
  
  
  
  
  
  
  
  
 
 
Immune function studiesᶜ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
 
 
TCR deep-sequencingd 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Tumor Biopsye 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
DATA REVIEW 
  
  
  
  
  
  
  
  
  
  
  
  
  
AE Assessment 
Xf 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Response Assessment 
  
  
  
  
Xg 
  
  
  
  
  
  
  
  
 
 
Follow-up 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Follow-up Cancer 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Follow-up Pregnancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Relapse and Progression Assessment 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Death 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
a- Hematology labs for CBC with differential WBC count; Clinical chemistry panel includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, aspartate transaminase,  
alanine transaminase) 
b- Imaging studies are not required with additional doses but if performed the data will be collected. 
 
 
 
 
 
 
 
 
 
 
 
 
c-  Blood will be used for immune function assays including ELISPOT and cytotoxicity assays  
 
 
 
 
 
 
 
 
 
 
 
 
 
d- If required, TCR deep-sequencing will be performed to compare the infused product with the patient’s peripheral blood per section 5.2 
 
 
 
 
 
 
 
 
e- Should the patient undergo a tumor biopsy at any time on the study, a sample will be used to determine the tumor antigen expression profile per section 7.2  
 
 
 
 
 
f-  Adverse events are assessed throughout the clinical safety monitoring timeframe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
g- Data pertaining to clinical efficacy and safety monitoring will be obtained 6 weeks after the final injection per section 9.2 
 
 
 
 
 
 
 
 
 
 
 
 

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8.0 RESPONSE CRITERIA 
 
 A 6-week period after the second infusion will constitute a course, which will be evaluated 
for critical toxicity, and a 6-week period after the second CTL infusion will be required for 
evaluation for antitumor activity. 
 
Patients with measurable disease will be assessed by standard criteria to determine clinical 
response. Evaluations of tumor size will be performed pre-infusion and 6 weeks after the 
second injection.  Additional imaging performed as part of standard clinical care will also be 
evaluated. All patients who receive CTL infusion and continue to be enrolled on the study will 
be evaluable for response. Patient long term overall and progression free survival will also 
be evaluated at 1 year and then annually for up to an additional 4 years (total of 5 years 
follow-up).  
 
8.1 
Definitions  
This study will use the RECIST 1.1 criteria  
 
 
 
Definitions  
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Committee51. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT 
scan, MRI, or clinically using calipers. The investigator will identify up to 5 measurable lesions 
to be followed for response. Serial measurements are to be done with CT or MRI. The same 
method of assessment is to be used to characterize each identified and reported lesion at 
baseline and during follow-up. 
 
Complete Response:  Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
 
9.0 STATISTICAL CONSIDERATIONS 
 
This is a phase II study evaluating the safety and clinical efficacy of multiTAA-specific CTLs 
administered in patients with breast cancer. All patients will receive 2 injections at a fixed 
dose, 28 days apart, of T cells specific for all 5 tumor associated antigens.   

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9.1 Study Design and Sample Size 
 
9.1.1 Sample Size  
 
The primary endpoint is clinical benefit rate at 6 weeks after the second dose. Clinical benefit 
rate is defined as the proportion of evaluable patients with complete response or partial 
response or stable disease for ≥10 weeks from the first infusion (6 weeks after the second 
infusion) according to the RECIST criteria (see Section 8.4.1). This study is designed to 
detect an increase in clinical benefit rate from 5% to 30%. A Simon’s two-stage optimal 
design will be employed to test the null hypothesis that clinical benefit rate is 5% vs. the 
alternative target rate of 30%. A sample of 9 evaluable patients will be accrued during the 
first stage. If none of these 9 patients shows clinical benefit at the analysis of the first stage, 
the study will be stopped early for lack of efficacy. If at least 1 patient shows clinical benefit, 
then a second stage will enroll additional evaluable patients. If we observe at least 3 clinical 
benefit responses out of the total of 17 evaluable patients enrolled into the study, we will 
consider further investigation is warranted. The proposed sample size is based on testing the 
above hypotheses with 90% power and 5% significance level. This design has 63% 
probability of stopping early and an expected sample size of 12 if the true clinical benefit rate 
is only 5%. Taking into account a 20% drop-out rate for non-evaluable patients, we propose 
to accrue a total of 22 patients.  
 
9.2 Data Analysis  
 
Safety and toxicity outcomes, and laboratory evaluations will be summarized using 
descriptive statistics. Information on the expansion, persistence and anti-tumor effects of the 
adoptively transferred tumor-specific CTL will be analyzed for the immunological parameters 
based on multimer analysis, intracellular cytokine staining and ELIspot assays to assess the 
frequency of cells secreting IFN using the descriptive statistics such as mean, median, 
standard deviation at each time point. Comparison of diagnostic imaging studies from pre-
infusion to 6 weeks following the second infusion will be summarized. Frequencies, 
proportions and their 95% confidence intervals of clinical benefit responders (adjusted to 
account for the two-stage nature of the design) will be summarized overall. Overall survival 
and progression free survival will be estimated using the Kaplan-Meier survival curve and 
summarized by median and 95% confidence interval. 
 
Growth curves of immune response over time within a patient will be generated to visualize 
general patterns of immune response. Pairwise comparisons will compare changes of these 
immunological parameters from pre-infusion to each time point of post-infusion 
measurements using paired t-tests or Wilcoxon signed-ranks tests. Longitudinal analysis is 
employed to model repeatedly-measured immunologic parameters. This will allow us to 
model patterns of immune response per patient while allowing for varying intercepts and 
slopes for a patient. The normality assumption will be assessed and transformations to 
achieve approximate normality will be carried out if necessary.  
 
If a patient has stable disease or a partial response as assessed by the RECIST criteria (see 
Section 8.4.1) after the first two infusions, they may receive up to 6 additional infusions at 
monthly intervals. We will collect data on the survival, immunological efficacy and anti-tumor 
activity of cytotoxic T-lymphocyte lines after these additional infusions so it may be compared 
with results obtained after the initial two infusions.     

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To obtain preliminary data on the clinical efficacy and safety monitoring, patients will be 
monitored for 6 weeks after the final injection for toxicity using standard NIH criteria. If a 
patient develops Grade III-IV toxicity attributable to the CTL infusions at any time during the 
extended dosing regimen, they will not be able to receive any more CTL infusions.   
 
9.3 Analysis Set  
 
Evaluable for response: Only patients who receive both infusions will be evaluable for 
response.  
 
Evaluable for adverse events: All patients who received the first infusion will be evaluable 
for adverse events.   
 
9.4 Stopping Rule 
 
If there are 2 patients with grade 4 events considered possibly related to the study drug, the 
study will be halted for review by the Data Safety Monitoring Committee and the FDA. 
 
 
10.0 MODIFIED FOLLOW-UP AND OFF STUDY CRITERIA  
 
10.1 
 Criteria for Modified Follow-Up 
The following criteria will result in the patient being ineligible for further treatment on 
the protocol, although response data will continue to be collected as applicable.  
 
 
10.1.1 Any patient who develops grade > III infusional and/or organ toxicity 
that is NOT (1) pre-existing, or (2) due to infection or (3) due to 
underlying malignancy and is considered to be possibly, probably, or 
definitely related to the study drug. In such patients, the toxicities will 
be followed until resolution or their off-study date. Although no toxicity 
has been associated with the infusion of this product in patients with 
Hodgkin and non-Hodgkin lymphoma, we will actively look for 
evidence of any adverse events, such as cytokine release syndrome. 
 
10.1.2 Any patient who receives any other hematopoietic progenitor cell 
product.  In such patients, adverse event data collection will cease.  
 
10.1.3 Any patient who receives therapy for progression of their breast 
cancer.  In such patients, adverse event data collection will cease.  
 
 
10.1.4 Any patient who desires to withdraw from the study or if the physician 
feels that it is in the best interest of the patient, treatment will be 
discontinued. 
 
 

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Patients who meet modified follow-up criteria remain on long-term follow-up as per the 
Summary of Monitoring (see table in Section 7.3.1) 
 
10.2 OFF STUDY 
10.2.1 Completion of study-specified procedures. 
10.2.2 Refusal of study follow up by patient  
10.2.3 Lost to follow up 
10.2.4 Death 
 
Any questions regarding patients on this study should be addressed to Dr. Rimawi at 713-
798-1999. 
 
11.0 
RECORDS TO BE KEPT  
 
The research nurse/coordinator will maintain a database documenting on study information, 
adverse events, off study notification and death information. The dates and doses of therapy 
as well as clinical chemistries, hematologic parameters, the clinical status and occurrence of 
any adverse events and subsequent interventions are to be kept on all patients. 
 
Imaging reports 
Surgical summaries 
Autopsy summaries, where appropriate 
Informed consent documents 
 
All required clinical evaluation records will be the responsibility of Principal Investigator who 
will also be responsible for analysis of the clinical outcome and toxicity. 
 
The laboratory evaluation of immunological efficacy will be the responsibility of Dr. Tzannou.  
 
12.0 
REPORTING REQUIREMENTS  
 
12.1 
Register all patients with the research nurse/research coordinator. 
 
12.2 
Enter all patients by phoning Dr. Rimawi. The following data will be captured: 
 
Eligibility 
Pre-study  
Concomitant Medication  
Adverse event   
CRS Adverse Event  (if applicable) 
Off study   
Death  
 
12.3 
Drug Toxicity and/or Adverse Reactions 
 
 
 
12.3.1 Toxicity Grading: The criteria listed in the CTEP (Version 4.X) of the NCI Common 
Toxicity Criteria Scale will be used in grading toxicity with the exception of CRS 

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toxicities that are related to T-cell infusions. CRS toxicities will be graded according 
to 
Appendix 
I.  
 
12.3.2 The CTEP CTCAE (Version 4.X) is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 
12.3.3 Adverse events will be collected as per SOP J 02.05.XX and J 02.75.XX.  Data on 
adverse experiences/toxicities regardless of seriousness, must be collected for 
documentation purposes only for 6 weeks after the last dosing of study drug/biologic. 
 
12.3.4 Serious adverse events will be collected as per SOP J 02.06.XX.   
 
 
13.0 
INFORMED CONSENT  
 
All patients must sign a document of informed consent consistent with local institutional and 
Federal guidelines stating that they are aware of the investigational nature of this protocol 
and of the possible side effects of treatment. Further, patients must be informed that no 
efficacy of this therapy is guaranteed, and that unforeseen toxicities may occur. Patients have 
the right to withdraw from this protocol at any time. No patient will be accepted for treatment 
without such a document signed by his or her legal guardian. Full confidentiality of patients 
and patient records will be provided according to institutional guidelines 
 
14.0 
 CLINICAL TRIAL OVERSIGHT AND MONITORING 
 
This protocol will be conducted in accordance with the Cell and Gene Therapy Monitoring 
Plan on file with the FDA. 
 
This protocol will be monitored in accordance with the current Data Safety Monitoring Plan 
for investigator-initiated Phase I and II studies in the Dan L Duncan Comprehensive Cancer 
Center at Baylor College of Medicine.  
 
The conduct of this clinical trial will be evaluated in accordance with Center for Cell and Gene 
Therapy Quality Assurance Policy and Procedure Plan.  
 
 
 
 

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Version 1.1 8/12/2016           Version 2.0 3/20/2017        Version 3.1 7/24/2017         Version 4.0 12/03/2018 
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Appendix I - Grading of CRS  
 
CRS Grading Scale 
Grade 
Symptoms 
1 
 
Symptoms are not life threatening and require symptomatic treatment 
only (e.g. fever, nausea, fatigue, headache, myalgia, malaise)  
2 
 
Symptoms require and respond to moderate intervention  
 
Oxygen requirement <40% or hypotension responsive to fluids or  
 
low dose of one vasopressor or Grade 2 organ toxicity  
3 
 
Symptoms require and respond to aggressive intervention  
 
Oxygen requirement ≥ 40% or  
hypotension requiring high dose or multiple vasopressors or  
 
Grade 3 organ toxicity or Grade 4 transaminitis  
4 
 
Life-threatening symptoms 
 
Requirements for ventilator support or  
Grade 4 organ toxicity (excluding transaminitis)  
5 
 
Death