A Phase I Trial of T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers
Phase: PHASE1
Conditions: Kita-kyushu Lung Cancer Antigen 1, Human
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:  KK-LC-1 TCR T cells
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Version Date:  12/20/2024
Abbreviated Title:  KK-LC-1 TCR T cells
NIH Protocol #:  000045
IBC Number:  RD-21-II-04
Version Date:  12/20/2024
NCT Number:  NCT05035407
A Phase I Trial of T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, 
Cervical, Lung and other KK-LC-1 Positive Epithelial Cancers
  
      NCI Principal Investigator:
Scott Norberg, DO
Center for Immuno-Oncology (CIO)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 10, Rm 3-3132
9000 Rockville Pike
Bethesda, MD 20892
Phone: 301-275-9668
E-mail: scott.norberg@nih.gov
Drug Name:
KK-LC-1 TCR 
Transduced PBL
Fludarabine
Cyclophosphamide
IL-2 
(Aldesleukin)
IND Number:
27348
27348
27348
27348
Sponsor:
CCR, NCI
CCR, NCI
CCR, NCI
CCR, NCI
Manufacturer:
CC DTM
Generic
Generic
Generic
Supplier:
CC DTM
CC Pharmacy
CC Pharmacy
CC Pharmacy
Investigational Device:
Name:
KK-LC-1 positivity assay
IDE #:
Nonsignificant Risk Device (NSR)
Sponsor:
CCR, NCI
Coordinating Center: NIH NCI Center for Cancer Research (CCR)
Participating Sites:  See Appendix H for role of participating sites
Safety Monitoring Committee (SMC):  NCI Intramural CCR SMC

Abbreviated Title:  KK-LC-1 TCR T cells
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PRÉCIS 
Background:
•
KK-LC-1 is a cancer germline (CG) antigen with expression restricted to germ cells 
(which lack MHC class I expression) in adults and epithelial cancers including lung, 
breast and gastric.
•
This limited expression pattern makes it an ideal target for T Cell Receptor (TCR) gene 
therapy.
•
TCR T cell therapy targeting CG antigens has been shown to induce objective responses 
without autoimmunity or off-target toxicity in participants with melanoma, synovial 
sarcoma and cervical cancer
•
T cells genetically engineered with a TCR targeting KK-LC-1 display specific reactivity 
against HLA-A*01:01, KK-LC-1 target cells.  
•
KK-LC-1 TCR T cells can mediate tumor regression in pre-clinical mouse models of 
cancer
Objective:
•
To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus aldesleukin for 
the treatment of metastatic KK-LC-1 positive epithelial cancers.
Eligibility:
•
Participants greater than or equal to 18 years old with metastatic or refractory/recurrent 
KK-LC-1 positive epithelial cancer.
•
Prior first line systemic therapy is required unless the participant declines standard 
treatment. 
•
Participants must be HLA-A-*01:01-positive. 
Design:
•
This is a phase I clinical trial that will test the safety and efficacy of escalating doses of 
KK-LC-1 TCR T cells.
•
Participants will receive a non-myeloablative lymphocyte-depleting preparative regimen 
of cyclophosphamide and fludarabine followed by a single infusion of KK-LC-1 TCR T 
cells and high-dose aldesleukin.
•
Re-treatment will be allowed for a small number of subjects

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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS.................................................................................................................3
STATEMENT OF COMPLIANCE.................................................................................................6
1
INTRODUCTION....................................................................................................................6
1.1
Study Objectives ..............................................................................................................6
1.2
Background and Rationale...............................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................22
2.1
Eligibility Criteria ..........................................................................................................22
2.2
Recruitment Strategies ...................................................................................................24
2.3
Screening Evaluation .....................................................................................................24
2.4
Participant Registration and Status Update Procedures.................................................26
2.5
Baseline Evaluation........................................................................................................27
3
STUDY IMPLEMENTATION ..............................................................................................27
3.1
Study Design..................................................................................................................27
3.2
Drug Administration ......................................................................................................31
3.3
Aldesleukin: Intravenous Administration ......................................................................33
3.4
Potential Repeat Treatment............................................................................................34
3.5
On Study Evaluation ......................................................................................................34
3.6
Post treatment Evaluation (Follow-Up) .........................................................................35
3.7
Study Calendar...............................................................................................................37
3.8
Cost and Compensation..................................................................................................39
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria............................39
4
CONCOMITANT MEDICATIONS/MEASURES................................................................40
4.1
Prohibited Medications ..................................................................................................40
4.2
Infection Prophylaxis .....................................................................................................40
4.3
Other Concomitant medications to control side effects.................................................42
5
CORRELATIVE STUDIES FOR RESEARCH ....................................................................42
5.1
Biospecimen Collection .................................................................................................42
5.2
Summary of Sample Collection .....................................................................................44
5.3
Gene-therapy-specific follow-up ...................................................................................45
5.4
Sample Storage, Tracking and Disposition....................................................................45
6
DATA COLLECTION AND EVALUATION ......................................................................47

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6.1
Data Collection...............................................................................................................47
6.2
Data Sharing Plans.........................................................................................................48
6.3
Response Criteria ...........................................................................................................48
6.4
Toxicity Criteria.............................................................................................................55
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN....55
7.1
Definitions......................................................................................................................55
7.2
OHSRP Office of Compliance and Training / IRB Reporting.......................................55
7.3
NCI Clinical Director Reporting....................................................................................55
7.4
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials.........55
7.5
Institutional Biosafety Committee (IBC) Reporting Criteria.........................................56
7.6
NIH Required Data and Safety Monitoring Plan...........................................................57
8
SPONSOR PROTOCOL/SAFETY REPORTING.................................................................58
8.1
Definitions......................................................................................................................58
8.2
Assessment of Safety Events .........................................................................................59
8.3
Reporting of Serious Adverse Events ............................................................................59
8.4
Waiver of expedited reporting to CCR ..........................................................................60
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators.....................................61
8.6
Reporting Pregnancy......................................................................................................61
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND..................62
8.8
Sponsor Protocol Deviation Reporting ..........................................................................62
9
CLINICAL MONITORING...................................................................................................62
10 STATISTICAL CONSIDERATIONS ...................................................................................63
10.1
Statistical Hypothesis.....................................................................................................63
10.2
Sample Size Determination............................................................................................63
10.3
Populations for Analyses................................................................................................64
10.4
Statistical Analyses ........................................................................................................64
11 COLLABORATIVE AGREEMENTS...................................................................................65
11.1
Cooperative Research and Development Agreement (CRADA)...................................65
11.2
Multi-Institutional Guidelines........................................................................................65
12 HUMAN SUBJECTS PROTECTIONS.................................................................................65
12.1
Rationale For Subject Selection.....................................................................................65
12.2
Participation of Children................................................................................................66
12.3
Risk/Benefit Assessment................................................................................................66

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12.4
Consent Process and Documentation.............................................................................71
13 REGULATORY AND OPERATIONAL CONSIDERATIONS...........................................72
13.1
Study Discontinuation and Closure................................................................................72
13.2
Quality Assurance and Quality Control.........................................................................72
13.3
Conflict of Interest Policy..............................................................................................72
13.4
Confidentiality and Privacy............................................................................................73
14 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION................73
14.1
interleukin-2...................................................................................................................74
14.2
Fludarabine.....................................................................................................................75
14.3
Cyclophosphamide.........................................................................................................76
14.4
Cell Preparation (KK-LC-1 TCR Transduced PBL) (IND # 27348).............................77
14.5
Mesna.............................................................................................................................77
14.6
Filgrastim .......................................................................................................................78
14.7
Trimethoprim and Sulfamethoxazole Double Strength (TMP/SMX DS)......................79
14.8
Aerosolized Pentamidine in Place of TMP/SMX DS ....................................................79
14.9
Herpes Virus Prophylaxis ..............................................................................................79
14.10 Fungal Prophylaxis.........................................................................................................80
14.11 Support Medications ......................................................................................................80
14.12 KK-LC-1 Positivity Assay (NSR Device) .....................................................................80
15 REFERENCES .......................................................................................................................81
16 APPENDICES........................................................................................................................88
16.1
Appendix A:  Adverse Events Occurring In ≥10% Of Participants Treated With 
Aldesleukin (N=525)1 ....................................................................................................88
16.2
Appendix B:  Expected IL-2 Toxicities And Their Management..................................89
16.3
Appendix C:  Interleukin-2 Toxicities Observed In Participants Treated At The NIH 
Clinical Center ...............................................................................................................92
16.4
Appendix D:  Performance Status Criteria.....................................................................93
16.5
Appendix E:  Certificate Of Analysis KK-LC-1 TCR...................................................94
16.6
Appendix F:  Modification of Dose Calculations* in participants whose BMI is greater 
than 35............................................................................................................................96
16.7
Appendix G:  Infusion Reactions – Guidelines for Management..................................97
16.8
Appendix H:  Participating Site Roles and Oversight Plan............................................98

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus 
aldesleukin for the treatment of metastatic KK-LC-1 positive epithelial cancers.
1.1.2
Exploratory Objectives
•
To assess the safety and efficacy of KK-LC-1 TCR T cells plus aldesleukin for 
the treatment of KK-LC-1+ cancers.
•
To conduct exploratory immunologic studies to understand and improve the 
administered treatment. 
1.2
BACKGROUND AND RATIONALE
It is estimated that metastatic epithelial cancers are responsible for approximately 90% of 
cancer deaths [1-3]. The estimated 600,000 cancer deaths each year is driven largely by lung 
adeno- and squamous cell carcinoma and invasive breast cancer. These cancers account for 
approximately 30% of all cancer-related deaths in the United States (Figure 1) [4]. Furthermore, 
there are approximately 4,000 deaths per year due to cervical cancer and 10,000 from gastric 
cancer. 

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Figure 1. Leading Sites of New Cancer Cases and Deaths – 2020 Estimates. 
The current treatment landscape for metastatic non-small cell lung cancer (NSCLC) has 
evolved over the past several years to include PD-1 based therapies. A recent, double-blind, 
phase 3 clinical trial demonstrated an improvement in the rate of overall survival at 12 months 
from 49% to 69% with the addition of pembrolizumab to standard platinum-containing 
chemotherapy as first-line treatment for metastatic, PD-L1 positive non-small cell lung cancer 
(NSCLC) [5]. Another recent phase 3 clinical trial demonstrated an improvement in median 
overall survival from 14.7 months to 19.2 months with the addition of atezolizumab and 
bevacizumab to first-line standard of care platinum-containing chemotherapy in participants with 
untreated metastatic, PD-L1 negative NSCLC [6]. Though progress has been made, the outlook 
for these participants remains poor with a 5-year relative survival rate of approximately 20% [4].  
Metastatic, triple negative (ER/PR negative, HER2 negative) breast cancer portends a 
worse prognosis compared to metastatic, ER/PR positive breast cancer. Treatment with single 
agent chemotherapy is recommended for participants without germline BRCA 1/2 mutations or 
PD-L1-positive tumors. Clinical activity is modest with response rates anywhere from 10-40% 
[7-10]. In participants with PD-L1 positive disease, the addition of atezolizumab to single agent 
nab-paclitaxel resulted in a modest benefit in PFS of <2 months with a nonsignificant trend in 
improved median overall survival (17.6 vs 21.3 months) compared to single agent nab-paclitaxel 
[11]. A more substantial benefit in PFS and OS was seen in participants with tumors containing 
high populations of PD-L1-expressing immune effector cells [11]. Regardless, better therapies 
are still needed. 

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Like many other epithelial cancers, cervical cancer is incurable in the metastatic setting 
and difficult to palliate. Responses to chemotherapy are usually short-lived with a median PFS 
around 3 to 7 months [12, 13]. In a Gynecologic Oncology Group randomized trial comparing 
four cisplatin-based doublets as first line therapy for cervical cancer the response rates were 22 
to 29 percent, median PFS was 4 to 6 months and median overall survival (OS) was 10 to 13 
months [14]. The addition of bevacizumab to combination chemotherapy has been reported to 
increase overall survival by 3.7 months, but the vast majority of participants still die of their 
disease within 2 years [15]. Early evidence suggests that immune checkpoint therapy has only 
modest activity in this disease with a phase Ib trial (KEYSTONE 028) showing a 12.5% 
response rate (3/24 participants) and a phase II study showing a response rate of 13.3% (13/98 
participants) to pembrolizumab [16].
Worldwide, gastric cancer remains a global health concern with nearly 1 million new cases 
diagnosed each year [17]. Approximately 75% of participants are diagnosed with metastatic 
disease, where median survival is around 12 months [18, 19]. The preferred treatment for 
metastatic gastric cancer includes a two-drug cytotoxic regimen consisting of a fluoropyrimidine 
(fluorouracil or capecitabine) and platinum (oxaliplatin or cisplatin) [20-25]. The survival benefit 
of chemotherapy over best supportive care is approximately 6.7 months [19]. Combination 
chemotherapy extends survival only slightly compared to single agent chemotherapy which is 
counterbalanced by an increase in toxicity [26]. In participants with HER2 overexpressing 
adenocarcinoma, the addition of trastuzumab to first-line chemotherapy improves overall 
survival by 2.7 months compared to chemotherapy alone (13.8 vs 11.1 months) [27]. Second-line 
treatments include single agent chemotherapy. Most data are from participants that were 
treatment-naïve or received one line of prior systemic therapy [28-30]. A randomized, placebo-
controlled, double-blind, phase 3 trial comparing paclitaxel plus the VEGFR-2 antagonist 
ramucirumab to paclitaxel plus placebo demonstrated an improved overall survival of 2.2 months 
(9.6 vs 7.4 months) [31]. Pembrolizumab is recommended as second-line treatment for 
participants with MSI-H or dMMR tumors or as third-line therapy for adenocarcinomas with PD-
L1 expression levels by CPS >1 where the response rate only reached 11.6% in the 259 
participants treated [32-34]. More effective therapies are desperately needed. 
1.2.1
Adoptive T cell Therapy
Adoptive T cell Therapy (ACT) with antigen receptor gene-engineered T cells that express 
chimeric antigen receptors (CARs) or T cell receptors (TCRs) is a promising cancer treatment. 
CARs have demonstrated robust clinical activity against multiple hematologic malignancies 
including acute lymphoblastic leukemia, non-Hodgkin lymphoma and multiple myeloma [35-
37]. Translating this success to epithelial cancers has been a challenge [38, 39]. TCRs have 
shown clinical activity in melanoma and synovial cell sarcoma but success in epithelial cancers 
has been limited [39, 40]. A major challenge in targeting epithelial cancers is identification of a 
target antigen expressed on tumor cells that is not expressed by vital healthy tissue [41]. Initial 
efforts by our group focused on targeting human papillomavirus (HPV) associated epithelial 
cancers. HPV+ cancers are attractive candidates for T cell therapy because they express viral 
antigens that can be targeted by T cells [39]. The primary antigens for targeting with 
immunotherapy are the HPV E6 and E7 oncoproteins, which are viral proteins that are 
constitutively expressed by HPV+ cancers and not expressed by healthy human tissues. E6 and 
E7 contribute to malignant transformation and to survival of cancer cells, and this functional 
importance also makes them attractive therapeutic targets.

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Our initial clinical trial employing TCR T cell therapy in HPV-associated cancers targeted 
the E6 antigen. To accomplish E6 targeting, autologous peripheral blood T cells were genetically 
engineered to express an HLA-A*02:01-restricted, HPV16 E629-38-specific T cell receptor (TCR) 
[42]. The trial was a phase I/II, dose-escalation study. Participants had metastatic HPV16+ 
cancer that in most participants was refractory to multiple systemic agents. Participants received 
a conditioning regimen of cyclophosphamide 60 mg/kg for two days and fludarabine 25 mg/m2 
for five days. Cell infusion was followed by high-dose aldesleukin. Two of 12 participants 
experienced partial tumor responses; one subsequently had residual disease resected by surgery, 
and she is without evidence of cancer years later. This trial validated the ability of T cell therapy 
targeting a single antigen to mediate regression of a metastatic epithelial cancer. 
We are currently conducting a phase I/II clinical trial using a TCR targeting the E7 antigen. 
Similar to other T cell therapy trials, participants receive a conditioning regimen of 
cyclophosphamide 60 mg/kg or 30 mg/kg daily for two days and fludarabine 25 mg/m2 daily for 
five days. Cell infusion is followed by high-dose aldesleukin. Thus far, objective tumor 
responses have been seen in 10 of 20 participants treated. Five of these responses were seen in 
participants previously treated with PD-1 based therapy. These responses included marked 
regression of bulky tumors in heavily pretreated participants (Figure 2). This study provides 
further evidence of the potential of T cell therapy to mediate regression of widely metastatic, 
heavily pretreated epithelial cancers. 
1.2.2
TCR T cell therapy targeting Cancer Germline Antigens
Cancer germline (CG) antigens are normally expressed predominantly by germ cells but 
can be expressed in cancers. However, because they do not express MHC class I molecules, 
germ cells are not recognized by TCRs. CG antigens can be subcategorized as testis restricted, 
testis and/or brain restricted, or testis selective based on their expression pattern. Testis-restricted 
and certain testis-selective CG antigens are rational targets for TCR T cell therapy [41].
Successful targeting of CG antigens including NY-ESO-1 and the MAGE family proteins 
has been demonstrated in previous clinical trials. In a phase I, cell dose escalation trial of an 
MHC class II-restricted TCR targeting MAGE-A3, a total of 17 participants were treated. A 
complete response was seen in one participant with metastatic cervical cancer that was ongoing 
for more than 29 months. At the highest dose level of cells, 3 of 9 participants experienced 
partial responses [43]. There were no off-target toxicities or targeting of healthy tissue. Another 
clinical trial tested an MHC class I-restricted TCR targeting the CG antigen NY-ESO-1. 
Responses were seen in 11 of 18 participants with synovial cell sarcoma and 11 of 20 
participants with melanoma [40]. No autoimmune-mediated toxicities were seen. 

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Figure 2. Clinical 
Activity of E7 
TCR-T Cells. 
Participant 1 had 
metastatic vulvar 
cancer with 
extensive 
pulmonary, 
retroperitoneal, 
pelvic and thigh 
lesions. Participant 
5 had metastatic 
anal cancer with 
numerous 
pulmonary, pleural, 
and kidney lesions. 
Participant 12 had 
metastatic cervical 
cancer with chest 
wall, 
retroperitoneal, and 
rectal lesions. 
1.2.3
The Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1)
KK-LC-1 (encoded by CT83) is a cancer germline antigen that is reported to have 
restricted expression in healthy tissue and frequent expression in certain epithelial cancers 
including lung, gastric and breast cancer [44-46]. It is the only member of its family, and 
therefore might be targeted without risk of intra-family cross-reactivity. Like most CG antigens, 
expression is regulated by epigenetic mechanisms that often result in coordinate gene expression. 
KK-LC-1 was identified as a potential immunotherapy antigen by characterization of the target 
of a lung adenocarcinoma-reactive T cell clone [44]. 
In a report published by our group, we examined the distribution of the CG antigen KK-
LC-1 in normal tissue and epithelial cancers. CT83 expression was detected in the epididymis 
and testis, which lack HLA expression and thus, cannot be targeted by T cells, while absent from 
a broad range of normal tissue which included 51 non-neural and 24 neural tissues (Figure 
3A,B) [47]. These data suggest that KK-LC-1 is a testis-restricted CG antigen. To investigate 
whether KK-LC-1 is expressed by epithelial cancers, bioinformatic analysis of The Cancer 
Genome Atlas (TCGA) Provisional data set accessed on the cBioPortal Cancer Genomics public 
database was performed. This analysis showed a wide range of cancers that expressed CT83 
including testicular cancer, lung adenocarcinoma, pancreatic cancer, lung squamous cell 
carcinoma, cervical cancer, bladder cancer, head and neck cancer (Figure 4A). Furthermore, we 

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tested 57 cancer cell lines from 10 different types of cancer for CT83 expression by qRT-PCR. 
Lung, breast, cervical, ovarian, melanoma, prostate, and leukemia cancer cell lines were found to 
express CT83, albeit with varying levels and frequencies of expression (Figure 4B). We 
previously observed CT83 expression in an HPV+ metastatic cervical cancer. Examination of a 
bank of metastatic cervical cancer specimens revealed expression in 6/21 (29%) of cervical 
squamous cell carcinomas and 5/8 (63%) of cervical adenocarcinomas (Figure 4C). In other 
HPV+ cancers, expression was detected in 1/8 anal cancers, 0/5 head and neck cancers, and 0/2 
vaginal cancers [47].
To assess the frequency of cells within a tumor that express CT83, we performed RNA in 
situ hybridization with RNAScope on a variety of epithelial cancers. The highest frequency of 
positive cells occurred in gastric cancers, of the 13 samples tested, 9 were positive for CT83 
expression (median: 50%, range: 5 to 90%). Triple negative breast cancer and cervical cancer 
also had a high frequency of cells expressing CT83 (Figure 5). Non-small cell lung cancer had a 
few samples with a high frequency of CT83 expressing cancer cells. These studies demonstrate 
that KK-LC-1 may be an attractive target for TCR-T cell therapy in participants with gastric, 
breast, cervical and potentially lung cancer [47]. 
1.2.4
Discovery and characterization of the KK-LC-1 TCR
We identified a KK-LC-1 TCR from the tumor-infiltrating lymphocytes (TILs) of a 
participant with cervical cancer who had a complete tumor response to TIL therapy (Figure 6) 
[48]. The KK-LC-1 clonotype containing the TCR was the most dominate clonotype in the 
infused TIL product with a frequency of 67%. This frequency exceeded that of the HPV-specific 
TCR clonotype by a factor of at least 10 across all time points measured (as far out as 10 
months) (Figure 7) [48]. The relatively high frequency and persistence of the infused KK-LC-1 
clonotype suggests that it might have contributed to cancer regression in this participant.  
The KK-LC-1 TCR was found to target KK-LC-152-60, a naturally processed epitope, 
presented by the HLA-A*01:01 molecule [48]. Predicted binding of KK-LC-152-60 to other HLA 
molecules was weaker. The nucleotide sequence encoding the TCR was codon optimized for 
expression in human tissues and the TCR constant regions were swapped for their mouse 
counterparts, which in other receptors has improved TCR alpha/beta chain pairing. TCR 
expression was improved by reversing the order of the alpha and beta genes, and by making 
cysteine substitutions in the TCR constant regions and hydrophobic substitutions in the 
transmembrane region of the alpha chain constant region (Figure 8) [49, 50]. The TCR displayed 
recognition of as low as 10-3 µg/mL of the cognate peptide KK-LC-152-59 in the context of HLA-
A*01:01+ target cells  [51]. Peripheral blood T cells transduced to express the KK-LC-1 TCR 
display CD8-independent HLA-A*01:01/KK-LC-152-60 tetramer binding (Figure 9).

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Figure 3. CT83 expression in healthy tissue. A. cDNA from a custom-made panel of 51 non-neural tissues and 24 
neural tissues was assessed for CT83 and CTAG1A expression by qRT-PCR. cDNA from cancer cell lines and 
human T cells were included as controls. The y-axis displays total copy number. This experiment was performed 
twice with similar results. B. Healthy tissue expression of CT83 and CTAG1A is graphed as a heatmap based on 
data collected from the U133plus2 Affymetrix microarray available through BioGPS. The values shown are z-scores 
produced by the barcode function of the R package “frma.” z-scores greater than 5 are suggestive of gene expression 
in the tissue.

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Figure 4. CT83 expression by cancer cell lines and tumors. A. The frequency (% of tumors that express the 
antigen) of CT83 expression by different cancer types was assessed. Expression data are derived from TCGA 
Provisional dataset accessed through cBioportal. Fragments Per Kilobase of transcript per Million mapped reads 
(FPKM) values > 0 were considered positive. The number of samples per cancer type is indicated in parentheses. B. 
A panel of cancer cell lines was assessed for CT83 expression by qRT-PCR. The y-axis displays CT83 copies per 
105 copies of ACTB. This experiment was performed twice with similar results. C. The frequency of HPV+ 
metastatic cancers that express CT83 was assessed by qRT-PCR. The number of samples per cancer type is 
indicated in parentheses. Experiments were performed twice.

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Gastric
Breast
Cervical
Lung (adeno)
Lung (squamous)
Pancreas
Bladder
0
50
100
CT83 (% tumor cells positive)
Figure 5. Intratumoral heterogeneity of CT83 expression. Top row depicts sample images of CT83+ tumors by 
RNAScope. The epithelial cancer is indicated above each image. The bottom row depicts the frequency of CT83+ 
tumor cells scored by an independent, blinded pathologist.  
Gastri
c
Breas
t
Cervical
Lung
Pancrea
s

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Figure 6. Participant was a 36-year-old female with metastatic cervical adenocarcinoma in the para-aortic lymph 
node, abdominal wall, aortocaval lymph node, left pericolic pelvic mass, and right ureteral nodule (gold arrows). 
She was treated with TIL therapy and had no evidence of disease 15 months after treatment. Red arrowhead 
indicates ureteral stent that was removed after right ureteral tumor regressed.

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Figure 7. Frequency of KK-LC-1 clonotype in participant with complete response to TIL therapy. Frequency 
(f, %) and rank of individual tumor antigen–specific TCR clonotypes, as identified within TIL-3853 among PB 
mononuclear cells (PBMCs) before and after treatment (at the indicated months), were determined by TCRB deep 
sequencing. Posttreatment samples at 1 month during tumor regression and at 5.6 and 10.6 months during remission 
were analyzed. Pre indicates before treatment, Post indicates after treatment, and M indicates month(s).
We then tested to see if third-party human T cells that were transduced to express the 
KK-LC-1 TCR recognized tumor cell lines that express CT83 and HLA-A*01:01 in vitro. In 
overnight coculture assays, KK-LC-1 TCR-T cells from 2 donors displayed interferon (IFN)-γ 
release in response to cell lines that expressed the target antigen and the HLA restriction element, 
which indicated recognition of these lines (Figure 10A) [47]. These included the unmanipulated 
cell lines 4156 (cervical cancer), EKVX (lung cancer), and A375 (melanoma). All tested cell 
lines that expressed both the target antigen and the restriction element were recognized; 
conversely, all cell lines that did not express both the target antigen and the restriction element 
were not recognized. 
To assess if systemically administered KK-LC-1 TCR-T cells could mediate tumor 
responses in vivo, we employed a murine xenograft model for the treatment of subcutaneous, 
established 4156 or A375 tumors. A single intravenous injection of KK-LC-1 TCR-T cells 
induced regression of 4156 tumors (Figure 10B). At the highest dose (10 × 106 cells) all mice 
demonstrated complete tumor regression. A375 tumors, which display heterogenous CT83 
expression, eventually recurred, and recurrent tumors showed low CT83 expression, which may 
have contributed to their late relapse. Nonetheless, all mice with either 4156 or A375 tumors 
treated with at least 1x106 KK-LC-1 TCR-T cells displayed tumor regression. These data 
indicate that KK-LC-1 TCR-T cells can target tumor cells in vitro and can mediate the regression 
of tumors in vivo [47].
We next evaluated KK-LC-1 TCR-T cells for cross-reactivity against potential epitopes 
of other human proteins. To determine which residues in the KK-LC-152-60 epitope were critical 
for recognition by the KK-LC-1 TCR, we performed alanine and glycine scanning of the KK-
LC-152-60 peptide. Alanine substitutions at positions 3, 4, 5, 6, and 9 and glycine substitutions at 
positions 2, 3, 5, 6, 7, and 9 caused a greater than 75% decrease in IFN-γ release as compared to 
the wild type peptide. Based on these data, the residues at positions 3, 5, 6, and 7 were inferred to 
be the most essential non-anchor residues for TCR recognition (Figure 11A,B). The ScanProsite 
online tool was used to search for human proteins that shared these positions [52]. In addition, a 
Basic Local Alignment Search Tool (BLAST) search identified 6 more human peptides with 
high levels of sequence identity to KK-LC-152-60. KK-LC-1 TCR-T cells were tested for 

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recognition of the 10 candidate peptides in a coculture assay; recognition was not detected 
(Figure 11C). Thus, the KK-LC-1 TCR did not demonstrate detectable cross-reactivity against 
human peptides in vitro [47]. These characteristics demonstrate the potential efficacy and safety 
of KK-LC-1 TCR-T cells as a cancer therapeutic for participants with KK-LC-1+ epithelial 
cancers.  
Figure 8. KK-LC-1 TCR vector map. A TCR targeting KK-LC-152-60 was isolated from a participant with a 
complete response to tumor-infiltrating lymphocyte therapy. The nucleotide sequence of the alpha and beta chains 
was determined, codon optimized for expression in human tissues, and the constant regions swapped for their mouse 
counterparts. A MSGV1 retroviral vector encoding this TCR was constructed. This retroviral vector consists of 
7,313 base pairs and includes a 5’LTR from the murine stem cell virus (promoter), packaging signal including the 
splicing donor (SD) and splicing acceptor sites (SA).  Alpha and beta chains of the KK-LC-1 TCR are linked by a 
furin 2A peptide.

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Figure 9:  Peripheral blood T cells transduced to express the KK-LC-1 TCR display CD8-independent HLA-
A*01:01/KK-LC-152-60 tetramer binding. T cells from PBMC were transduced to express the KK-LC-1 TCR. Dot 
plots shown are gated on PI- lymphocytes and either CD8+ or CD8- cells as indicated above the dot plots. The x-
axis is mouse T cell receptor beta chain expression. The y-axis is tetramer binding.

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Figure 10. KK-LC-1 TCR-T cells display tumor recognition in vitro and mediate tumor regression in vivo. A. 
Human CD8+ T cells from each of 2 donors were transduced to express the KK-LC-1 TCR (KK-LC-1 TCR-T cells) 
or were not transduced (UT-Ts). Tumor recognition was tested in an overnight coculture assay with the target cell 
line indicated on the x-axis. The quantity of IFN-γ in the culture supernatants was determined by ELISA. Expression 
of CT83 and HLA-A*01:01 by each target cell line is indicated in the key below the x-axis. HLA-A*01:01 
transduced cell lines were CT83+ and transduced with a γ-retrovirus to express HLA-A*01:01. “PMA/Iono” 
indicates T cells that were stimulated with PMA and ionomycin. “T cells alone” indicates T cells that were cultured 
without target cells or stimulation. B. KK-LC-1 TCR-T cells or control T cells indicated in the figure legend were 
administered intravenously to NSG mice bearing established 4156 or A375 subcutaneous tumors (as indicated above 
each graph). Serial tumor measurements were plotted at the timepoints indicated on the x-axis. Untreated mice did 
not receive any therapy. UT-Ts were not transduced. DMF-5 TCR-T cells target an irrelevant antigen (melanoma 
associated antigen-1) [53]. N = 10 mice per group. Error bars indicate the standard error of the mean. This 
experiment was performed twice with similar results

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Figure 11. KK-LC-1 TCR-T cells did not demonstrate cross-reactivity with peptides derived from other 
human proteins. The IFN-γ production assays shown were performed by coculture of KK-LC-1 TCR-T cells with 
autologous EBV-LCLs loaded with 1 μg/mL of the peptide indicated. Coculture supernatants were harvested after 
overnight coincubation. IFN-γ concentration was determined by ELISA. Error bars represent the SD of 2 technical 
replicates. The “no peptide” conditions had target cells without peptide. “PMA/Iono” indicates T cells that were 
stimulated with PMA and ionomycin. “UT-Ts” were untransduced control T cells from the same donor as the KK-
LC-1 TCR-T cells. A. To guide cross-reactivity testing, alanine scanning of KK-LC-152-60 was performed. An 
alanine residue was substituted for the native residue at each position of KK-LC-152-60. B. To compliment alanine 
substitution and assess the influence of position 7 on target recognition, glycine scanning also was performed. Based 
on these data, the residues at positions 3, 5, 6, and 7 were inferred to be the most essential non-anchor residues for 
TCR recognition C. Peptides derived from human proteins that demonstrated identity at the contact residues inferred 
by the experiments in (a) and (b) or by a BLAST search for candidate peptides that shared at least 5/9 residues (55% 
identity) were tested for KK-LC-1 TCR-T recognition.
1.2.5
Safety Considerations
The safety of infusion of large numbers of retrovirally modified tumor reactive T cells 
has been demonstrated in prior clinical studies. Protocols at the NIH Clinical Center have 
administered over 1 X 1011 tumor infiltrating lymphocytes (TIL) with widely heterogeneous 

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reactivity including CD4, CD8, and NK cells. Experience at the NIH Clinical Center treating 
more than 200 participants with advanced cancers with genetically engineered T cells have not 
identified a risk of malignant transformation in this setting. The risk of insertional mutagenesis is 
a known possibility using retroviral vectors. It has been observed in the setting of CD34+ 
hematopoietic stem cells for the treatment of XSCID, WAS, and X-CGD. It has also been 
reported with lentiviral transduction in a participant who received CD19 CAR-T cells (it did not 
cause malignant transformation and may have enhanced the efficacy of the T cells) [54]. With 
retroviral vector-mediated gene transfer into mature T cells, there has been no evidence of 
malignancy due to genotoxicity since the first NCI sponsored gene transfer study in 1989. 
Although continued follow-up of all gene therapy participants will be required, data support the 
safety of retrovirally transduced mature T cells [55]. While the risk of insertional mutagenesis is 
low, the proposed protocol follows all current FDA guidelines regarding testing and follow up of 
participants receiving gene transduced cells [56].  Non-myeloablative chemotherapy 
conditioning and high-dose aldesleukin have well-characterized toxicity which is discussed in 
Section 12.4 of this study [57]. The chemotherapy used in this protocol has been administered to 
over 500 participants and all have reconstituted their hematopoietic system.  
Toxicity from the KK-LC-1 TCR is unlikely because 1) the TCR came from a human and 
therefore has been selected in thymus to not have autoreactivity, so autoimmunity is unlikely, 2) 
the TCR specificity has not been altered by affinity enhancement so there is no chance that cross 
reactivity against normal human proteins has been introduced, 3) testing against human peptides 
with similarity to the target epitope and with human peptides identified by alanine and glycine 
scanning revealed no cross reactivity, 4) gene expression data suggests that expression in healthy 
tissue is restricted to immune privileged germ cells.
The starting cell dose of 1x108 is the same starting dose used in other TCR T cell therapy 
trials at the NIH including an ongoing phase I/II trial of TCR T cell therapy targeting KRAS 
G12D (NCT03745326). Experience with solid tumors such as melanoma and synovial sarcoma 
indicate that T-cell numbers between 3x1010 and >1x1011 may be required to achieve durable 
tumor regressions. Therefore, with a slow dose escalation, an undesirably high number of 
participants may be treated with suboptimal cell numbers while being exposed to the risks of 
conditioning chemotherapy. To avoid this, an escalation of 1 log will be employed starting at 
1x108 to a maximum cell dose of 6x1010. Furthermore, an in situ hybridization (ISH) assay will 
be used to measure the intratumoral heterogeneity of CT83 expression in a participant’s tumor. 
This test may help us select participants with tumors that have homogenous expression of the 
target antigen and have a higher chance of receiving clinical benefit from this therapy while 
decreasing the chance of exposing a participant with tumors that have low or no expression of 
the target antigen to the risks of the conditioning chemotherapy. With Amendment A, an 
immunohistochemistry (IHC) assay will be used to select participants. Similar to the ISH assay, 
the IHC assay may help us select participants who may have a higher chance of receiving clinical 
benefit while decreasing the chance of exposing patients who may not receive benefit to the risks 
of conditioning chemotherapy. IHC is a reliable and common assay used in clinical medicine. 

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The same eligibility criteria used for the ISH assay (score of 25% or greater) will be used for the 
IHC assay.     
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Participants must have histologically or cytologically confirmed KK-LC-1 positive 
epithelial cancer (KK-LC-1 positivity assay performed at Rutgers Cancer Institute of New 
Jersey). KK-LC-1 expression will be determined by immunohistochemistry (IHC). KK-
LC-1 score of 25% or greater will be considered positive. 
2.1.1.2
Participants must be HLA-A*01 by low resolution typing, and HLA-A*01:01 by one of 
the high resolution type results
2.1.1.3
Measurable (per criteria in section 6.3) metastatic or refractory/recurrent KK-LC-1+ 
epithelial cancer (determined by IHC).
2.1.1.4
All participants must have received prior first line standard therapy or be ineligible to 
receive available therapies with known survival benefit. 
2.1.1.5
Participants with three or fewer brain metastases that have been treated with surgery or 
stereotactic radiosurgery are eligible.  Lesions that have been treated with stereotactic 
radiosurgery must be clinically stable for one month before protocol treatment. 
Participants with surgically resected brain metastases are eligible.
2.1.1.6
Age >18 years of age. Because no dosing or adverse event data are currently available 
on the use of KK-LC-1 TCR in participants <18 years of age, children are excluded 
from this study.
2.1.1.7
ECOG performance status <1 (Appendix D).
2.1.1.8
Participants must have adequate organ and marrow function as defined below: 
leukocytes
>3,000/mcL
absolute neutrophil count
>1,500/mcL
platelets
>100,000/mcL
hemoglobin
>9.0 g/dL
total bilirubin
within normal institutional limits
AST(SGOT)/ALT(SGPT)
<2.5 X institutional upper limit of normal
creatinine
within normal institutional limits
OR
creatinine clearance
>60 mL/min/1.73 m2 for participants with 

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creatinine levels above institutional normal.
2.1.1.9
Serology:
•
Seronegative for HIV antibody.  (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Participants who are HIV seropositive can 
have decreased immune-competence and thus are less responsive to the experimental 
treatment and more susceptible to its toxicities.)
•
Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.  If 
hepatitis C antibody test is positive, then the participant must be tested for the presence of 
antigen by RT-PCR and be HCV RNA negative.
2.1.1.10 The effects of the study agent on the developing human fetus are unknown. For this 
reason and because other therapeutic agents used in this trial are known to be 
teratogenic, individuals of child-bearing potential and their partners must agree to use 
adequate contraception (barrier method of birth control; abstinence) prior to study entry 
and up to twelve (12) months after treatment. Individuals of childbearing potential must 
have a negative pregnancy test. Individuals of childbearing potential are defined as all 
individuals except individuals who are postmenopausal or who have had a 
hysterectomy. Postmenopausal will be defined as individuals over the age of 55 who 
have not had a menstrual period in at least one year or a participant that has received a 
treatment (i.e., chemotherapy or pelvic radiation) that has resulted in them becoming 
postmenopausal. Should an individual become pregnant or suspect pregnancy while 
individuals or partner is participating in this study, individuals should inform treating 
physician immediately. 
2.1.1.11 Because there is a potential risk for adverse events in nursing infants secondary to 
treatment of the mother with KK-LC-1 TCR transduced PBL, breastfeeding should be 
discontinued if the mother is treated with KK-LC-1 TCR transduced PBL. These 
potential risks may also apply to other agents used in this study. 
2.1.1.12 More than four weeks must have elapsed since any prior systemic therapy at the time 
the participant receives the KK-LC-1 TCR T cells.
2.1.1.13 Participants may have undergone minor surgical procedures within the past three weeks, 
as long as all toxicities have recovered to Grade 1 or less or as specified in the 
eligibility criteria in Section 2.1.
2.1.1.14 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
Participants who are receiving any other investigational agents.
2.1.2.2
History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine 
or aldesleukin.
2.1.2.3
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 

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study requirements. Participants with abnormal pulmonary function tests but stable 
obstructive or restrictive pulmonary disease may be eligible.
2.1.2.4
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease).
2.1.2.5
Concurrent opportunistic infections (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Participants who have decreased 
immune competence may be less responsive to the experimental treatment and more 
susceptible to its toxicities).
2.1.2.6
Participants with autoimmune diseases such as Crohn’s disease, ulcerative colitis, 
rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus 
rythematosus.  Hypothyroidism, vitiligo and other minor autoimmune disorders are not 
exclusionary.
2.1.2.7
Participants on active systemic immunosuppressive therapy that cannot be safely 
withheld.
2.1.2.8
Participants with a history of coronary revascularization or ischemic symptoms unless 
participant has a normal cardiac stress test.
2.1.2.9
Any condition which would, in the opinion of the Principal Investigator, indicate that 
the subject is a poor candidate for the clinical trial or would jeopardize the subject or the 
integrity of the data obtained. 
2.1.2.10 Documented LVEF ≤ 45% 
2.2
RECRUITMENT STRATEGIES
Participants for this protocol will be recruited via standard CCR mechanisms including posting 
to NIH websites (i.e., clinicaltrials.gov) and social media platforms, physician and self-referrals 
as well as various advertising venues.  All advertisements, letters and other recruitment efforts 
will be submitted to the IRB for approval prior to their implementation.
2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc. 
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a participant has 
signed the consent. 

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2.3.2.1
Within 24 hours prior to screening activities:
•
Negative pregnancy test
2.3.2.2
Any time prior to starting the chemotherapy regimen:
a.
HLA typing**
b. KK-LC-1 testing of tumor. Archival tissue may be used or a new biopsy may be 
obtained***
c.
Venous assessment (as per apheresis clinic policy)
2.3.2.3
Within 4 weeks prior to starting the chemotherapy regimen:
a.
Complete history and physical examination, including weight, and vital signs noting in 
detail the exact size and location of any lesions that exist.  (Note: Participant history may 
be obtained within 8 weeks.)
b. EKG
c.
Pulmonary Function Testing for participants with a prolonged history of cigarette 
smoking (20 pack/year of smoking within the past 2 years) or symptoms of respiratory 
dysfunction. (Note: If performed within 1 year of screening, this does not need to be 
repeated unless clinically indicated.  Test results from outside the CCR may be accepted 
per investigator discretion).
d. If available, previous CT of the chest, abdomen and pelvis, and brain MRI or PET to 
evaluate the status of disease. Additional scans and x-rays may be performed if required 
to determine participant eligibility or if clinically indicated based on participants’ signs 
and symptoms. (Note: Test results from outside the CCR may be accepted per 
investigator discretion if performed within 3 months of screening).
e.
Cardiac evaluation for participants who are greater than or equal to age 50, or who have a 
history of ischemic heart disease, chest pain, or clinically significant atrial and/or 
ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular 
tachycardia, heart block.  Participants with a LVEF of less than or equal to 45% will not 
be eligible.  Participants under the age of 50 who present with cardiac risk factors may 
undergo cardiac evaluation (e.g., diabetes, hypertension, obesity.) (Note: Test results 
from outside the CCR may be accepted per investigator discretion if performed within 6 
months of screening).   
f.
HIV antibody titer and HbsAG determination, anti-HCV.  (Note: may be performed 
within 3 months of chemotherapy start date but must be within one month before initial 
apheresis for generation of a cell product).
g. Anti CMV antibody titer, HSV serology, and EBV panel.  (Note:  participants who are 
known to be positive for any of the above do not need to be retested; may be performed 
within 3 months of chemotherapy start date).
2.3.2.4
Within 14 days prior to starting the chemotherapy regimen:
a.
Blood tests:
•
Complete Blood count with differential

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•
Chemistries: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (Bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium 
total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, 
Total Bilirubin, Direct Bilirubin, and Total Protein.
•
Thyroid Panel
b. Urinalysis and culture if indicated
2.3.2.5
Within 7 days prior to starting the chemotherapy regimen:
a.
Beta-HCG pregnancy test (serum or urine) on all individuals of child-bearing potential
b. ECOG performance status of 0 or 1
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at:  
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.4.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
2.4.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Phase I: Dose Escalation 
Cohort
 Evaluable participants with KK-LC-1 positive epithelial cancer to 
determine MTD of KK-LC-1 TCR T cells plus aldesleukin
Arms
Number
Name
Description
1
Treatment at dose levels 1 
through 6
Non-myeloablative, lymphocyte depleting preparative regimen, 
followed by KK-LC-1 TCR T cells plus aldesleukin at escalating 
doses
Arm Assignment
Participants in Cohort 1 will be directly assigned to Arm 1. 

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2.5
BASELINE EVALUATION
The following are baseline evaluations. Some of the screening evaluations may be used as 
baseline. 
2.5.1
Within 4 weeks prior to starting the chemotherapy regimen:
a.
Participants with lesions that can be biopsied under sedation and/or local anesthesia (skin 
lesions, visceral lesions approachable by CT, USG or MRI guided core biopsy) and who 
are willing to have biopsies performed, will have a baseline pre-treatment biopsy 
followed by two additional biopsies, one following treatment (6 weeks post treatment 
preferred) and the second at the time of progression.  Refer to Section 5.1.3 for guidelines 
for handling specimens.  
b. CT of the chest, abdomen and pelvis, PET scan and brain MRI may be performed to 
evaluate the status of disease.  
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a single-center, phase I clinical trial that will determine a safe dose of KK-LC-1 TCR T 
cells. Participants will receive a non-myeloablative lymphocyte-depleting preparative regimen of 
cyclophosphamide and fludarabine followed by a single infusion of KK-LC-1 TCR T cells and 
high-dose aldesleukin. 
A small number of subjects may be eligible for re-treatment, and would be required to meet all 
eligibility criteria at the time of re-enrollment. Participants will be assigned a new sequential 
study number for the re-enrollment study period. Any cryopreserved cells produced from a 
participant who was removed from the study can be used to treat that participant after re-
enrollment. We do not anticipate changes in the risk profile for the initial versus re-enrollment.
*Details regarding the number of participants in each dose level group are provided in section 3.1.5.
-6
-5
-4
-3 -2 -1
0
3
2
1
Cyclophosphamide 30 mg/kg
Fludarabine 25 mg/m
2
KK-LC-1 TCR T cells 
Aldesleukin 720,000 IU/Kg 

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3.1.1
Leukapheresis
The participant will undergo a 10-15 liter leukapheresis (generally, 12 liters will be processed to 
target a yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) 
Dowling Apheresis Clinic according to DTM standard operating procedures. This procedure may 
occur on this protocol, or protocol 16C0061, if the participant chooses to co-enroll on that 
protocol. The procedure requires dual venous access and takes approximately 3-4 hours to 
complete. A central line will be placed if peripheral venous access is not sufficient. 
Leukapheresis material that is not required for clinical use may be retained and cryopreserved in 
10 vials at 100x106 cells per vial with remaining cells stored at 300x106 cells per vial for 
research and banked on protocol 16C0061 (Tissue Procurement Protocol).
3.1.2
KK-LC-1 TCR T cell preparation
After cells are obtained by apheresis (either on this protocol or protocol 16C0061 if the 
participant has co-enrolled on that protocol), further cell processing to generate KK-LC-1 TCR T 
cells will occur in the CCE according to standard operating procedures and the KK-LC-1 TCR 
investigational new drug application. If apheresis has been performed on protocol 16C0061 and 
the participant consents and is eligible for treatment on this study, cells will be transferred to this 
study and all cell preparation will occur as part of this protocol. Any unused cells from this 
protocol can be transferred to 16C0061 and banked for research if a participant is co-enrolled. 
KK-LC-1 TCR T cells can be produced in approximately 11 to 15 days. Cell products may be 
cryopreserved during production to accommodate participant treatment schedules. Either freshly-
collected cells or cryopreserved cells can be used to initiate the cell-preparation process. 
Peripheral blood mononuclear cells (PBMC) will be isolated. Sufficient cells for three complete 
cell productions (10 vials at 3-4.5 x 108 cells/vial) will be retained in the CCE; the remaining 
cells may first be frozen in 10 vials at 100 x 106 cells per vial with excess frozen at 300 x 106 
cells/vial. Excess PBMC may be transferred from DTM to the Blood Processing Core (BPC) 
where they may be frozen and stored. The contact for the Blood Processing Core (BPC): pager 
#11964 and telephone # 240-760-6180. 
Before infusion, the percentage of T cells expressing the KK-LC-1 TCR will be determined by 
flow cytometry.  In addition to flow cytometry, further testing of the cells will take place prior to 
infusion to evaluate for microbial contamination, replication-competent retroviruses, and 
viability.  Details of this testing can be found in the appropriate DTM SOPs. When a participant 
is no longer eligible for retreatment on this protocol due to meeting any of the off-study criteria 
listed in Section 3.9, any remaining cryopreserved pretreatment PBMC collected on this protocol 
may be transferred from the Center for Cellular Engineering to the Principal Investigator of this 
protocol for storage in the Blood Processing Core (BPC) and possible use in research and banked 
according to protocol 16C0061.
3.1.3
Treatment Phase
PBMC will be obtained by leukapheresis (approximately 2x109 to 1x1010 cells are obtained).  
PBMC will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate 
T-cell growth. Transduction is initiated by exposure of approximately 10x106 to 500x106 cells to 
supernatant containing the KK-LC-1 TCR retroviral vector. These transduced cells will be 
expanded and tested for their anti-tumor activity. Successful TCR gene transfer will be 
determined by FACS analysis for the TCR protein. Successful TCR gene transfer for each 
transduced peripheral blood lymphocyte (PBL) population will be defined as greater than 15% 

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TCR positive cells.  A central line catheter may be used for the intravenous infusion of KK-LC-1 
TCR T cells.
Prior to receiving the engineered PBL cells, participants will receive a non-myeloablative but 
lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine, on 
days -6 to -2 before the intravenous infusion of in vitro tumor reactive TCR gene-transduced 
PBL plus IV high dose aldesleukin, as indicated in Section 3.2. Participants will receive one 
course of treatment.  The start date of the course will be the start date of the chemotherapy; the 
end date will be the day of the first post-treatment evaluation and the first safety and response 
assessment at the first follow-up visit.  
3.1.4
Dose Limiting Toxicity
The dose-limiting toxicity (DLT) evaluation period for determination of the maximum tolerated 
cell dose (MTD) will begin at the time of cell infusion and 30 days after cell infusion. A DLT is 
defined as follows: All grade 3 and greater toxicities related to cell infusion, with the exception 
of:
•
Cytokine Release Syndrome (CRS) that resolves < grade 2 within 14 days of the last dose 
of aldesleukin
•
Autoimmune toxicity that resolves < grade 2 within 14 days from starting symptoms 
treatment (e.g. steroids)
•
Cardiac, gastrointestinal, dermatological, hepatic, pulmonary, renal, hematologic, 
neurologic toxicity, or toxicity in Appendix B attributable to aldesleukin that resolves to 
≤ grade 2 within 14 days of the last dose of aldesleukin
•
Transient grade 3 hypoxia associated with cell infusion that corrects to < grade 2 with 
supplemental oxygen and/or that resolves to < grade 2 within 24 hours 
•
Hemorrhage due to underlying cancer or prior radiotherapy
•
Infection that is controlled within 7 days of onset
•
Hematological toxicities because they are expected from the conditioning regimen and 
their duration is unpredictable
•
Grade 3 metabolic laboratory abnormalities without significant clinical sequela that 
resolve to grade 2 within 7 days
•
Grade 3 fever that resolves < grade 2 within 14 days of cell infusion
•
If a DLT is clearly due to progressive disease the subject will be replaced and the DLT 
will not be included
3.1.5
Dose Escalation
Participants will be entered in sequential dose levels and receive escalating doses of cells 
beginning at 1 x 108. The protocol will enroll one participant in each dose level unless a 
participant experiences a DLT. A total of 12 participants will be enrolled at the MTD or highest 
safe dose level. The total number of transduced KK-LC-1 TCR T cells infused at each dose level 
will be:

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Dose Escalation Schedule
Dose Level
Dose of IND Agent  
Level 1
1 x 108 transduced KK-LC-1 TCR T cells
Level 2
5 x 108 transduced KK-LC-1 TCR T cells
Level 3
1 x 109 transduced KK-LC-1 TCR T cells
Level 4
5 x 109 transduced KK-LC-1 TCR T cells
Level 5
1 x 1010 transduced KK-LC-1 TCR T cells
Level 6
6 x 1010 transduced KK-LC-1 TCR T cells
The cell dose administered will be in a range of +/- 30% of the target dose above. The number of 
transduced cells will be quantified by multiplying the frequency of cells expressing the mouse 
TCR constant region (determined by flow cytometry) by the number of cells produced. If fewer 
than the target number of cells are generated the participant will still be treated but toxicity data 
from the participant will not be used in determining the MTD. 
In each dose level, if a participant experiences a DLT, a total of 6 participants will be treated at 
that dose level to confirm that no greater than 1 of 6 participants have a DLT prior to proceeding 
to the next higher dose level. If a level with 2 or more DLTs in 6 participants has been identified, 
participants will be accrued at the next-lowest dose, for a total of 6 participants. If 2 DLTs occur 
in the first dose level, the study may be amended to treat participants at lower doses. 
The MTD is the highest dose at which < 1 of 6 participants experienced a DLT or the highest 
dose level studied if 2 DLTs are not observed at any of the dose levels. Six more participants will 
be enrolled at the MTD or highest safe dose explored in order to obtain more toxicity 
information and to provide additional participants for the exploratory efficacy evaluations. Thus, 
a total of 12 participants will be treated at the MTD or highest dose level explored.   
There will be a 30-day delay between each dose level in order to determine if the participant 
experiences a DLT. There will be a 14-day delay in treatment between participants within each 
dose level. Therefore, after a participant in a dose level starts chemotherapy, the next participant 
in the same dose level will not start chemotherapy until at least 14 days after the start of 
chemotherapy to allow more time for the analysis of adverse events. 
3.1.6
Safety Protocol Stopping Rules
The study will be halted (immediately stop accrual and treatment) if any of the following safety 
conditions are met and we will promptly investigate and submit an amendment to the IRB and 
FDA if necessary:
1. If one or more deaths (other than death related to progressive disease) occurs within 30 
days of treatment regimen.
2. If two or more participants develop a Grade 3 or greater toxicity related to the cell 
product that does not resolve to grade 2 within 10 days, with the exception of:

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a.
Grade 3 metabolic laboratory abnormalities without significant clinical sequela 
that resolve to grade 2 or less within 14 days
b. Grade 3 fever that resolves < grade 2 within 14 days of cell infusion
3. If 2 DLTs occur on dose level 1. 
3.2
DRUG ADMINISTRATION
3.2.1
Preparative Regimen 
The following will comprise a course of therapy:
Drug
Dose
Route and 
Administration
Treatment Days
Cyclophosphamide
30 mg/kg 
IV infusion over 1  
hour (+ 10 min)
Once daily x 2 doses
Days -6 and -5
Fludarabine
25 mg/m2
IV infusion over 30 
minutes (+ 10 min)
To be administered 
following completion 
of cyclophosphamide.
Once daily x 5 doses
Days -6, -5, -4, -3, -2
Dose modifications: Cyclophosphamide and fludarabine will be dosed on actual body weight 
unless the participant has a body mass index (BMI) > 35. If the participant is obese (BMI > 35) 
drug dosage will be calculated using practical weight as described in Appendix E. 
Fludarabine will be dose modified in participants with renal impairment. In participants with a 
creatinine clearance calculated by the CKD-EPI equation < 80 mL/minute/1.73 m2 of BSA, 
the daily dose of fludarabine will be reduced by 20%.
Note: Chemotherapy infusions maybe slowed or delayed as medically indicated.
Supportive care: 
1. Hydration and Mesna uroprotection
Begin hydration with 0.9% sodium chloride injection at 1.5 ml/kg/hour (max rate capped at 100 
ml/hour) starting at least 6 hours pre-cyclophosphamide and continuing until 24 hours after last 
cyclophosphamide infusion.  Furosemide 10-20 mg IV will be given once daily on 
cyclophosphamide treatment days to promote diuresis.  At any time during the preparative 
regimen, if the urine output <1.5 ml/kg/hour or if body weight >2 kg over pre-cyclophosphamide 
value, additional doses of furosemide 10-20 mg IV may be administered. Intravenous hydration 
administered during cyclophosphamide will be individualized for participant clinical factors. 
Participants at risk of adverse clinical consequences from volume overload (e.g. participants with 
history of pulmonary hypertension or cardiac dysfunction) may be considered for low-dose 
hydration rates and/or volumes or hemorrhagic cystitis prevention strategies that include mesna 
alone without intravenous hydration. 

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Mesna 30 mg/kg/day will be administered by IV continuous infusion starting at approximately 
the same time as cyclophosphamide. The daily dose will be divided into two 12-hour infusion 
bags. 
2. Antiemetic prophylaxis for chemotherapy induced nausea and vomiting
Antiemetics should be given prophylactically to prevent chemotherapy induced nausea and 
vomiting. A suggested regimen includes:
Ondansetron 0.15 mg/kg (rounded to the nearest even mg dose between 8 mg and 16 mg based 
on participant weight) IV every 8 hours x 3 days on Days -6, -5, and -4.
Aprepitant 125 mg PO one-time dose on Day -6 and Aprepitant 80 mg once daily x 2 doses on 
Days  -5 and -4.
Olanzapine 5 to 10 mg PO once daily x 5 days starting on Day -6.
Modifications to the antiemetic regimen may be made based on clinical considerations but 
corticosteroids should be avoided.
3.2.2
Cell Infusion and other treatment Administration
The KK-LC-1 TCR T cells will be delivered to the participant care unit by an authorized staff 
member.  Prior to infusion, the cell product identity label is double-checked by two authorized 
staff (MD or RN), an identification of the product and documentation of administration are 
entered in the participant’s chart, as is done for blood banking protocols. See Appendix G on 
guidelines for management of infusion reactions.  
Day 0 (two to four days after the last dose of fludarabine):
•
 KK-LC-1 TCR T cells will be administered intravenously over 20 to 30 minutes via non-
filtered tubing, gently agitating the bag during infusion to prevent cell clumping.  
Day 0-4 (Day 0 is the day of cell infusion): 
•
Fluconazole: can be used at the discretion of the treating clinician
•
Valacyclovir po or Acyclovir IV, PO: will be administered until CD4 counts > 
200/mm3 X 2
Day 1-4 (Day 0 is the day of cell infusion):
•
Aldesleukin as described in section 3.3 below. 
•
TMP/SMX may be administered at 160mg/800mg every other day at the time of count 
recovery
Dose 1-4 Schedule
Day
-6
-5
-4
-3
-2
-1
0
1
2
3
4
Therapy
Cyclophosphamide
X
X

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Day
-6
-5
-4
-3
-2
-1
0
1
2
3
4
30 mg/kg IV once 
daily x 2 days
Ondansetron 0.15 
mg/kg IV every 8 
hours x 3 days
X
X
X
Olanzapine 5-10mg 
PO once daily x 5 
days
X
X
X
X
X
Aprepitant 125 mg 
PO X1, 80 mg PO 
daily X2
X
X
X
Mesna 30 mg/kg
X
X
Fludarabine
25 mg/m3 IV once 
daily x 5 days
X
X
X
X
X
KK-LC-1 TCR cells
X
Aldesleukin
X
X
X
X
X
Valacyclovir PO or 
Acyclovir IV, PO7
X
X
X
X
X
3.3
ALDESLEUKIN: INTRAVENOUS ADMINISTRATION
Aldesleukin will be administered at a dose of 720,000 IU/kg (based on total body weight) as an 
intravenous bolus over a 15 minute period beginning within 24 hours of cell infusion and 
continuing for up to four days (maximum 12 doses). The start of aldesleukin treatment may be 
delayed up to 3 days after cell infusion if medically necessary. Doses will be preferentially 
administered every eight hours; however, up to 24 hours may elapse between doses depending 
on participant tolerance. Aldesleukin dosing will be stopped if toxicities are not sufficiently 
recovered with supportive measures within 24 hours of the last dose of aldesleukin. Doses will 
be delayed or stopped if participants reach Grade 3 or 4 toxicity due to aldesleukin except for the 
reversible Grade 3 toxicities common to aldesleukin such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix C. Toxicities will be managed as outlined in 
Appendix B. In addition, dosing may be held or stopped at the discretion of the treating 
investigator. Because confusion is a possible side effect of aldesleukin administration, a Durable 

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Power of Attorney will be signed by the participant to identify a surrogate to make decisions if a 
participant becomes unable to make decisions.
3.4
POTENTIAL REPEAT TREATMENT 
Participants who were enrolled at a lower dose level may receive a second treatment course at 
the currently enrolling dose level. For instance, if a participant treated at dose level 1 progresses, 
and the study is currently enrolling participants at dose level 3, then the participant may receive a 
second treatment course at the currently enrolling higher dose level (in this case dose level 3). 
Participants must continue to meet the original eligibility criteria to be considered for 
retreatment. Research assessments will be performed at the same time intervals used for initial 
treatment. Participants who develop grade 3 or 4 toxicity due to cell infusion will not be 
retreated. A maximum of 1 retreatment course may occur. The second treatment will not begin 
prior to 6-8 weeks after the last dose of aldesleukin.
Note: Response data for all treatments will be captured in the database however only the 
response data from the first treatment will be used in the determination of response.
3.5
ON STUDY EVALUATION
Note:  Refer to section 5 for research evaluations
3.5.1
Prior to starting the preparative regimen
•
Apheresis as indicated
•
Within 14 days prior to starting the preparative regimen, participants will have a 
complete blood count (CBC with differential), electrolytes, BUN, creatinine, liver 
function tests, TBNK, and serum chemistries performed.  If any results are beyond the 
criteria established for eligibility, the treatment may be put on hold until the 
abnormalities can be resolved.  
3.5.2
During the preparative regimen: (day -6 to cell infusion)
•
Tests will be performed every 1-2 days, including Complete Blood Count (CBC with 
differential) Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, Total Protein
•
Urinalysis (every 1-2 days)
3.5.3
After Cell Infusion
3.5.3.1
Daily (Day +1 to Day +7)
•
Following cell administration - Vital signs will be monitored hourly (+/- 15 minutes) for 
four hours and then routinely (every 4-6 hours) unless otherwise clinically indicated
•
CBC 
•
Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin 

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•
Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly (within one business day, while the participant is 
hospitalized)
•
Other tests may be performed as clinically indicated including Calcium total, Magnesium 
total (Mg), Phosphorus, LD, Total Protein, Total CK, Uric Acid
3.5.4
During Hospitalization (approximately 14-21 days)
3.5.4.1
Every 1-2 days
•
A review of systems and physical exam as clinically indicated
•
Tests may be performed as clinically indicated including Complete Blood Count (CBC 
with differential), Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid
•
Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly Monday through Thursday (within one business day, while 
the participant is hospitalized).
•
KK-LC-1 TCR assay may be collected 1-2 times per week 
•
Surveillance blood cultures may be drawn at the discretion of the investigator and 
continue as clinically indicated. 
•
Other tests will be performed as clinically indicated.
3.6
POST TREATMENT EVALUATION (FOLLOW-UP)
At each scheduled safety and response evaluation, participants will undergo:
a.
Physical examination
b. Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, Total Protein 
c.
Complete blood count
d. Thyroid panel as clinically indicated
e.
TBNK, until CD4 > 200/mm3 x 2
f.
Toxicity assessment, including a review of systems
g. CT of the chest, abdomen and pelvis as clinically indicated. If clinically indicated, other 
scans or x-rays may be performed, e.g. PET, brain MRI, bone scan
h. KK-LC-1 TCR Assay
i.
An approximately 5 liter apheresis may be performed at the first follow up visit. If the 
subject is unable to undergo apheresis, approximately 96 ml of blood may be obtained.  
Subsequently, approximately 60 ml of blood will be obtained at follow up visits for at 
least three months. Peripheral blood mononuclear cells will be cryopreserved so that 

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immunologic testing may be performed and will be banked under protocol 16C0061 
(Tissue Procurement Protocol).  PBMC from apheresis will be stored in 10 vials at 
100x106 cells per vial with remaining cells stored at 300x106 cells per vial.
3.6.1
Stable Disease, Partial Response, Complete Response or Unresolved Toxicities
Participants who experience stable disease, a partial response, or a complete response or have 
unresolved toxicities will be evaluated for response as noted below:
•
Week 12 (+/- 2 weeks) 
•
Every 3 months (+/- 1 month) x3
•
Every 6 months (+/- 1 month) x 5 years
•
As per PI discretion for subsequent years
Note: Participants may be seen more frequently as clinically indicated
3.6.2
Long-Term Follow-up
Long-term follow up of participants receiving gene transfer is required by the FDA and must 
continue even after the participant comes off the study. Long-term follow-up will be performed 
as indicated in the long term gene therapy follow-up protocol (20C0051) and participants will be 
co-enrolled. A baseline (pre-treatment) sample will be collected on protocol 20C0051 to improve 
analysis of the long term follow up testing.  
After the participant comes off study, health status data will be obtained from surviving 
participants via telephone contact or mailed questionnaires for a total of 15 years after cell 
infusion. Refer to section 5.3.

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3.7
STUDY CALENDAR
For the treatment schedule, please refer to Section 3.2.2.
Note:  The retreatment schedule (see Section 3.4) will be identical to the schedule for 
participants being treated for the first time, including eligibility assessments.  A maximum of one 
course of treatment will be allowed on retreatment. 
Procedure
Screening/ 
Baseline2
Before 
treatment
Preparative 
regimen5
Day 0
During 
hospitalization6
Follow-up9
(End of Treatment)
Medical history
X
Physical exam
X
X
X
X
Confirmation of Diagnosis (KK-LC-1 positivity 
assay), Rutgers Cancer Institute
X
ECOG performance status
X
NIH Advance Directives Form16
Chest x-ray
X
EKG
X
CT and MRI or PET
X
X
Pulmonary Function Test1
X
Cardiac evaluation10
X
Viral titers
X
Optional Biopsy
X
X12
Blood chemistries8
X
X
X
X
X
Complete blood count (CBC with diff.)
X
X
X
X
X
Thyroid panel
X
X13
HLA typing
X
TBNK
X
X7
X
Urinalysis
X
X
Pregnancy test3
X
Leukapheresis
X17
X15
Infusion of transduced cells4
X
Additional apheresis or blood draw11
X
Research blood
X
X
X14
X
KK-LC-1 TCR assay18
X
X

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1.
For participants with a prolonged history of cigarette smoking, as indicated in Section 2.3.2.3
2.
Exact timeline is indicated in Sections 2.3 and 2.5
3.
For women of child-bearing potential as defined in Section 2.1.1.10
4.
See other treatments in Schedules, Section 3.2.2
5.
On days -6 to -1, every 1 -2 days as clinically indicated
6.
Every 1 to 2 days while hospitalized
7.
Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 count will 
be drawn weekly (within one business day, while the participant is hospitalized)
8.
Chemistries Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic 
Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, Total 
Protein
9.
End of treatment visit will occur approximately 40 days (+/- 2 weeks) after cell infusion, 
additional visits as indicated in Section 3.6.1
10.
For participants who are greater than or equal to 50 years of age, or who have a history of ischemic 
heart disease, chest pain or clinically significant atrial and/or ventricular arrhythmias.  Participants 
with a LVEF of less than or equal to 45% will not be eligible, as noted in section 2.3.2 
11.
As described in section 3.6.
12.
Following treatment (6 weeks post treatment preferred) and at disease progression.
13.
As clinically indicated
14.
Monday, Wednesday, Friday during hospitalization once ALC > 200/mm3
15.
If the participant is unable to undergo apheresis, approximately 96 ml of blood may be obtained. 
Apheresis will only be done in the first follow-up visit; in the following visits, blood will be 
collected.
16.
All subjects will be offered the opportunity to complete an NIH advanced directives form. This 
should be done preferably at baseline but can be done at any time during the study as long as the 
capacity to do so is retained. The completion of the form is strongly recommended but is not 
required.
17.
This can occur at any time prior to treatment on protocol 16C0061 if the participant is co-enrolled 
on that protocol. See Section 3.1.1 for further details.  For participants undergoing retreatment, 
retreatment will only occur if there are enough cells stored from their prior course. See Section 3.4 
for details on retreatment.
18. Clinical assay performed by the NCI Flow Cytometry Laboratory in the Laboratory of Pathology. 
The assay may be collected at follow-up visits

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3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs. 
3.8.2
Compensation
No compensation is provided for participation in this study.
3.8.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 40 days following cell infusion. 
3.9.1
Criteria for removal from protocol therapy
Participants will be taken off treatment for the following:
•
Completion of treatment
•
Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, 
liver, colon, adrenal gland, lungs). 
•
If a subject experiences Grade 3 or higher toxicity due to cell infusion (reaction to 
cellular product or infusion reaction), the participant will receive no further treatment.
•
Participant requests to be withdrawn from active therapy
•
Investigator Discretion
•
Positive pregnancy test
3.9.2
Off-Study Criteria 
Participants will be taken off study for the following:
•
Screen failure
•
The participant voluntarily withdraws
•
There is significant noncompliance
•
Progressive disease
•
Death
•
Study closure
•
Completion of study follow-up period
•
Participant lost to follow-up
•
Investigator discretion
Note: Participants who are taken off study for study closure may be followed on the Long-Term 
Gene Therapy Follow-up Protocol (20C0051). 

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3.9.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site will attempt to contact the participant and reschedule the missed visit within 1-2 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
 PROHIBITED MEDICATIONS
Current use of immunosuppressive medication, EXCEPT for the following:
•
Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection)
•
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
or,
•
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
4.2
INFECTION PROPHYLAXIS
Note: Other medications may be substituted or held at the discretion of the treating investigator. 
Below are guidelines and suggested medications and schedule to be used, however they can be 
altered by the treating physician as clinically indicated.
4.2.1
Pneumocystis Jirovecii Pneumonia
Participants may receive the fixed combination of trimethoprim and sulfamethoxazole [SMX] as 
double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) P.O. daily three 
times a week on non-consecutive days at the time of count recovery. 
Pentamidine may be substituted for TMP/SMX-DS in participants per investigator discretion. It 
will be administered aerosolized at 300 mg per nebulizer approximately within one week of 
chemotherapy start date.

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4.2.2
Herpes Virus Prophylaxis
Participants may be given either acyclovir 800mg PO twice daily (preferred) or valacyclovir 
500mg PO daily (alternate) or, if unable to tolerate PO: acyclovir 250mg/m2 IV q 12 hr.  
Reversible renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic 
toxicity including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs 
have been reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will 
be made or the drug will be discontinued.  Acyclovir will not be used concomitantly with other 
nucleoside analogs which interfere with DNA synthesis, e.g. ganciclovir.  In renal disease, the 
dose is adjusted as per product labeling.
Prophylaxis for Pneumocystis and Herpes will continue for 6 months post chemotherapy.  If the 
CD4 count is less than 200 at six months post chemotherapy, prophylaxis will continue for at 
least six months and until the CD4 count is greater than 200 for two consecutive measures.
4.2.3
Fungal Prophylaxis (Fluconazole)
Participants may start Fluconazole 400 mg po. starting on the day of cell infusion and continue 
until the absolute neutrophil count is greater than 1000/mm3.  The drug may be given IV at a 
dose of 400 mg in 0.9% sodium chloride USP daily in participants unable to take it orally.
4.2.4
Empiric Antibiotics 
Participants will start on broad-spectrum antibiotics as per current institutional guidelines for 
fever of 38.3°C once or two temperatures of 38.0°C or above at least one hour apart, AND an 
ANC                  < 500/mm3.  Infectious disease consultation will be obtained for all participants 
with unexplained fever or any infectious complications.
4.2.5
Blood Product Support 
Using daily CBC’s as a guide, the participant will receive platelets and packed red blood cells 
(PRBC’s) as needed.  As a general guideline, participants may be transfused for: 
•
Hemoglobin < 8 gm/dl
•
Platelets < 10,000/mm3 
Note: Participants may be transfused at a higher platelet count as clinically indicated, e.g.:
o
Increased risk for bleeding such as undergoing an invasive procedure or 
presence of metastatic lesion likely to bleed 
o
fever greater than 38.5°C
o
sepsis
All blood products will be irradiated.  Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused WBC’s and decrease the risk of CMV 
infection.
4.2.6
Neutrophil Recovery
Participants may receive Filgrastim (or filgrastim biosimilar) for count recovery when clinically 
indicated per national guidelines.

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4.3
OTHER CONCOMITANT MEDICATIONS TO CONTROL SIDE EFFECTS
Concomitant medications to control side effects of therapy may be given.  Meperidine (25-50 
mg) may be given intravenously if severe chilling develops.  Other supportive therapy may be 
given as required and may include acetaminophen (650 mg q4h), indomethacin (50-75 mg q8h) 
and famotidine (20 mg g12h). If participants require steroid therapy they will be taken off 
treatment.  Participants who require transfusions will receive irradiated blood products.  
Ondansetron 0.15 mg/kg/dose IV every 8 hours may be administered for nausea and vomiting.  
Additional anti-emetics may be administered as needed for nausea and vomiting uncontrolled by 
ondansetron.  Antibiotic coverage for central venous catheters may be provided at the discretion 
of the investigator.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
The amount of blood that may be drawn from adult participants for research purposes shall not 
exceed 10.5 mL/kg or 550mL; whichever is smaller, over any 8-week period.  
Note: Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
5.1.1
Pre-cell infusion evaluations
•       At baseline/screening 12 CPT tube and 2 SST tubes may be collected starting on the day 
of chemotherapy. One CPT tube may be used to collected 4mL of plasma, which may be 
frozen in 4mL vials. PBMC from the remainder of the CPT tubes may be frozen in 
aliquots of 10 x 106 cells/vial. Serum from SST tubes may aliquoted into four vials of 
0.5-1mL each. All samples will be processed in the Blood Processing Core (BPC). All 
baseline/screening blood research specimens will be collected. 
•        At day -6 prior to cell infusion 6 CPT tubes and 1 SST tube may be collected starting on 
the day of chemotherapy. One CPT tube may be used to collect 4mL of plasma, which 
may be frozen in 4mL vials. PBMC from the remainder of the CPT tubes may be frozen 
in aliquots of 10 x 106 cells/vial. Serum from SST tubes may be aliquoted into four vials 
of 0.5-1mL each. All samples will be processed in the Blood Processing Core (BPC).
5.1.2
Post cell infusion evaluations
•
2 SST tubes (4mL) may be collected daily for serum starting on the day of chemotherapy 
and continuing through the end of hospitalization. Serum will be processed in the Blood 
Processing Core (BPC) and may be aliquoted into four vials of 0.5-1 mL each.
•
Once total lymphocyte count is greater than 200/mm3, the following samples may be 
drawn and sent to the Blood Processing Core (BPC) on Monday, Wednesday, and Friday 
x 5 days, then weekly (while the participant is hospitalized). Send to the Blood 
Processing Core (BPC). Attention: NCIBloodcore@mail.nih.gov. Building 10, room 
5A08 pager is 11964, tel # 240 760 6180.
o
6 CPT tubes (8mL each). One CPT tube daily may be used to collect 4mL 
of plasma, which may be frozen in 4mL vials. PBMC from the remainder 
of the CPT tubes may be frozen in aliquots of 10 x 106 cells/vial

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•       Following discharge, at each scheduled follow-up visit 6 CPT tubes and 1 SST tube may 
be collected. One CPT tube may be used to collect 4mL of plasma, which may be frozen 
in 4mL vials. PBMC from the remainder of the CPT tubes may be frozen in aliquots of 
10 x 106 cells/vial. Serum from SST tubes may be aliquoted into four vials of 0.5-1mL 
each. Samples will be processed in the Blood Processing Core (BPC). 
5.1.3
Tumor Biopsies
•
Tumor may be biopsied pre- and post-treatment in order to test for KK-LC-1 expression, 
HLA expression, and other characteristics that may affect response to therapy. Biopsies 
are not required; a maximum of three biopsies, with three cores/attempts, may be 
performed. 
•
Tissue may be obtained pre-treatment, following treatment (6 weeks post treatment 
preferred) and at the time of progression. Biopsies will only be performed at the NCI 
CCR. 
•
Tissue may be obtained via CT, MRI or US guided biopsy under IV (conscious) sedation 
as appropriate.
•
Specimens may be transported by the assigned research nurse to the CIO cellular therapy 
lab for sample labeling. Contact: Scott Norberg, Bldg 10, room 4B-04, phone 301-275-
9668. Following labeling, samples may be transported by an assigned lab member to the 
Blood Processing Core (BPC) where they will be stored. Samples may also be 
transported to and labeled by BPC. Contact: Blood Processing Core (BPC) Attention: 
NCIBloodcore@mail.nih.gov, Building 10, room 5A08 pager is 11964, tel # 240 760 
6180.
•
Some of these samples may be archived and analyzed under another protocol 16C0061 
(Tissue Procurement Protocol) if the subject is also enrolled on that study.  
5.1.4
Immunological Testing
•
Apheresis may be performed prior to and about four to six weeks after the treatment.  
Apheresis product will be transferred to the Blood Processing Core (BPC) Attention: 
NCIBloodcore@mail.nih.gov.  Building 10, room 5A08 pager is 11964, tel # 240 760 
6180. Cell product may be frozen in 10 vials at concentration 100 x 106 cells/mL and 
additional vials at 300 x 106 cells/mL.
•
At other time points, peripheral blood lymphocytes (PBL) and plasma may be obtained 
from whole blood by purification using centrifugation. These samples may be transferred 
directly to the Blood Processing Core (BPC) lab for processing. Plasma may be frozen in 
4mL vials. PBL may be frozen in aliquots of 10 x 106 cells/vial
•
Possible laboratory research studies on tumor biopsies are as follows: Expression of CD3, 
CD4, CD8, MHC I, and MHC II by immunohistochemistry; flow cytometry to determine 
the frequency of KK-LC-1 TCR T cells in the samples; generation and characterization of 
TIL cells; generation and characterization of tumor cell lines. IHC quantification may be 
by blinded scoring of the intensity and frequency of staining. Flow cytometry data will be 
analyzed with FlowJo software. Biopsies - will only be performed if minimal morbidity is 
expected based on the procedure performed. 

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•
Possible laboratory research studies on PBMC and PBL are as follows:  Specific 
cytolysis determined by impedance-based assay, frequency of effector cells as 
determined by ELISPOT, quantity of cytokine production as determined by coculture 
assay with cytokine quantification, cytokine production by intracellular flow cytometry, 
phenotypic analysis by flow cytometry. Immunological assays may be standardized by 
the inclusion of 1) pre-infusion PBMC and 2) an aliquot of the T cells cryopreserved at 
the time of infusion. 
•
Possible laboratory research on serum or plasma are as follows: cell free DNA 
quantification, cytokine quantification
•
The planned methods for performing the laboratory studies above are as described in 
Stevanovic, et al, Journal of Clinical Oncology, 2015 and Draper, et al, Clinical Cancer 
Research, 2015. [42, 51]
•
The laboratory studies are considered exploratory. Statistical analysis will be performed 
in consultation with a biostatistician. 
•
Specimens collected in the course of this research project may be banked and used in the 
future to investigate new scientific questions related to this study and protocol 16C0061 
(Tissue Procurement Protocol).
5.1.5
Samples/Data sent to Rutgers Cancer Institute of New Jersey
KK-LC-1 testing will be performed via an IHC assay developed by Rutgers Cancer Institute of 
New Jersey. This testing will be performed on archival samples or on fresh tissue that is 
collected at screening for confirmation of diagnosis. 
The data may include demographic and clinical outcome information. Samples and data will be 
deidentified. Identifiable information will only be provided, if needed, to interpret data. 
5.2
SUMMARY OF SAMPLE COLLECTION
Test/assay
Volume blood
(approx)
Type of 
tubea
Collection point 
(+/- 48hrs)
Location of specimen analysis
Plasma/ 
PBMC
48-96 mL
CPT
<4 weeks prior to cell 
infusion, day-6 
Blood Processing Core 
(BPC)
Serum
8-16 mL
SST
<4 weeks prior to cell 
infusion, day-6
Blood Processing Core 
(BPC)
Plasma/ 
PBMC
48 mL
CPT
Post cell infusion day 
1, 3, every 
Mon/Wed/Fri x 5 
days, weekly until 
discharge and follow-
up visits
Blood Processing Core 
(BPC)

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Test/assay
Volume blood
(approx)
Type of 
tubea
Collection point 
(+/- 48hrs)
Location of specimen analysis
Serum
Variable, 
based on 
length of 
hospitalization 
and duration 
of follow-up
SST
Daily at the start of 
chemo until 
discharge from 
hospital, follow-up 
visits
Blood Processing Core 
(BPC)
Optional 
Biopsy 
N/A
N/A
Prior to starting 
chemotherapy, at the 
first response 
assessment visit and 
at the time of 
progression
Transported and processed in 
CIO cellular therapy lab or 
Blood Processing Core 
(BPC)
a.
Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
5.3
GENE-THERAPY-SPECIFIC FOLLOW-UP 
Persistence of TCR transduced cells will be assessed by quantitative PCR and/or flow cytometry 
at follow-up visits 1, 3, 6 and 12 months after cell infusion, or until TCR-expressing cells are no 
longer detectable. Participants’ blood samples will be obtained and undergo analysis for 
detection of replication competent retroviruses (RCR) by PCR prior to cell infusion, and at 3, 6, 
and 12 months post cell administration, and annually thereafter for 4 more years. RCR testing 
will continue until three negative consecutive tests results are obtained. These cells will be 
obtained from the CPTs drawn for research at follow up visits or under the long-term gene 
therapy follow up protocol if the participant is off study.
5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.4.1
Samples Managed by the Blood Processing Core (BPC)
5.4.1.1
Blood Collection
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov

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The samples will be processed, barcoded, and stored in the BPC lab until requested by the 
investigator.
5.4.1.2
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined BPC lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by the BPC. These computers all have a password 
restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant number are provided in the system. For each sample, there are notes associated 
with the processing method (delay in sample processing, storage conditions on the ward, etc.).
5.4.2
CIO Cellular Therapy Laboratory
Samples transferred to the CIO cellular therapy laboratory may be barcoded and tracked with 
Labmatrix.
Laboratory research data will be stored on the NCI secure server with secure access by 
laboratory personnel only. Access to personally identifiable information (PII) is limited to the PI 
and study personnel who interact directly with the participant and their samples.
5.4.3
Sample Storage and Destruction
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a participant withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, the samples will be destroyed (or returned to the participant, if so requested). The PI will 
record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of section 7.1.
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 

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Labmatrix. It is critical that the sample remains linked to participant information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The NIH PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant 
data capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The Principal Investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
The key for assignment of participant code identification numbers with the personal identifiers 
will be stored in a secure data base. This key will not be shared with other investigators. 
Investigators conducting the individual sample testing will only have access to coded 
identification numbers and coded participant information (i.e. treatment regimens, treatment 
responses, diagnoses, pathology information).
Data from analyses performed at participating site will be provided to the NIH team by secure 
email and entered into the study database. 
6.1.1
Adverse Event (AE) Recording
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. All study 
related adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of attribution will be captured in study database up to 40 days following 
last administration of investigational agent. AEs will be documented from the start date of 
chemotherapy through 40 days after the cell administration. Beyond 40 days after the cells were 
administered, only adverse events which are serious and related to the study intervention need to 
be recorded.
In addition, all incidences of intubation including the duration of and reason for intubation will 
be captured in study database. 
6.1.2
Reporting of Laboratory Events
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.

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End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
6.2.2
What data will be shared?
I will share human data generated in this research for future research as follows:
•
Coded, linked data in an NIH-funded or approved public repository.  
•
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
•
Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through: 
•
An NIH-funded or approved public repository: ClinicalTrials.gov.
•
BTRIS (automatic for activities in the Clinical Center)
•
Approved outside collaborators under appropriate individual agreements.
•
Publication and/or public presentations.
When will the data be shared? 
•
Before publication.
•
At the time of publication or shortly thereafter.
6.3
RESPONSE CRITERIA
For the purposes of this study, participants should be re-evaluated for response as indicated in 
Section 3.6.1.  In addition to a baseline scan, confirmatory scans should also be obtained 4 to 8 
weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) for participants with solid tumors [58]. In cases where participants have isolated 
bony metastases that do not meet RECIST criteria, Positron Emission Tomography Response 
Criteria in Solid Tumors (PERCIST) (version 1.0) guidelines will be used [59].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria.  Normalization of 
standardized uptake value on FDG-PET is used in PERCIST.  For participants that have both 
bony lesions and lesions that meet RECIST criteria, only RECIST criteria will be used to 
evaluate best overall response.
6.3.1
Definitions
Evaluable for toxicity:  All participants will be evaluable for toxicity from the time of their first 
treatment with KK-LC-1 TCR transduced PBL.
Evaluable for objective response: Only those participants who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These participants will have their response classified 

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according to the definitions stated below.  (Note:  Participants who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response:  Participants who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.
6.3.2
Disease Parameters
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
•
By chest x-ray:  > 20 mm; 
•
By CT scan: 
o
Scan slice thickness 5 mm or under: as > 10 mm
o
Scan slice thickness > 5 mm: double the slice thickness 
•
With calipers on clinical exam: > 10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.
Measurable bone metastases: Any size bone lesions with a baseline SUL (standard uptake value, 
corrected for lean body mass) on FDG-PET of 1.5 x mean liver SUL + 2 standard deviations of 
mean SUL is considered measurable. Bone lesions are only measured in participants with 
isolated bone metastases.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  Lesions that have been previously treated with loco-regional therapy 

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or in a previously irradiated area can be considered target lesions if they have demonstrated 
unequivocal progression by radiographic imaging.
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET:  Participants with isolated bony metastases will have FDG-PET to determine if 
lesions meet criteria to be followed by PERCIST version 1.0. While FDG-PET response 
assessments in solid tumors being followed by RECIST need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression of lesions (particularly possible 'new' disease).  New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 

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PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published. [60-62]   I In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[63] 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.

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6.3.4
Response Criteria
6.3.4.1
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.4.2
Evaluation of Bony Lesions in Participants with Isolated Bone Metastases
Complete Response (CR): Normalization of all bony lesions (target and nontarget) to SUL less 
than mean liver SUL and equal to normal surrounding tissue SUL. Verification with follow-up 
study in 1 month if anatomic criteria indicate disease progression.
Partial Response (PR): > 30% decrease in SUL peak; minimum 0.8 unit decrease. Verification 
with follow-up study if anatomic criteria indicate disease progression. 
Progressive Disease (PD): > 30% increase in SUL peak (minimum 0.8 unit increase in SUL 
peak), > 75% increase in TLG of the 5 most active lesions, Visible increase in extent of FDG 
uptake, or new lesions. Verification with follow-up study if anatomic criteria indicate complete 
or partial response.
Stable Disease (SD): Does not meet other criteria.
6.3.4.3
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).

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6.3.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.
6.3.5
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
*
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised
6.3.6
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time of cell 
infusion until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 

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6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem or present new information that 
might affect the willingness of participants to enroll or remain on the study will need to be 
reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802: Non-compliance in Human Subjects Research, found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.  The participating site PI must 

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immediately report to the coordinating center PI any deaths possibly related to the research 
within 24 hours of PI awareness of the event.  The Site PI must also report any other events 
required by Policy 801 to the coordinating center PI within 7 days of PI awareness.  
A reporting form will be provided with the participating site documents for such reports. 
7.5
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.5.1
Serious Adverse Event Reports to IBC
The NIH Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of KK-LC-1 TCR T cells as soon as possible but 
in no event later than 7 calendar days of initial receipt of the information.  Serious adverse events 
that are unexpected and associated with the use of the KK-LC-1 TCR T cells, but are not fatal or 
life-threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 
calendar days after the investigator’s initial receipt of the information.  Adverse events may be 
reported by using the FDA Form 3500a.
7.5.2
Annual Reports to IBC
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the NIH Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report.  Please include the 
IBC protocol number on the report.
7.5.3
Clinical Trial Information 
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information: 
•
the title and purpose of the trial 
•
clinical site
•
the Principal Investigator
•
clinical protocol identifiers; 
•
participant population (such as disease indication and general age group, e.g., adult or 
pediatric); 
•
the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons 
•
the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed, 
•
if the trial has been completed, a brief description of any study results. 
7.5.4
Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, 
including: 

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•
a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system
•
a summary of all serious adverse events submitted during the past year
•
a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications
•
if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death
•
a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.
7.6
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.6.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular biweekly basis when participants are being 
actively treated on the trial to discuss each participant. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior participants. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The NIH principal investigator will review adverse event and response data on each participant 
to ensure safety and data accuracy. The site principal investigator will personally conduct or 
supervise the investigation at the respective site and provide appropriate delegation of 
responsibilities to other members of the research staff. 
7.6.2
Safety Monitoring Committee (SMC) – NCI CCR SMC
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 
comprising physicians, biostatisticians and a lay member selected based on experience, area of 
expertise, reputation for objectivity, absence of conflicts of interest and knowledge of or 
experience with clinical trial research. Initial review will occur as soon as possible after the 
annual NIH Intramural IRB continuing review date. Subsequently, each protocol will be 
reviewed as close to annually as the quarterly meeting schedule permits or more frequently as 
may be required by the SMC based on the risks presented in the study. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. 
The SMC will operate under the rules of an approved charter that will be written and reviewed at 
the organization meeting of the SMC.  Each review will focus on unexpected protocol-specific 
safety issues that are identified during the conduct of the clinical trial.
Written outcome letters will be generated in response to the monitoring activities and submitted 
to the Principal Investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.

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8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death
•
A life-threatening adverse event (see section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant or subject convenience) is not considered a serious 
adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the participant or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (21CFR312.32)

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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1.16.1. All serious adverse 
events recorded from the time of first investigational product administration must be reported to 
the sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the 
expedited reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions

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Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As the conditioning regimen is known to result in Hematological toxicities, only those SAEs that 
are not specified in the table below will be reported to the Sponsor in an expedited manner.
CTCAE System 
Organ Class
Adverse Event
Grade
Prolongation of 
Hospitalization
Expected 
Frequency Attribution
Investigations
Neutrophil count 
decreased
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Neutrophil count 
decreased
4 if < 14 
days
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Blood and 
lymphatic system 
disorders
Anemia
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Platelet count 
decreased
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Platelet count 
decreased
4 if < 14 
days
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
White blood cell 
decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Lymphocyte 
count decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
CD4 
lymphocytes 
decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)

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Blood and 
lymphatic system 
disorders
febrile 
neutropenia 
(without an 
associated 
infection)
3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months. The report shall include the number of participants treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month 
timeframe and in total since the start of the study, attribution, and type/category of serious. 
Reports will be submitted to the Center for Cancer Research (CCR) at 
OSROSafety@mail.nih.gov
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement with T-Cure Bioscience (CRADA #03313)
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.6.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Participants should refrain from fathering a child or donating sperm during the study and for up 
to 4 months after the last dose of KK-LC-1 TCR T cells.
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 4 months after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.

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8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expediated manner to the FDA in 
accordance to 21 CFR 312.32. CCR will report an AE as a suspected adverse reaction only if 
there is evidence to suggest a causal relationship between the study product and the adverse 
event.  CCR will notify FDA and all participating investigators (i.e., all investigators to whom 
the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety 
report of potential serious risks from clinical trials or any other source, as soon as possible, in 
accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements.
Non-NIH participating sites not using the CCR Protocol Deviation Tracking System 
(PDTS) will report any protocol deviation on the OSRO Site Protocol Non-
Adherence/Deviation Log, or a site-generated protocol deviation report approved by 
OSRO. The Non-Adherence/Deviation Log should be maintained in the site essential 
documents file and submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first 
business day of each month throughout the study.  
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures;  
•
that the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 

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Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study start to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations.  Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable) and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS
10.1 STATISTICAL HYPOTHESIS
10.1.1 Primary Objective
To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus aldesleukin for the 
treatment of metastatic KK-LC-1 positive epithelial cancers.
10.1.2 Secondary objectives
None
10.1.3 Exploratory Objective(s)
To assess the safety and efficacy of KK-LC-1 TCR T cells plus aldesleukin for the treatment of 
KK-LC-1+ cancers
To conduct exploratory immunologic studies to understand and improve the administered 
treatment. 
10.2 SAMPLE SIZE DETERMINATION
The protocol will enroll one participant per dose level, unless the participant has a DLT, in which 
case 6 participants will be treated at the dose level with subsequent escalation only if the 
remaining 5 participants do not have a DLT (1/6 total has a DLT at the dose level). Then, the 

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trial will enroll up to 6 participants per dose level for the remaining dose levels if there is no 
more than 1 participant with a DLT per dose level. With up to 6 dose levels explored and 6 more 
participants at the MTD, the maximum number of participants who could be treated will be 36, 
but as few as 5 (6 dose levels x 1 participant per level) +6 at the MTD plus another 6 at the MTD 
equals 17 participants if there is no more than minimal toxicity up through dose level 5, and 
6+6=12 participants are enrolled at the MTD or highest safe dose level. 
As indicated in section 3.4, participants may be re-enrolled on the study as new participants to 
allow retreatment, and these participants will be considered both times in the total accrual ceiling 
for the study. Response data for all treatments will be captured in the database however only the 
response data from the first treatment will be used in the determination of response.
It is expected that up to 10 evaluable participants could be accrued onto this trial per year; 
accrual could be completed within 2-3 years. With up to 30 evaluable participants needed for 
treatment, as well as planning for a small number of inevaluable participants (5), we intend to 
initiate intervention in up to 35 participants.  Note:  To allow for screen failures (65), a total of 
100 will be set for the purposes of the NIH accrual ceiling.
10.3 POPULATIONS FOR ANALYSES 
10.3.1 Evaluable for toxicity    
All participants receiving at least one dose of cells will be evaluable for toxicity from the time of 
their first treatment.
10.3.2 Evaluable for Objective Response 
Only those participants who have measurable disease present at baseline, have received at least 
one course of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. Participants who exhibit progression before disease can be re-evaluated will also be 
considered as part of the denominator for the fraction of participants who have responded.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The toxicities experienced by participants at each dose level will be reported per dose level.
10.4.2 Measures to Minimize Bias: Randomization and Blinding
None are used.
10.4.3 Analysis of the Primary Endpoints
The toxicities experienced by participants at each dose level will be reported per dose level. The 
grade as well as the type of toxicity will be tabulated per dose level. The fraction of participants 
who experience a DLT will be identified at a given dose level, with information reported about 
the number and grade of each type of DLT identified. 
10.4.4 Analysis of the Secondary Endpoint(s) 
None
10.4.5 Safety Analyses
The toxicities experienced by participants at each dose level will be reported per dose level. The 
grade as well as the type of toxicity will be tabulated per dose level. The fraction of participants 

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who experience a DLT will be identified at a given dose level, with information reported about 
the number and grade of each type of DLT identified. 
10.4.6 Baseline Descriptive Statistics
Standard sample statistics will be reported for participants enrolled on the trial.
10.4.7 Planned Interim Analyses
Toxicities will be evaluated at each dose level to establish the ability to accrue participants onto 
the next dose level.
10.4.8 Sub-Group Analyses
None
10.4.9 Tabulation of individual Participant Data
None
10.4.10 Exploratory Analyses
The exploratory objectives are to: 
•
To assess efficacy of KK-LC-1 TCR T plus aldesleukin for the treatment of KK-LC-1+ 
cancers. The clinical response rates found at the MTD will be reported along with a 95% 
confidence interval and noted to be an exploratory result.
•
To conduct exploratory immunologic studies to understand and improve the administered 
treatment. Any statistical tests performed on research samples for this purpose will be 
considered exploratory with results presented without formal adjustment but interpreted 
in the context of the number of tests performed.
11 COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
A CRADA between NCI and T-Cure Bioscience, Inc. is in place (CRADA #03313). 
11.2 MULTI-INSTITUTIONAL GUIDELINES
Documents requiring submission to the reviewing IRB as provided in the Participating Site 
Information Sheet should be provided to the coordinating center for submission to the IRB.  
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
The participants to be entered in this protocol have metastatic or recurrent/refractory locally 
advanced epithelial cancers that are refractory to standard therapy, and limited life expectances.
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another.  Efforts 
will be made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between participant safety considerations and limitations on the number 

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of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the 
need to explore gender and ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a 
follow-up study may be written to investigate those differences more fully.
12.2 PARTICIPATION OF CHILDREN
The use of the non-myeloablative regimen in this protocol entails serious discomforts and 
hazards for the participant, such that fatal complications are possible.  It is therefore only 
appropriate to carry out this experimental procedure in the context of life threatening metastatic 
cancer.  Since the efficacy of this experimental procedure is unknown, it does not seem 
reasonable to expose children to this risk without further evidence of benefit.  Should results of 
this study indicate efficacy in treating metastatic cancer, which is not responsive to other 
standard forms of therapy, future research can be conducted in the pediatric population to 
evaluate potential benefit in that participant population.
12.3 RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
Over 400 participants have been treated in the Surgery Branch, NCI with TIL.  Early toxicities 
related specifically to the infusion of the cells (those which are seen immediately following cell 
infusion and prior to aldesleukin administration) are generally mild and include fevers, chills, 
headache, and malaise.  Toxicities which occur following administration of aldesleukin but are 
thought to be related to the cells include immune mediated events such as vitiligo, transient 
uveitis, hearing loss and vestibular dysfunction.  The use of the non-myeloablative regimen prior 
to cell administration increases the toxicity of this treatment as profound myelosuppression 
occurs in all participants.  In 93 participants treated with TIL using the non-myeloablative 
chemotherapy regimen with or without total body irradiation, there was one treatment related 
death (NMA + 200 cGy TBI) due to an unexpected but preexisting diverticular abscess.  In the 
101 participants treated in a subsequent randomized trial, 2 treatment-related deaths occurred – 
both due to the TBI component of the treatment regimen. 
The major discomforts of the research are those of nausea and vomiting, mucositis, anorexia, 
diarrhea, fever and malaise.  Side effects of common drugs used in this regimen include:
•
Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic cystitis, 
myocardial damage, alopecia, infertility, nausea and vomiting, SIADH.  
•
Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise, fatigue, 
anorexia, weakness, neurologic toxicity, and interstitial pneumonitis.  Serious 
opportunistic infections have occurred in CLL participants treated with fludarabine.
•
Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting, 
hepatic damage, marrow suppression, photosensitivity. 
•
High-dose aldesleukin administration: A listing of these side effects in 525 participants 
who received 1,039 treatment courses are listed in Appendix C.
12.3.1.1 Cell infusion
The risks of KK-LC-1 TCR-T cells are not known as the agent has not been studied in humans. 
Experience with diverse types of cell therapy including tumor-infiltrating lymphocytes, CAR-T 

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cells, and TCR-T cells, indicates that the risk of cell therapy may include cytokine release 
syndrome (where the T cell therapy causes the release of chemicals called cytokines that 
aggressively ramp up the immune system), autoimmunity (an immune reaction against normal 
tissues) and neurotoxicity (damage to the nervous system). Cytokine release syndrome may only 
cause mild symptoms such as fever, fatigue, headache, rash, joint stiffness, and muscle aches. It 
can also cause severe symptoms such as low blood pressure, high fever, uncontrolled systemic 
inflammatory response, hemophagocytic lymphohistiocytosis (a rare condition in which certain 
types of white blood cells build up in organs and destroy other blood cells), shock, vascular 
leakage (where fluids and proteins leak out of small blood vessels and into surrounding tissues), 
disseminated intravascular coagulation (a serious disorder where proteins that control blood 
clotting become overactive), and multi-organ system failure.
Gene-engineering of T cells may carry a risk of leukemia due to insertional mutagenesis (a 
mutation caused by insertion of new genetic material into a normal gene), but this event has not 
been reported in clinical experience with T cell products. Gene-engineering may also carry a risk 
of replication competent retrovirus (RCR) infection, which could be caused by the recombination 
of viral and cellular components during vector manufacturing, but this event has not been 
reported with T cell products. Severe autoimmune toxicity has occurred with some engineered T 
cell therapies. Immune-related toxicities are autoimmune conditions that could affect any organ 
in the body after product administration. The risk of severe autoimmunity with KK-LC-1 TCR 
T-cells is mitigated by preclinical studies that indicate that KK-LC-1 expression is restricted to 
tumors and germ cells. It is also mitigated by use of a TCR with targeting domains from a human 
TCR that has been through human thymic selection (which causes cells with strong reactivity to 
self-antigens to be eliminated). It is also mitigated by experience with prior safe treatment of a 
patient with 74.7 billion TIL cells, 67% of which naturally expressed the KK-LC-1 TCR.
12.3.1.2 Biopsy
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. CT 
guidance may be used in obtaining biopsies. If so, there will also be a risk of exposure to 
radiation from up to 3 CT scans. This radiation exposure is not required for medical care and is 
for research purposes only. The amount of radiation received in this study is 0.43 rem which is 
below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety 
Committee.
12.3.1.3 Blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
12.3.1.4 Leukapheresis
There may be some tingling in the face, mouth and fingers due to the medicine used to keep the 
blood from clotting during the procedure. The nurses may give a calcium-containing antacid to 
take away this tingling. Rarely, people may experience lightheadedness or dizziness. Rare 
complications of this procedure are lowered blood pressure, lightheadedness, dizziness, nausea, 
possible problems with the cell separator machine which would not allow the red cells and 
plasma to be returned and bleeding or bruising where the needles are put in arms.

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12.3.1.5 X-ray examination 
An x-ray examination exposes participants to a small amount of radiation, corresponding to one-
fifth of the dose a person gets each year from natural sources, such as the sun and the ground. 
This small amount of radiation is not considered dangerous.
12.3.1.6 Cardiac Stress Test
A cardiac stress test may check for risks of a possible heart problem or diagnose an existing heart 
problem. During a cardiac stress test, participants may be asked to walk or jog on a treadmill. 
While doing this, their heart will be watched on a monitor. Problems can happen during or after 
the test. Blood pressure may decrease, and participants may feel dizzy, lightheaded, and weak. 
They may feel their heart throbbing or have extra heartbeats. Participants may have a chest pain 
or heart attack. Doctors are there before, during, and after the test to help.
12.3.1.7 Electrocardiogram (ECG)
An electrocardiogram or ECG is a test that records the electrical activity of the heart.  It is used to 
measure the rate and regularity of heartbeats as well as the size and position of the heart chambers, 
and the presence of any damage to the heart.  For this test, participants will be asked to lie down, 
and small patches that have an adhesive edge with a gel in the middle, called electrodes, will be 
placed on arms, legs, and chest. The areas where the electrodes are placed will be cleaned and, if 
needed, some hair may be shaved or clipped to allow for better attachment of the electrodes.  The 
adhesive from the patches may irritate the skin.
12.3.1.8 Echocardiogram (ECHO)
An echocardiogram is an ultrasound to evaluate heart structure and function.  This test is very 
safe and is performed using a probe with gel placed on the chest.
12.3.1.9 Pulmonary Function Tests (PFT)
PFTs are safe for most participants; however, some may experience dizziness, shortness of breath 
and fainting. In rare PFTs may lead to a collapsed lung.  In participants with asthma, PFTs may 
precipitate an asthma attack. 
12.3.1.10
6 Minute Walk Test (6MWT)
This is a low risk medical assessment that measures how far participants can walk in 6 minutes. 
Participants may experience chest pain or breathing trouble during the assessment and should tell 
the doctor.
12.3.1.11
Intravenous Catheter
The risks associated with placing some catheters include pain, bleeding, infection and collapsed 
lung. The long-term risks of the catheter include infection and clotting of veins. It may be 
necessary to remove the catheter.
12.3.1.12
X-ray examination
An x-ray examination exposes participants to a small amount of radiation, corresponding to one-
fifth of the dose a person gets each year from natural sources, such as the sun and the ground. 
This small amount of radiation is not considered dangerous.

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12.3.1.13
Imaging Scans
CT, PET, and/ or MRI scans may be used. MRI scans can be claustrophobic. CT and PET scans 
expose a participant to radiation; the amount depends on the number of body areas scanned. In 
addition, CT, PET, and MRI scans involve use of contrast (oral and/or IV). An IV line may need 
to be inserted for administration of the contrast agent and can cause pain at the site where the IV 
is placed. There is also a small risk of bruising or infection. If a contrast agent is given with the 
scan, there is a small risk of having a reaction to the contrast. In the small group of participants 
who have a reaction, the most common symptoms are nausea, pain in the vein where the contrast 
was given, headache, a metallic or bitter taste in the mouth, and a warm or flushing feeling that 
lasts from 1-3 minutes. Rarely, these symptoms may require treatment. In very rare cases, people 
have had more severe allergic reactions that result in skin rashes, shortness of breath, wheezing, 
or lowering of the blood pressure.
12.3.1.14
Gadolinium enhanced MRI 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, 
hives, and lowering of blood pressure. Participants should not receive gadolinium if they 
previously had an allergic reaction to it.  They will be asked about such allergic reactions before 
gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of 
deaths.  A blood test of kidney function may be done within the month before an MRI scan with 
gadolinium contrast. Participants will not receive gadolinium for a research MRI scan if the 
kidney function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well.  Some types of gadolinium 
contrast drugs are less likely to remain in the body than others.  In this study, we will use the 
gadolinium contrast drugs that are less likely to remain in the body. We will also give 
participants additional information called a “Medication Guide.”  Upon request, we will give 
individual information about retained gadolinium we see on their studies.
12.3.1.15
Radiation Exposure
Screening:
This research study involves exposure to radiation from a chest x-ray, CT scan, PET scan, or CT-
guided biopsy. The amount of radiation exposure participants may receive from these procedures 
is equal to approximately 3.1 rem. A rem is a unit of absorbed radiation. 

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The PET scan and CT scan in this study will expose participants to the roughly the same amount 
of radiation as 10 years’ worth of background radiation. Most of the time, this amount of extra 
radiation is not harmful. However, scientists believe that being exposed to too much radiation 
can cause harmful side effects. This could include getting a new cancer. We estimate that this 
could happen in about 1 out of every 1000 people who get a very large amount of extra radiation. 
Treatment:
This research study involves exposure to radiation from chest x-ray, CT and PET scans, or CT-
guided biopsies. The amount of radiation exposure from these procedures is equal to 
approximately 8.1 rem. A rem is a unit of absorbed radiation. 
The chest x-ray, CT scans, PET scans, or CT-guided biopsies in this study will expose 
participants to the roughly the same amount of radiation as 27 years’ worth of background 
radiation. Being exposed to too much radiation can cause harmful side effects such as an increase 
in the risk of cancer.  The risk depends on how much radiation participants are exposed to. 
Please be aware that about 40 out of 100 people (40%) will get cancer during their lifetime, and 
20 out of 100 (20%) will die from cancer. The risk of getting cancer from the radiation exposure 
in this study is 0.8 out of 100 (0.8%) and of getting a fatal cancer is 0.4 out of 100 (0.4%).
Total:
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.”  
This study will expose participants to more radiation than they get from everyday background 
radiation. No one knows for sure whether exposure to these low amounts of radiation is harmful 
to the body. 
The chest x-ray, PET and CT scans in this study may expose participants to roughly the same 
amount of radiation as 37.4 years’ worth of background radiation. Being exposed to too much 
radiation can cause harmful side effects such as an increase in the risk of cancer. The risk 
depends on how much radiation they are exposed to. Please be aware that about 40 out of 100 
people (40%) will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. 
The risk of getting cancer from the radiation exposure in this study is 1.1 out of 100 (1.1%) and 
of getting a fatal cancer is 0.6 out of 100 (0.6%).
12.3.2 Known Potential Benefits
The experimental treatment has a chance to provide clinical benefit though it is not known if it 
will do so.  
12.3.3 Assessment of Potential Risks and Benefits
The standard approach to the administration of high-dose aldesleukin in all studies is to continue 
dosing until Grade 3 or 4 events occur. The most commonly seen Grade 4 events are pulmonary 
and renal impairment, and mental status changes. These toxicities may sometimes require 
intubation for protection of the participant’s airway. It is important to note that although these 
participants require significant supportive measures during this period, all toxicities are 
reversible and the overwhelming majority of participants have suffered no long term sequelae 
following this treatment regimen.  However, fatal complications are possible and it is therefore 

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only appropriate to carry out this experimental treatment in the context of life threatening 
metastatic cancer.
Toxicities seen on protocols using this non-myeloablative regimen and aldesleukin that occur 
during the follow up period are rare but have included EBV lymphoma following prolonged 
lymphopenia, herpes zoster infection, and sensory neuropathy likely related to fludarabine.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant.  Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (e.g., clinic consult room). When consent is conducted remotely, the participant will 
be informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant as described below.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or 
mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent remotely) found at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.

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13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 

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design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NCI CCR. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION 
Note:  The package insert/prescribing information for each commercial supply used should 
supersede any information included below. 

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14.1
INTERLEUKIN-2
14.1.1 Other Names
 (Aldesleukin, proleukin, recombinant human interleukin-2)
14.1.2 How Supplied
Aldesleukin (interleukin-2) will be provided by the NIH Clinical Pharmacy Department from 
commercial sources.
14.1.3 Formulation/Reconstitution
Aldesleukin, NSC #373364, is provided as single-use vials containing 22 million IU (~1.3mg) 
IL-2 as a sterile, white to off-white lyophilized cake plus 50mg mannitol and 0.18 mg sodium 
dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium 
phosphate to a pH of 7.5 (range 7.2 to 7.8).  The vial is reconstituted with 1.2 mL of Sterile 
Water for Injection, USP, and the resultant concentration is 18 million IU/mL or 1.1 mg/mL.  
Diluent should be directed against the side of the vial to avoid excess foaming.  Swirl contents 
gently until completely dissolved.  Do not shake.  Since vials contain no preservative, 
reconstituted solution should be used with 24 hours.
14.1.4 Storage
Intact vials are stored in the refrigerator (2 to 8C) protected from light.  Each vial bears an 
expiration date.
14.1.5 Dilution/Stability
Reconstituted aldesleukin should be further diluted with 50 mL of 5% Human Serum Albumin 
(HSA).  The HSA should be added to the diluent prior to the addition of IL-2.  Dilutions of the 
reconstituted solution over a 1000-fold range (i.e., 1 mg/mL to 1 mcg/mL) are acceptable in 
either glass bottles or polyvinyl chloride bags.  Aldesleukin is chemically stable for 48 hours at 
refrigerated and room temperatures, 2 to 30C. As there are no formal stability studies of 
aldesleukin diluted with HSA, the expiration time will be limited to 4 hours, per pharmacy 
guidance.
14.1.6 Administration
The dosage will be calculated based on total body weight.  The final dilution of aldesleukin will 
be infused over 15 minutes.  Aldesleukin will be administered as an inpatient.
14.1.7 Toxicities
Expected toxicities of aldesleukin are listed in the product label and in Appendix C.  Grade 3 
toxicities common to aldesleukin include diarrhea, nausea, vomiting, hypotension, skin changes, 
anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory changes as detailed in 
Appendix B.  Additional Grade 3 and 4 toxicities seen with aldesleukin are detailed in 
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14.2 FLUDARABINE
14.2.1 Description
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine 
antagonist antimetabolite.
14.2.2 How Supplied
It will be purchased by the NIH Clinical Pharmacy Department from commercial sources.  
Fludarabine is supplied in a 50 mg vial as a fludarabine phosphate powder in the form of a white, 
lyophilized solid cake or as an intravenous solution 25 mg/mL, 2 mL vial.
14.2.3 Stability
Following reconstitution with 2 mL of sterile water for injection to a concentration of 25 mg/mL, 
the solution has a pH of 7.7.  The fludarabine powder is stable for at least 18 months at 2 to 8C; 
when reconstituted, fludarabine is stable for at least 16 days at room temperature.  Since no 
preservative is present, reconstituted fludarabine will typically be administered within 8 hours.  
Specialized references should be consulted for specific compatibility information.  Fludarabine is 
dephosphorylated in serum, transported intracellularly and converted to the nucleotide 
fludarabine triphosphate; this 2-fluoro-ara-ATP molecule is thought to be required for the drug’s 
cytotoxic effects.  Fludarabine inhibits DNA polymerase, ribonucleotide reductase, DNA 
primase, and may interfere with chain elongation, and RNA and protein synthesis.
14.2.4 Storage
Intact vials should be stored refrigerated (2 to 8°C).
14.2.5 Administration
Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP or 5% 
dextrose in water, USP over 30 minutes.  The doses will be based on body surface area (BSA).  
If participant is obese (BMI >35), drug dosage will be calculated using practical weight as 
described in Appendix F. 
14.2.6 Toxicities
At doses of 25 mg/m2/day for 5 days, the primary side effect is myelosuppression; however, 
thrombocytopenia is responsible for most cases of severe and life-threatening hematologic 
toxicity.  Serious opportunistic infections have occurred in CLL participants treated with 
fludarabine.  Hemolytic anemia has been reported after 1 or more courses of fludarabine with or 
without a prior history of a positive Coomb’s test; fatal hemolytic anemia has been reported.  In 
addition, bone marrow fibrosis has been observed after fludarabine therapy.  Other common 
adverse effects and potentially fatal central nervous system toxicity in the form of progressive 
encephalopathy, blindness, and coma is only rarely observed at the currently administered doses 
of fludarabine.  More common neurologic side effects at the current doses of fludarabine include 
weakness, pain, malaise, fatigue, paresthesia, visual or hearing disturbances, and sleep disorders.  
Adverse respiratory effects of fludarabine include, cough, dyspnea, allergic or idiopathic 
interstitial pneumonitis.  Tumor lysis syndrome has been rarely observed in fludarabine 
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have caused persistently low (below 200) CD4 counts, and 1 participant developed 
polyneuropathy manifested by vision blindness, and motor and sensory defects.
Unless otherwise specified in this protocol, actual body weight is used for dose calculations of 
treatment agents.  In participants who are determined to be obese (BMI >35), the practical 
weight will be used.
14.3 CYCLOPHOSPHAMIDE
14.3.1 Description
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3 to 12 hours; the drug and/or its metabolites can be detected in the serum for up to 72 
hours after administration.
14.3.2 How Supplied
Cyclophosphamide will be obtained from commercially available sources by the Clinical Center 
Pharmacy Department.
14.3.3 Stability
Following reconstitution as directed with sterile water for injection, cyclophosphamide is stable 
for 24 hours at room temperature or 6 days when kept at 2 to 8C.
14.3.4 Administration
It will be diluted in 100 to 250 mL of 0.9% sodium chloride, USP or 5% dextrose in water, USP 
and infused over approximately 30-60 minutes.  The dose will be based on the participant’s body 
weight.  If participant is obese (BMI>35) drug dosage will be calculated using practical weight 
as described in Appendix F. 
14.3.5 Toxicities
Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia and 
thrombocytopenia.  Anorexia, nausea and vomiting, rash and alopecia occur, especially after 
high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and oral 
ulceration have been reported.  Sterile hemorrhagic cystitis occurs in about 20% of participants; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis.  
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 
lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been 
used prophylactically as an uroprotective agent in participants receiving cyclophosphamide.  
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all participants.  
Participants who receive high dose cyclophosphamide may develop interstitial pulmonary 
fibrosis, which can be fatal.  Hyperuricemia due to rapid cellular destruction may occur, 
particularly in participants with hematologic malignancy.  Hyperuricemia may be minimized by 
adequate hydration, alkalinization of the urine, and/or administration of allopurinol.  If 
allopurinol is administered, participants should be watched closely for cyclophosphamide 
toxicity (due to allopurinol induction of hepatic microsomal enzymes).  At high doses, 
cyclophosphamide can result in a syndrome of inappropriate antidiuretic hormone secretion; 
hyponatremia with progressive weight gain without edema occurs.  At high doses, 

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cyclophosphamide can result in cardiotoxicity.  Deaths have occurred from diffuse hemorrhagic 
myocardial necrosis and from a syndrome of acute myopericarditis; in such cases, congestive 
heart failure may occur within a few days of the first dose.  Other consequences of 
cyclophosphamide cardiotoxicity include arrhythmias, potentially irreversible cardiomyopathy, 
and pericarditis.  Other reported adverse effects of cyclophosphamide include headache, 
dizziness, and myxedema; faintness, facial flushing, and diaphoresis have occurred following IV 
administration.  Mesna (sodium 2-mercaptoethanesulphonate; given by IV injection) is a 
synthetic sulfhydryl compound that can chemically interact with urotoxic metabolites of 
cyclophosphamide (acrolein and 4-hydroxycyclophosphamide) to decrease the incidence and 
severity of hemorrhagic cystitis.
14.4 CELL PREPARATION (KK-LC-1 TCR TRANSDUCED PBL) (IND # 27348)
The procedure for the expanding the human PBL and the Certificate of Analysis (CoA) are 
similar to those approved by the Food and Drug Administration and used at the NCI in ongoing 
protocols.  The CoA is included in Appendix E.  The PBL will be transduced with retroviral 
supernatant containing the KK-LC-1 TCR.
14.4.1 Retroviral Vector Containing the KK-LC-1 TCR gene
The retroviral vector supernatant (PG13-MSGV1-KK-LC-1-TCR) encoding a T cell receptor 
directed against KK-LC-1 (KK-LC-152-60) was prepared and preserved following cGMP 
conditions in the Cincinnati Children’s Hospital Vector Production Facility (CCHMC).  The KK-
LC-1 TCR vector was produced by the Cincinnati Children’s Hospital Vector Production 
Facility. The backbone is the MSGV1 retrovirus that has been used in prior gene therapy clinical 
trials. It was produced using a PG13-based packaging line.
The retroviral vector KK-LC-1 TCR consists of 7,313 bps including the 5’LTR from the murine 
stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing 
acceptor sites, alpha and beta chain genes of the KK-LC-1 TCR.  The alpha and beta chains are 
linked by a P2A peptide.  The vector was codon optimized for expression by human cells with 
constant region exchanged for murine counterparts with an added disulfide bond and 
hydrophobic substitutions in the alpha chain constant region transmembrane domain.    
The physical titer will be determined by transduction of PBL with serial dilutions of the vector.  
TCR expression on the cell surface will be measured using FACS following staining with an 
anti-mouse constant region antibody.  The titer will be measured as transducing units per 
milliliter.  Portions of the supernatant will be stored at ≤ -65C at CCHMC (for long term stability 
testing), NCI at Frederick Central Repository and the NIH Clinical Center, Center for Cellular 
Engineering.  These storage facilities are equipped with around-the-clock temperature 
monitoring.  Upon request, supernatant will be delivered on dry ice to be used in ex vivo 
transduction of participant PBL.  There will be no re-use of the same unit of supernatant for 
different participants. Handling of the vector should follow the guidelines of Biosafety Level-2 
(BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at 
http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5_sect_IV.pdf.
14.5 MESNA
14.5.1 Other Names
Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891 

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14.5.2 How Supplied
Mesna will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied as a 100 mg/mL solution.
14.5.3 Storage
Intact ampules are stored at room temperature. 
14.5.4 Stability
Diluted solutions (1 to 20 mg/mL) are physically and chemically stable for at least 24 hours 
under refrigeration.  Mesna is chemically stable at room temperature for 48 to 72 hours in D5W, 
48 to 72 hours in D5W/0.45% NaCl, or 24 hours in 09% NaCl.
14.5.5 Administration
Dilute to concentrations less than or equal to 20 mg Mesna/mL fluid in D5W or 0.9% NaCl and 
to be administered intravenously as a continuous infusion.  If participant is obese (BMI >35) 
drug dosage will be calculated using practical weight as described in table 6 (FDA-approved 
package insert).  
14.5.6 Toxicities
Include nausea, vomiting, and diarrhea.
14.6 FILGRASTIM
Note:  Filgrastim or its biosimilar may be used interchangeably on this protocol. 
14.6.1 Other Names
Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen
14.6.2 How supplied
Filgrastim will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied in 300 ug/mL and 480 ug/1.6mL vials.  
14.6.3 Storage
G-CSF should be refrigerated and not allowed to freeze.  The product bears the expiration date.  
The product should not be shaken. 
14.6.4 Stability
It is generally stable for at least 10 months when refrigerated. 
14.6.5 Administration
The appropriate dose is drawn up into a syringe.  G-CSF will be given as a daily subcutaneous 
injection.  
14.6.6 Toxicities
The side effects of G-CSF are skin rash, myalgia, and bone pain, an increase of pre-existing 
inflammatory conditions, enlarged spleen with occasional associated low platelet counts, 
alopecia (with prolonged use) elevated blood chemistry levels.

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14.7 TRIMETHOPRIM AND SULFAMETHOXAZOLE DOUBLE STRENGTH (TMP/SMX DS)
14.7.1 How supplied 
TMP/SMX DS will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  
It may be used for the prevention of PCP pneumonia.  
14.7.2 Administration
The oral dose is 1 tablet PO daily 3 times a week (MUST be on non-consecutive days) beginning 
at or near the time of discharge from the hospital and continuing for at least 6 months and until 
the CD4 count is greater than 200 on 2 consecutive lab studies. 
14.7.3 Toxicities 
Like other sulfa drugs, TMP/SMX DS can cause allergies, fever, photosensitivity, nausea, and 
vomiting.  Allergies typically develop as a widespread itchy red rash with fever 8 to 14 days after 
beginning the standard dose.  Neutropenia, a reduction in the number of neutrophils, can also 
occur.
14.8 AEROSOLIZED PENTAMIDINE IN PLACE OF TMP/SMX DS
Participants with sulfa allergies may receive aerosolized Pentamidine 300 mg per nebulizer at or 
around the time of discharge from the hospital and continued monthly until the CD4 count is 
above 200 on 2 consecutive follow up lab studies and for at least 6 months post chemotherapy.  
Pentamidine Isethionate will be obtained by the Clinical Center Pharmacy Department from 
commercial sources.  It will be used to prevent the occurrence of PCP infections.  It is supplied 
in 300 mg vials of lyophilized powder and will be administered via nebulizer.  Toxicities 
reported with the use of Pentamidine include metallic taste, coughing, bronchospasm in heavy 
smokers and asthmatics; increased incidence of spontaneous pneumothorax in participants with 
previous PCP infection or pneumatoceles, or hypoglycemia.
14.9
 HERPES VIRUS PROPHYLAXIS
14.9.1  Valacyclovir (Valtrex)
Valacyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It may be used orally to prevent the occurrence of herpes virus infections in participants 
with positive HSV serology.  It is supplied in 500 mg tablets.  Valacyclovir may be started on 
day 0 at a dose of 500 mg orally daily if the participant is able to tolerate oral intake.  See 
package insert for dosing adjustments in participants with renal impairment.  Common side 
effects include headache, upset stomach, nausea, vomiting, diarrhea, or constipation.  Rare 
serious side effects include hemolytic uremic syndrome and thrombotic thrombocytopenic 
purpura.
14.9.2  Acyclovir
Acyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It may be used to prevent the occurrence of herpes virus infections in participants who 
cannot take oral medications.  It is supplied as powder for injection in 500 mg/vials.  
Reconstitute in 10 mL of sterile water for injection to a concentration of 50 mg/mL.  
Reconstituted solutions should be used within 12 hours.  IV solutions should be diluted to a 

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concentration of 7 mg/mL or less and used within 12 hours.  IV solutions should be diluted to a 
concentration of 7 mg/mL or less and infused over 1 hour to avoid renal damage.  Reversible 
renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic toxicity 
including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs have been 
reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will be made or 
the drug will be discontinued.  Stomach upset, headache or nausea, rash or hives; peripheral 
edema; pain, elevated liver function tests; and leukopenia, diarrhea, lymphadenopathy, myalgias, 
visual abnormalities and elevated creatinine have been reported.  Hair loss from prolonged use 
has been reported.  Acyclovir will not be used concomitantly with other nucleoside analogs that 
interfere with DNA synthesis, e.g. ganciclovir.  In renal disease, the dose is adjusted as per 
product labeling.
14.10  FUNGAL PROPHYLAXIS
14.10.1 Fluconazole
Fluconazole will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It can be used as prophylaxis against fungal infections.  It is available in 200 mg tablets.  
It can cause headache, nausea, vomiting, diarrhea, or abdominal pain, and liver damage which 
may be irreversible.  It can cause rashes and itching, which in rare cases has caused Stevens 
Johnson Syndrome.  It has several significant drug interactions.  The package insert should be 
consulted prior to prescribing.  For IV administration in participants who cannot tolerate the oral 
preparation, Fluconazole comes in 2 mg/mL solution for injection, and prepared according to 
Clinical Center Pharmacy standard procedures.  It should be administered at a maximum IV rate 
of 200 mg/hr.
14.11  SUPPORT MEDICATIONS
14.11.1 Ondansetron hydrochloride
Ondansetron hydrochloride will be obtained by the Clinical Center Pharmacy Department from 
commercial sources.  It will be used to control nausea and vomiting during the chemotherapy 
preparative regimen.  It can cause headache, dizziness, myalgias, drowsiness, malaise, and 
weakness.  Less common side effects include chest pain, hypotension, pruritus, constipation and 
urinary retention.  Consult the package insert for specific dosing instructions.
14.11.2 Furosemide
Furosemide will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It will be used to enhance urine output during the chemotherapy preparative regimen 
with cyclophosphamide.  Adverse effects include dizziness, vertigo, paresthesias, weakness, 
orthostatic hypotension, photosensitivity, rash, and pruritus.  Consult the package insert for a 
complete list of all side effects. 
14.12 KK-LC-1 POSITIVITY ASSAY (NSR DEVICE)
In order to be eligible for the study, participants are required to have histologically or 
cytologically confirmed KK-LC-1 positive epithelial cancer. KK-LC-1 positivity assay is not 
FDA approved for this purpose; however, it is being used as a diagnostic device. Validation 
assays to support the use of the assay have been submitted to IND. All of the documentation is in 
the IND files.

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According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to 
the health, safety and welfare of a subject and meets the significant risk criteria listed in the table 
below along with the sponsor’s conclusions with regard to the applicability of these criteria to 
the current study. The device has been assessed by the sponsor as non-significant risk per the 
below.
Applicable 
to current 
study
Justification
Is an implant 
No 
The KK-LC-1 positivity assay is not introduced into the 
subject 
Is used in supporting or 
sustaining human life 
No 
The device is diagnostic 
Is of substantial 
importance in diagnosing 
mitigating or treating 
disease or preventing 
impairment of human 
health 
No 
While the device is diagnostic, we do not believe it 
presents a potential for serious risk to the health and 
welfare of the subject. The assessment of KK-LC-1 
positivity is only used to determine eligibility for the 
study and is assessed to help to increase the possibility 
that all persons enrolling on the study might derive benefit 
from therapy. Persons that are deemed ineligible to 
enroll on the basis of this test are eligible for studies 
within CIO that are not reliant on this test. 
Otherwise poses a risk 
No 
Testing will be performed on archival samples or on 
fresh tissue that is collected at screening for 
confirmation of diagnosis. No additional collection of 
tissue will occur for purposes of KK-LC-1 testing. 
Source: Testing will be performed via an IHC assay developed by Rutgers Cancer Institute of 
New Jersey.  
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cells directed against Kita-Kyushu Lung Cancer Antigen-1. J Immunother Cancer 
2019, 7(1):229.
48.
Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, 
Robbins PF, Klebanoff CA, Rosenberg SA et al: Landscape of immunogenic tumor 
antigens in successful immunotherapy of virally induced epithelial cancer. Science 
2017, 356(6334):200-205.
49.
Cohen CJ, Li YF, El-Gamil M, Robbins PF, Rosenberg SA, Morgan RA: Enhanced 
antitumor activity of T cells engineered to express T-cell receptors with a second 
disulfide bond. Cancer Res 2007, 67(8):3898-3903.
50.
Haga-Friedman A, Horovitz-Fried M, Cohen CJ: Incorporation of transmembrane 
hydrophobic mutations in the TCR enhance its surface expression and T cell 
functional avidity. J Immunol 2012, 188(11):5538-5546.
51.
Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, 
Dudley ME, Yang JC, Sherry RM, Kammula US et al: Complete regression of 
metastatic cervical cancer after treatment with human papillomavirus-targeted 
tumor-infiltrating T cells. J Clin Oncol 2015, 33(14):1543-1550.

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52.
de Castro E, Sigrist CJ, Gattiker A, Bulliard V, Langendijk-Genevaux PS, Gasteiger E, 
Bairoch A, Hulo N: ScanProsite: detection of PROSITE signature matches and 
ProRule-associated functional and structural residues in proteins. Nucleic Acids Res 
2006, 34(Web Server issue):W362-365.
53.
Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, 
Royal RE, Sherry RM, Wunderlich JR et al: Gene therapy with human and mouse T-
cell receptors mediates cancer regression and targets normal tissues expressing 
cognate antigen. Blood 2009, 114(3):535-546.
54.
Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, 
Morrissette JJD, DeNizio JE, Reddy S et al: Disruption of TET2 promotes the 
therapeutic efficacy of CD19-targeted T cells. Nature 2018, 558(7709):307-312.
55.
Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, 
Kalos M, Riley JL, Deeks SG et al: Decade-long safety and function of retroviral-
modified chimeric antigen receptor T cells. Sci Transl Med 2012, 4(132):132ra153.
56.
Bear AS, Morgan RA, Cornetta K, June CH, Binder-Scholl G, Dudley ME, Feldman SA, 
Rosenberg SA, Shurtleff SA, Rooney CM et al: Replication-competent retroviruses in 
gene-modified T cells used in clinical trials: is it time to revise the testing 
requirements? Mol Ther 2012, 20(2):246-249.
57.
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, 
Kammula U, White DE, Mavroukakis SA et al: Adoptive cell transfer therapy 
following non-myeloablative but lymphodepleting chemotherapy for the treatment 
of participants with refractory metastatic melanoma. J Clin Oncol 2005, 23(10):2346-
2357.
58.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-247.
59.
Costelloe CM, Chuang HH, Madewell JE, Ueno NT: Cancer Response Criteria and 
Bone Metastases: RECIST 1.1, MDA and PERCIST. J Cancer 2010, 1:80-92.
60.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, 
Higano C, Bubley GJ, Dreicer R et al: Design and end points of clinical trials for 
participants with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol 2008, 26(7):1148-1159.
61.
Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer 
E, Sagae S, Greven K, Vergote I et al: Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004, 96(6):487-488.
62.
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, 
Freidlin B, Halabi S, Hudes G et al: Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the 
Prostate-Specific Antigen Working Group. J Clin Oncol 1999, 17(11):3461-3467.
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Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, 
Friedlander M, Jakobsen A, Vermorken JB: Re: new guidelines to evaluate the 

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response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer 
Intergroup. J Natl Cancer Inst 2000, 92(18):1534-1535.

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16 APPENDICES
16.1 APPENDIX A:  ADVERSE EVENTS OCCURRING IN ≥10% OF PARTICIPANTS TREATED 
WITH ALDESLEUKIN (N=525)1
Body System
% Participants 
Body System
  
 % 
Participants
Body as a Whole 
Metabolic and Nutritional Disorders
Chills 
52 
Bilirubinemia 
40
Fever 
29 
Creatinine increase 
33
Malaise 
27 
Peripheral edema 
28
Asthenia 
23
SGOT increase 
23
Infection 
13 
Weight gain 
16
Pain 
12 
Edema 
15
Abdominal pain 
11 
Acidosis 
12
Abdomen enlarged 
10 
Hypomagnesemia 
12
Cardiovascular 
Hypocalcemia 
11
Hypotension 
71 
Alkaline phosphatase incr
10
Tachycardia 
23
Nervous
Vasodilation 
13 
Confusion 
34
Supraventricular tachycardia
12 
Somnolence 
22
Cardiovascular disordera 
11 
Anxiety 
12
Arrhythmia 
10 
Dizziness 
11
Digestive 
Respiratory
Diarrhea 
67 
Dyspnea 
43
Vomiting 
50 
Lung disorderb 
24
Nausea 
35 
Respiratory disorderc 
11
Stomatitis 
22 
Cough increase 
11
Anorexia 
20 
Rhinitis 
10
Nausea and vomiting 
19 
Skin and Appendages
Hemic and Lymphatic 
Rash 
42
Thrombocytopenia 
37
Pruritus 
24
Anemia 
29 
Exfoliative dermatitis 
18
Leukopenia
16 
Urogenital
Oliguria 
63
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF.
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi.
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes.
1Source: Proleukin® Prescribing Information – June 2007

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16.2 APPENDIX B:  EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT
Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Chills
3
IV Meperidine 25-50mg IV 
q1hr, prn
No 
No
Fever
3
Acetaminophen 650mg po 
q4hr; Indomethacin 50-75mg 
po q8h
No
No
Pruritus
3
Hydroxyzine HCl 10-20mg po 
q6h, prn; Diphenhydramine 
HCl 25-50mg po q4h prn
No 
No
Nausea/Vomiting/A
norexia
3
Ondansetron 10mg IV q8hr 
prn, Granisetron 0.01 mg/kg 
IV qday prn, Droperidol 1mg 
IV a4-6h prn; Prochlorperazine 
25mg PR prn or 10mg IV q6hr 
prn
No
No
Diarrhea
3
Loperamide 2mg po q3h prn; 
Diphenoxylate HCl 2.5mg and 
Atropine sulfate 25mcg po q3h 
prn; Codeine sulfate 30-60mg 
po q4h prn
If uncontrolled 
after 24h despite 
all supportive 
measures
No
Malaise
3 or 4
Bedrest
If other toxicities 
occur 
simultaneously
No
Hyperbilirubinemia
3 or 4
Observation
If other toxicities 
occur 
simultaneously
No
Anemia
3 or 4 
Transfusion with PRBCs
If uncontrolled 
despite all 
supportive 
measures
No
Thrombocytopenia
3 or 4 
Transfusion with platelets
If uncontrolled 
despite all 
supportive 
measures
No

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Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Edema/Weight gain
3
Diuretics prn
No 
No
Hypotension
3
Fluid resuscitation, 
Vasopressor support
If uncontrolled 
despite all 
supportive 
measures
No
Dyspnea
3 or 4 
Oxygen or ventilator support
If requires 
ventilator 
support
No
Oliguria
3 or 4 
Fluid boluses or dopamine at 
renal doses
If uncontrolled 
despite all 
supportive 
measures
No
Increased Creatinine
3 or 4
Observation
Yes (Grade 4)
No
Renal Failure
3 or 4 
Dialysis/CVVH
Yes
Yes
Pleural Effusion
3
Thoracentesis
If uncontrolled 
despite all 
supportive 
measures
No
Bowel Perforation
3
Surgical intervention
Yes
Yes
Confusion
3
Observation
Yes
No
Somnolence
3 or 4 
Intubation for airway 
protection
Yes
Yes
Arrhythmia
3
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy
If uncontrolled 
despite all 
supportive 
measures
No
Elevated Troponin 
Levels
3 or 4 
Observation
Yes
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose

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Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Myocardial 
Infarction
4
Supportive care
Yes
Yes
Elevated 
Transaminases
3 or 4
Observation
For Grade 4 
without liver 
metastases
If changes 
have not 
improved to 
baseline by 
next dose
Hyperbilirubinemia
3 or 4 
Observation
For Grade 4 
without liver 
metastases
If changes 
have not 
improved to 
baseline by 
next dose
Electrolyte 
Imbalances
3 or 4
Electrolyte replacement
If uncontrolled 
despite all 
supportive 
measures
No
Neutropenia
4
Observation
No
No
*Unless the toxicity is not reversed within 12 hours.
**Unless the toxicity is not reversed to Grade 2 or less by next treatment.

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16.3 APPENDIX C:  INTERLEUKIN-2 TOXICITIES OBSERVED IN PARTICIPANTS TREATED AT 
THE NIH CLINICAL CENTER

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16.4 APPENDIX D:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
5
Dead.

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16.5 APPENDIX E:  CERTIFICATE OF ANALYSIS KK-LC-1 TCR
Date of preparation of final product:
Participant:
Tests performed 
on final product:
Test
Method
Limits
Results 
Initials/Date
Cell viability1
Trypan blue 
exclusion
>70%
Total viable cell 
number1
Visual microscopic 
count
>1x109
TCR expression2
FACS analysis of 
the transduced 
cells
PBL, >10%
Microbiological 
studies
Gram stain1,3
No micro-
organisms 
seen
Aerobic culture3,4
No growth
Fungal culture3,4
No growth
Anaerobic 
culture3,4
No growth
Mycoplasma test5
Negative
Endotoxin
Limulus assay1
<5 E.U./kg
RCR
RCR-PCR6
Negative
1Performed on sample of the final product immediately prior to infusion.  Results are available at the time 
of infusion.
2Performed 2 to 10 days post-transduction.  Results are available at the time of infusion.
3Performed 2 to 4 days prior to infusion.  Results are available at the time of infusion but may not be 
definitive.
4Sample collected from the final product prior to infusion.  Results will not be available before cells are 
infused into the participant.

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5Performed 2 to 10 days prior to infusion.  Results are available at the time of infusion.
6Performed on sample approximately 1 to 4 days prior to infusion.  Results are available at the time of 
infusion.
Prepared by:  _________________________  Date:______________________
QC sign-off:  _________________________  Date: ______________________
    Qualified Clinical or Laboratory Supervisor

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16.6 APPENDIX F:  MODIFICATION OF DOSE CALCULATIONS* IN PARTICIPANTS WHOSE BMI 
IS GREATER THAN 35 
1. BMI Determination:
BMI = weight (kg) / [height (m)]2
2. Calculation of ideal body weight
Male = 50kg + 2.3 (number of inches over 60 inches)
Example: ideal body weight of 5’10” male
50 + 2.3 (10) = 73 kg
Female = 45.5kg + 2.3 (number of inches over 60 inches)
Example: ideal body weight of a 5’3” female
45.5 + 2.3 (3) = 57kg
3. Calculation of “practical weight”
Calculate the average of the actual and the ideal body weights.  This is the 
practical weight to be used in calculating the doses of chemotherapy and 
associated agents designated in the protocol.  

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16.7 APPENDIX G:  INFUSION REACTIONS – GUIDELINES FOR MANAGEMENT 

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16.8 APPENDIX H:  PARTICIPATING SITE ROLES AND OVERSIGHT PLAN
The study will also be conducted at a participating site under a reliance agreement.  The role of 
the participating site is limited to sample and data analysis as described in sections 5.1.5.  
Enrollment and routine follow up per protocol will not be conducted at participating site. 
Data will be collected from the sites as outlined in section 6.1 and expedited reporting will be per 
section 7.4. Protocol and regulatory compliance will be ensured as described in section 7.6.1 and 
13.2.
IRB determinations will be forwarded to the participating site PI/study coordinator by a member 
of the study team.