A Phase II Study of Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
Phase: PHASE2
Conditions: Squamous Lntraepithelial Lesions of Vulva, Neoplasms, Squamous Cell, Vulvar HSIL
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Immunotherapy for vulvar HSIL  
Version Date: 4/27/2020 
 
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Abbreviated Title: Immunotherapy for vulvar HSIL  
CC Protocol #: 19C0091 A 
IBC #: RD-18-XII-01 
NCT #: NCT03937791 
Version Date: 4/27/2020 
 
Title: A Phase II Study of Immunotherapy with E7 T Cell Receptor T Cells for Vulvar High-
Grade Squamous Intraepithelial Lesions 
 
Principal Investigator: Christian S. Hinrichs, MD  
                                        Experimental Transplantation and Immunotherapy Branch 
                                        National Cancer Institute (NCI) 
                                        10 Center Drive, Room 4B04  
                                        Bethesda, MD 20892 
                                        Phone: 240-760-6059 
                                        Email: Hinrichs@nih.gov 
   
 
 
Investigational Agents:     
Drug Name: 
E7 TCR 
IND Number: 
16959 
Sponsor: 
Center for Cancer Research  
Manufacturer: 
CC DTM 
 
Commerical Agents:  None 

Abbreviated Title: Immunotherapy for vulvar HSIL  
Version Date: 4/27/2020 
 
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PRÉCIS  
Background: 
• Vulvar high-grade squamous intraepithelial lesion (HSIL) is a premalignant epithelial 
lesion that is frequently multifocal and/or recurrent. 
• The primary treatment is surgery, which may result in disfigurement and compromise of 
the urethra, anus, or clitoris. Recurrence after surgery is common and primarily treated with 
additional surgery.  
• Vulvar HSIL is caused by chronic infection with the human papillomavirus (HPV) type 16 
infection. In this clinical trial the HPV-16 infection is targeted with a single infusion of 
autologous T cells that have been genetically engineered to express a HPV-16 E7-specific 
T cell receptor (E7 TCR T cells). 
Objective: 
• Determine the complete response rate for E7 TCR T cells in the treatment of vulvar HSIL. 
Eligibility: 
• Histologically confirmed diagnosis of HPV-16+ vulvar HSIL. 
• Expression of the HLA-A2*02:01 allele. 
• Measurable lesion(s) that are recurrent or cannot be resected with acceptable cosmetic or 
functional results. 
• Age greater than or equal to 18 years old. 
• Eastern Oncology Cooperative Group Performance Score of 0 or 1. 
Design: 
• This is a phase II clinical trial  
• Simon minimax two-stage design with initial enrollment of 12 patients and expansion to 
16 patients if one or more complete response(s) is/are observed in the initial patients.  
• Subjects will receive 1x1011 E7 TCR T cells  
• No conditioning regimen or aldesleukin will be given   
• Re-enrollment will be allowed for a small number of subjects. 
 
 

Abbreviated Title: Immunotherapy for vulvar HSIL  
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TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1. 
INTRODUCTION .................................................................................................................. 5 
1.1 
Study Objectives .............................................................................................................. 5 
1.2 
Background and Rationale ............................................................................................... 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 14 
2.1 
Eligibility Criteria .......................................................................................................... 14 
2.2 
Screening Evaluation...................................................................................................... 16 
2.3 
Registration Procedures.................................................................................................. 17 
2.4 
Baseline Procedures ....................................................................................................... 18 
3 
STUDY IMPLEMENTATION ............................................................................................ 18 
3.1 
Study Design .................................................................................................................. 18 
3.2 
Drug Administration ...................................................................................................... 21 
3.3 
Study Calendar ............................................................................................................... 22 
3.4 
Potential Repeat Treatment ............................................................................................ 26 
3.5 
On-Study Evaluations .................................................................................................... 26 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 26 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 27 
4.1 
Prohibited Medications .................................................................................................. 27 
4.2 
Blood Product Support ................................................................................................... 27 
4.3 
Other concomitant medications/measures ...................................................................... 27 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 27 
5.1 
Correlative Studies for Research .................................................................................... 27 
5.2 
Summary of Sample Collection ..................................................................................... 29 
5.3 
Gene-therapy-specific follow-up.................................................................................... 30 
5.4 
Sample Storage, Tracking and Disposition .................................................................... 30 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 32 
6.1 
Data Collection ............................................................................................................... 32 
6.2 
Data Sharing Plans ......................................................................................................... 33 
6.3 
Response Criteria ........................................................................................................... 33 
6.4 
Toxicity Criteria ............................................................................................................. 36 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 36 

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7.1 
Definitions ...................................................................................................................... 36 
7.2 
OHSRP Office of Complaince and Training / IRB Reporting ....................................... 36 
7.3 
NCI Clinical Director Reporting .................................................................................... 36 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ......................................... 36 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 38 
8 
SPONSOR SAFETY REPORTING ..................................................................................... 38 
8.1 
Definitions ...................................................................................................................... 38 
8.2 
Assessment of Safety Events.......................................................................................... 39 
8.3 
Reporting of Serious Adverse Events ............................................................................ 40 
8.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 40 
8.5 
Reporting Pregnancy ...................................................................................................... 40 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 40 
9 
CLINICAL MONITORING ................................................................................................. 41 
10 STATISTICAL CONSIDERATIONS.................................................................................. 41 
10.1 Statistical Hypotheses .................................................................................................... 41 
10.2 Statistical Analyses ........................................................................................................ 42 
11 COLLABORATIVE AGREEMENTS ................................................................................. 43 
11.1 Cooperative Research and Development Agreement (CRADA) ................................... 43 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 43 
12.1 Rationale For Subject Selection ..................................................................................... 43 
12.2 Strategies/Procedures for Recruitment ........................................................................... 44 
12.3 Participation of Children ................................................................................................ 44 
12.4 Participation of Subjects Unable to Give Consent ......................................................... 44 
12.5 Evaluation of Benefits and Risks/Discomforts .............................................................. 44 
12.6 Risks/Benefits Analysis(including who are or may become unable to consent) ........... 44 
12.7 Consent Process and Documentation ............................................................................. 45 
13 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION .............. 45 
13.1 Description of the Investigational Product (IND #16959) ............................................. 45 
14 REFERENCES ..................................................................................................................... 47 
15 APPENDICES ...................................................................................................................... 49 
15.1 Appendix A: Performance Status Criteria ...................................................................... 49 
 
 

Abbreviated Title: Immunotherapy for vulvar HSIL  
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1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
Objectives: 
1.1.1 Primary Objective 
• To determine the complete response rate for E7 TCR T cells in the treatment of patients 
with vulvar HSIL. 
1.1.2 Secondary Objectives 
• Characterize the safety profile of E7 TCR T cells administered in a low intensity setting 
without conditioning or systemic aldesleukin.  
1.1.3 Exploratory Objectives  
• To evaluate a novel assay to genotype HPV using a ddPCR-based blood test. 
• Test for clearance of HPV infection from vulvar tissues. 
• Evaluate the expansion, survival, trafficking, phenotype, and function of E7 TCR cells 
following infusion. 
• Investigate the vulvar HSIL microenvironment including immune cell subsets and 
costimulatory/inhibitory molecules. 
• Assess circulating HPV DNA levels associated with treatment. 
1.2 
BACKGROUND AND RATIONALE 
Vulvar high-grade squamous intraepithelial lesion (HSIL) is a premalignant condition that is 
caused by high-risk human papillomavirus (HPV) infection. The primary treatment for vulvar 
HSIL is surgical. Surgery can result in substantial morbidity, particularly for lesions that are 
multifocal, extensive, or adjacent to important anatomic structures (e.g. the anus, clitoris, or 
urethra). Following surgery, disease recurrence is common due to persistence of the underlying 
HPV infection. Therefore, a systemic treatment directed against the viral infection at the 
foundation of the disease may be more effective. This research protocol seeks to target the HPV 
infection that is causing vulvar HSIL with immunotherapy. The immunotherapy consists of 
autologous T cells that are genetically engineered to recognize the HPV-16 E7 oncoprotein, 
which is expressed by HPV-16 infected cells. The protocol is designed as a one-time treatment to 
clear the HPV infection and thereby cause regression of the HSIL lesions. 
1.2.1 Vulvar high-grade squamous intraepithelial lesion (HSIL) 
Vulvar HSIL is defined by the 2015 International Society for the Study of Vulvovaginal Disease 
(ISSVD) as an HPV-associated lesion of the vulva that has high malignancy potential. The term, 
vulvar HSIL, is equivalent to the previously used nomenclature of vulvar intraepithelial 
neoplasia, usual type (1). It does not include low-grade squamous intraepithelial lesions without 
malignant potential such as condyloma acuminatum. It also does not include premalignant 
lesions that are not associated with HPV, which are classified as differentiated-type vulvar 
intraepithelial neoplasia. Multiple HPV types can cause vulvar HSIL but HPV-16 is the most 
prevalent (2). HPV-18 causes only 6% of cases of high-grade vulvar HSIL (3, 4). Spontaneous 

Abbreviated Title: Immunotherapy for vulvar HSIL  
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regression of vulvar HSIL is rare, reportedly occurring in fewer than 1.5% of patients per year 
(5).  
Patients with vulvar HSIL may present with symptoms of local itching, burning, or pain. 
Diagnosis is suggested by careful inspection of the lesion(s) and is confirmed by biopsy. 
Multicentric disease is common due to diffuse spread of HPV infection throughout vulvar 
epithelium. Vulvar HSIL transforms into vulvar squamous cell carcinoma (SCC) in 3 to 9% of 
patients. Therefore, all lesions require surveillance with physical exams and biopsies to rule out 
invasive cancer (6). For lesions that do not regress, excision is required. The type of surgery 
depends on the extent and anatomic location of disease. Treatment of multifocal lesions, 
extensive disease, or lesions in proximity to the urethra, clitoris, or anus can result in deformity 
and functional impairment. Even with radical excision to negative margins, recurrence occurs in 
approximately 30% of patients (7). Thus, surgery may be an unsatisfactory treatment option as it 
often fails to prevent disease recurrence, results in morbidity, and negatively impacts 
psychological and sexual health (8). 
1.2.2 Studies of the natural history and treatment history of vulvar HSIL  
Studies of the natural history and treatment of vulvar HSIL are scientifically limited as they are 
mostly retrospective and have small sample sizes. One systematic review reported that 6.5% of 
3322 patients with vulvar HSIL progressed to develop an invasive vulvar carcinoma (6). In 
untreated patients, invasive vulvar carcinoma developed in nine percent of subjects within one to 
eight years. Invasive cancers are treated with radical local excision or modified radical 
vulvectomy, depending on the tumor stage. Locally advanced cancers are treated with 
chemoradiation. Salvage surgery with pelvic exenteration and colostomy or ureteral diversion 
may be employed. Five-year survival for local, regional, and distant vulvar cancers are 86%, 
54%, and 16% respectively. A study based on data from the United States reported the incidence 
of vulvar HSIL to be 2.86 per 100,000 women (9).  
Vulvar HSIL is caused by HPV infection, and HPV infections can be recognized and attacked by 
the immune system. Hence, immunotherapy is an attractive treatment strategy for vulvar HSIL. 
Topical immunotherapy with imiquimod, an immune response modifier that activates dermal 
dendritic cells through Toll-like receptor 7, has been reported to have response rates of 13-81%, 
but vulvar inflammation and pain limits its use and it is not currently FDA-approved (10). 
Nonetheless, it is a treatment option that some patients should consider as an alternative to this 
protocol. Experimental vaccines have been tested for the treatment of vulvar HSIL. A clinical 
trial of a vaccine targeting HPV-16 E6 and E7 showed promising results in a single-arm phase II 
study(11, 12). Recently, a DNA-based vaccine against HPV-16 E6, E7 and HPV-18 E6,E7 
showed an improvement in histopathological regression in cervical intraepithelial neoplasia 
compared to placebo (49% vs 30%)(13, 14). These results led to a phase II clinical trial 
comparing the DNA-based vaccine alone or in combination with imiquimod for patients with 
vulvar HSIL. This trial is actively accuring patients (NCT03180684). The preventative vaccines 
for HPV (e.g. Gardasil and Cervarix) are highly effective at preventing HPV infections but not 
considered effective for the treatment of VIN(15). 
1.2.3 Targeting of HPV-associated cancers with adoptive T cell therapy 
In a clinical trial of HPV-16 E7 TCR T cells for patients with metastatic cancers associated with 
HPV-16 (e.g. cervical cancer, anal cancer, head and neck cancer, etc.), subjects received a 

Abbreviated Title: Immunotherapy for vulvar HSIL  
Version Date: 4/27/2020 
 
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chemotherapy conditioning regimen followed by E7 TCR T cells and aldesleukin (protocol 16-
C-0154). A total of 12 patients were treated. Four patients experienced confirmed partial 
responses. Two patients had unconfirmed partial responses.  One dose-limiting toxicity occurred 
in the 12 patients on this protocol. The patient had impaired lung function from rapidly 
progressing cancer in the lungs and experienced severe lung, cardiovascular, and kidney toxicity 
that required temporary mechanical ventilation, pressors, and hemodialysis, that resulted in soft 
tissue injury to the distal lower extremities. No other patients experienced dose-limiting 
toxicities. No off-target toxicity or healthy tissue targeting was observed. The maximum 
administered dose was deemed the maximum tolerated dose (100 billion E7 TCR T cells). 
Separately, in a clinical trial of autologous tumor-infiltrating T cells generated from cultures with 
HPV reactivity for metastatic HPV+ cancers, objective tumor responses occurred in 3/9 patients 
with cervical cancer (12, 16). Adoptive T cell therapy has not been reported for the treatment of 
premalignant HPV-related diseases.  
 
Tumors appear to acquire mutations that confer resistance to T cell immunity as they progress 
(13, 17, 18). This may make targeting of pre-malignant conditions more successful than in the 
setting of advanced disease.  
 
The amount of E7 TCR T cell engraftment required to treat this condition is not known. 
Furthermore, the high cell dose (100 billion cells) will increase the chance of engraftment in the 
absence of conditioning chemotherapy compared to lower cell doses used in our previous 
protocol with E6 TCR T cells (7 to 70 billion cells).  
1.2.4 E7 TCR discovery and characterization 
E711-19 is a naturally processed epitope of HPV-16 E7 that binds to HLA-A*02:01 and that has 
been isolated from the surface of HPV-16+ HLA-A*02:01+ tumor cells (19). We identified the 
nucleotide sequence of a TCR targeting E711-19 from the cervix-infiltrating T cells of a patient with 
cervical intraepithelial neoplasia who received a therapeutic cancer vaccine targeting HPV-16 E7. 
The nucleotide sequence 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. (20, 21) 
The TCR sequence insert was cloned into the MSGV1 retroviral vector (Figure 1), which was 
chosen for this clinical trial based on its excellent safety record in treating greater than 200 patients.  
 

Abbreviated Title: Immunotherapy for vulvar HSIL  
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Figure 1:  E7 TCR vector map. A TCR targeting E711-19 was isolated from the cervix-infiltrating 
lymphocytes of a patient with cervical intraepithelial neoplasia. 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 7,310 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 E7 TCR are linked by a furin 2A peptide. 
  
Peripheral blood T cells transduced to express the E7 TCR display high avidity for the E711-19 
peptide (Figure 2) and CD8-independent HLA-A*02:01/E711-19 tetramer binding (Figure 3). 
They specifically recognize a panel of HPV-16+ HLA-A*02:01+ cervical and oropharyngeal 
cancer cell lines but not cell lines that lack HLA-A*02:01 or HPV-16 (Figure 4). Thus, gene 
engineered T cells expressing the E7 TCR can specifically target HPV-16+ HLA-A*02:01+ 
cancers. In contrast to TCRs that have had unexpected cross-reactivity against normal human 
proteins, this TCR was isolated directly from a human T cell (2). Hence, it was subjected to 
thymic selection and is unlikely to possess avid reactivity against self-antigens. The 
complementarity determining regions of the TCR have not been modified; therefore, there is no 
chance that cross-reactivity has been artificially introduced.  The target epitope is derived from a 
viral protein, and no more than 6 of its 9 amino acids are shared with any human protein (Table 
1). There is no cross reactivity of this TCR with epitopes of human proteins that share six amino 
acids or five amino acids plus a conservative amino acid substitution (Figure 5). In addition, 
alanine scanning of E711-19 identified four important residues for recognition ( 
 
 
E7 TCR
7310 bp
AmpR
SD
SA
3' LTR
5' LTR
Furin 2A linker
Beta Chain
Alpha Chain
EcoRI (1804)
Nco I (2)

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9 
Figure 6). Cross reactivity was not detected against epitopes of human proteins that shared these 
residues (Table 1).  
I F N - γ  ( p g / m L )
6
7
8
9
1 0
1 1
1 2
N o  p e p t i d e
0
5 0 0 0
1 0 0 0 0
E 7  T C R
E 6  T C R
>
- l o g [ E 7 1 1 - 1 9 ]  ( M )
 
Figure 2:  T cells transduced to express the E7 TCR demonstrated high avidity for the E711-19 
peptide. T cells from PBMC were transduced to express the E7 TCR.  Functional avidity was tested by 
coculture with T2 cells pulsed with titrated concentrations of E711-19 peptide. 
 
 
Figure 3:  Peripheral blood T cells transduced to express the E7 TCR display CD8-independent 
HLA-A*02:01/E711-19 tetramer binding. T cells from PBMC were transduced to express the E7 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. 
Donor 1
CD8 +
CD8 -
Donor 2
79
2
0
19
84
1
0
15
70
2
0
27
68
3
0
29
HLA-A2/E711-19 tetramer
mTRBC

Abbreviated Title: Immunotherapy for vulvar HSIL  
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I F N - γ  ( p g / m
L )
2 9 3 - A 2  +  E 7 ( 1 1 - 1 9 )
2 9 3 - A 2  +  E 6 ( 2 9 - 3 8 )
C a S k i
S C C 9 0
S C C 1 5 2
6 2 4  E 7
6 2 4  E 6
A l b
P a n c 1
S i H a
A n e
0
5 0 0 0
1 0 0 0 0
1 0 0 0 0
5 0 0 0 0
U n t r a n s d u c e d
E 7  T C R
+    +    +    +    -    -    -    +    -
H P V - 1 6
>
+    +    +    +    +    +    -    -    -
H L A - A 2
         
Figure 4:  T cells transduced to express the E7 TCR specifically recognized HPV-16+ HLA-
A*02:01+ tumor lines   T cells transduced with E7 TCR were cocultured with targets expressing HPV-
16 and HLA-A2 or with negative controls. Target cell line expression of HPV-16 and HLA-A2 is 
indicated below each label on the x-axis.   
 
 
IFN-γ (pg/mL)
E7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
no peptide
0
5000
10000
15000
20000

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Figure 5: E7 TCR transduced T cells did not show cross reactivity against human peptides. E7 
TCR transduced human T cells were tested for recognition of peptides identified by the BLAST search 
shown in Table 1. Target cells were T2 cells loaded with either the E7 peptide (E7) as a positive control, 
peptides identified by number in Table 1, or no peptide (A).  Peptides which elicited a weak response by 
E7TCR were further tested for recognition at titrated concentrations (B). 
 
 
IFN-γ (pg/mL)
E7
1
6
7
9
12
17
no peptide
0
10000
20000
30000
1
0.1
0.01
0.001
>
Peptide Conc. [uM]

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12 
 
 
 
 
 
 
 
 
 
 
Figure 6: Serial alanine substitutions to the E711-19 target peptide revealed positions 4-7 to be the 
most crucial for recognition by E7 TCR transduced T cells. Human T cells were transduced to express 
the E7 TCR. The transduced cells were cocultured with T2 cells loaded with varying concentrations of 
E711-19 peptide (E7) or E711-19 with an alanine substitution at the position indicated by the x-axis labels. E7 
peptide (E7) is an HLA-A2 restricted negative control peptide. 
 
 
IF N -γ  (p g/m L)
E 7
1 A
2 A
3 A
4 A
5 A
6 A
7 A
8 A
9 A
E 6
0
4 0 0 0
8 0 0 0
1 2 0 0 0
1 6 0 0 0
1
0 .1
0 .0 1
0 .0 0 1
>
P e p tid e  C o n c. [u M ]

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Table 1 BLAST search for peptides with at least 6 (or least 5 identical + 1 conservative change) 
amino acids shared with E711-19.  Capital/Underlined = Amino Acid Identical to E7 epitope, Capital/Not 
Underlined = Conservative change. *=Peptides that demonstrates weak cross-reactivity only at 
supraphysiological concentrations. 
1.2.5 Safety Considerations 
HPV-16 E7 TCR  
The safety of infusion of large numbers of retrovirally modified tumor reactive T-cells has been 
demonstrated in clinical studies conducted at the NIH Clinical Center. (22, 23) Patients at the NIH 
Clinical Center have been treated with up to 1.77 x 1011 gene engineered cells. The clinical safety 
of E7 TCR T cells has been studied in a protocol for the treatment of metastatic HPV-16 cancer 
(16-C-0154). In that study, a conditioning chemotherapy regimen that enchances T cell survival 
and function, and increases the toxicity of the treatment was employed, and high-dose aldesleukin 
was administered to individual patient tolerance. Twelve patients were treated and one dose-
limiting toxicity for E7 TCR T cell infusion was encountered at the highest dose level of cells. The 
one patient who experienced a dose-limiting toxicity developed rapid progression of metastatic 
disease in her lungs during conditioning chemotherapy. The patient went on to develop grade 4 
hypoxia following infusion of E7 T cells. No other patients at that dose level experienced a dose-
limiting toxicity. The E7 TCR T cells did not demonstrate off-target toxicity, targeting of healthy 
tissues, or cytokine storm. The maxium administered dose was thus declared to be the maximum 
tolerated dose (1 x 1011 transduced cells).  
In the present protocol, the safety margin of treatment has been increased by the following 
measures: 1) No conditioning chemotherapy will be given. 2) No aldesleukin will be given. 
Other protocols at the NIH Clinical Center have administered over 1 X 1011 tumor infiltrating 
lymphocytes (TIL) with widely heterogeneous reactivity including CD4, CD8, and NK cells 
without infusional toxicities. Experience at the NIH Clinical Center treating more than 200 patients 
with advanced cancers with genetically engineered T cells indicates that these cells do not have a 
significant risk of malignant transformation in this setting. While the risk of insertional 
mutagenesis is a known possibility using retroviral vectors, this has only been observed in the 
setting of infants treated for XSCID, WAS and X-CGD using retroviral vector-mediated gene 
transfer into CD34+ bone marrow cells. It has also been reported with lentiviral transduction in a 
patient who received CD19 CAR-T cells (it did not cause malignant transformation and may have 
enhanced the efficacy of the T cells(24). In the case of retroviral vector-mediated gene transfer 
into mature T cells there has been no evidence of long-term toxicities including leukemia since the 
first NCI sponsored gene transfer study in 1989. Although continued follow-up of all gene therapy 
patients will be required, data suggest that administration of retrovirally transduced mature T cells 
is a safe procedure. While the risk of insertional mutagenesis is extremely low, the proposed 

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protocol follows all current FDA guidelines regarding testing and follow up of patients receiving 
gene transduced cells. 
 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have vulvar HSIL as confirmed by pathology report from a CLIA-certified 
laboratory. 
2.1.1.2 Vulvar HSIL must be HPV-16+ by a PCR, RNA, or in situ hybridization test from a 
CLIA certified laboratory. 
2.1.1.3 Patients must have measurable lesion(s) as defined in section 6.3.1 and one or more of 
the following criteria: 
a. Failure of surgery to control disease (i.e. positive margins after surgery or 
recurrence of HSIL after surgery). 
b. Multifocal or extensive disease for which surgery would result in 
disfigurement that is not be acceptable to the patient. 
c. Disease for which surgery would have a risk of functional impairment that 
is not be acceptable to the patient (i.e. involve partial or complete excision 
of the clitoris, anus, vagina, or urethra). 
2.1.1.4 Patients may have received any previous therapy, including surgical excision. Patients 
with recurrent disease must have histologically documented recurrence on new biopsy 
and a measurable lesion that meets the above criteria. 
2.1.1.5 Patients must have the HLA-A*02:01 allele  
2.1.1.6 Age >18 years.  
2.1.1.7 ECOG performance status of 0-1 as defined by Appendix A.  
2.1.1.8 Able to understand and sign the Informed Consent Document. 
2.1.1.9 Women of child-bearing potential must have a negative pregnancy test. Women of 
child-bearing potential are defined as all women who are not post-menopausal or who 
have not had a hysterectomy.  Postmenopausal will be defined as women over the age 
of 55 who have not had a menstrual period in at least 1 year. 
2.1.1.10 The effects of E7 TCR T Cells on the developing human fetus are unknown.  For this 
reason, women of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she is participating in this study, she should inform her treating 
physician immediately. 

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15 
2.1.1.11 Seronegative for HIV antibody. The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who are HIV seropositive can 
have decreased immune-competence and thus be less responsive to the experimental 
treatment. 
2.1.1.12 Seronegative for hepatitis B antigen and hepatitis C antibody.  If hepatitis C antibody 
test is positive, then the patient must be tested for the presence of antigen by RT-PCR 
and be HCV RNA negative. 
2.1.1.13 Must be willing to participate in Gene Therapy Long Term Followup 
Protocol20C0051), which will follow patients for up to 15 years per Food and Drug 
Administration (FDA) requirements. 
2.1.1.14 Patients must have normal organ and marrow function as defined below:  
• leukocytes  
 
 
 
 
>3,000/mcL 
• absolute neutrophil count  
>1,000/mcL 
• platelets  
 
 
 
 
>100,000/mcL 
• hemoglobin  
 
 
 
 
>9.0 g/dL 
• total bilirubin  
 
 
 
within 1.5X normal institutional limits except        
 
 
 
 
 
in patients with Gilbert’s Syndrome who                
 
 
 
 
 
must have a total bilirubin < 3.0 mg/dL 
• AST(SGOT)/ALT(SGPT)  
Serum ALT/AST < 3X ULN 
• creatinine  
 
 
 
 
< 1.5X baseline, < 1.5X ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OR 
• creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with   
 
 
 
 
 
 
 
 
 
 
 
 
 
 creatinine levels above institutional normal               
(by the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation) 
2.1.2 Exclusion Criteria 
2.1.2.1 
Patients who are receiving any other investigational agents 
2.1.2.2 
Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with E7 TCR, breastfeeding should 
be discontinued if the mother is treated with E7 TCR.  These potential risks may 
also apply to other agents used in this study. 
2.1.2.3 
Uncontrolled intercurrent illness including, but not limited to, any ongoing or 
active infection (e.g. requiring anti-infective therapy), coagulation disorders, 
cardiovascular disorders, respiratory disorders, cancer, or psychiatric illness/social 
situations (within the last six months) that would limit compliance with study 
requirements.  
2.1.2.4 
Any form of systemic immunodeficiency, including acquired deficiency such as 
HIV or primary immunodeficiency such as Severe Combined Immunodeficiency 
Disease. The experimental treatment being evaluated in this protocol depends on 

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16 
an intact immune system. Patients who have decreased immune competence may 
be less responsive to the treatment.  
2.1.2.5 
Concurrent systemic steroid therapy if greater than the equivalent of 5 mg 
prednisone PO daily. Patients previously on steroids must be off steroids for four 
weeks prior to treatment. 
2.1.2.6 
Cardiac stress test and pulmonary function tests maybe required for patients with 
a clinical history of significat cardiopulmonary disease. Patients with active 
cardiac ischemia or severe chronic obstructive pulmonary disease are not eligible. 
2.1.2.7 
Patients with any active invasive cancer are not eligible. 
2.1.2.8 
Patients with vulvar HSIL that is not HPV-16+ or is associated with multiple 
types of high-risk HPV at the time of eligibility assessment are not eligible. 
2.2 
SCREENING EVALUATION 
2.2.1 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 
2.2.2 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. Results from outside laboratories or on another NIH protocol are accepted 
for screening evaluations provided that they were performed in the appropriate timeframe. 
2.2.2.1 Any time prior to starting the therapeutic regimen:  
a. HLA-Testing 
b. Review of most recent cervical cytology and HPV testing. Cervical cytology testing 
will be performed if clinically indicated. 
c. If a pathology report confirming vulvar HSIL is not available, if available results are 
unclear, or there is a lack of necessary information in the available results, a vulvar 
biopsy will be performed to confirm diagnosis in the NCI Laboratory of Pathology. 
d. Cervical high-risk HPV testing 
e. Venous assessment (as per apheresis clinic policy) 
2.2.2.2 Within 4 weeks prior to starting the therapy unless otherwise indicated: 
a. Complete history and physical examination, noting in detail the exact size and 
location of all lesions.  (Note: Patient history may be obtained within 8 weeks prior to 
starting therapy.) 
b. Chest x-ray 

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17 
c. EKG 
d. Cardiac stress test and/or pulmonary function tests may be needed for patients with 
significant cardiopulmonary disease 
e. HIV antibody titer, HbsAG determination, and anti-HCV antibody. (Note: may be 
performed within 3 months prior to therapy start date). 
f. Past medical history including family history, social history, allergies, and current 
medications. 
2.2.2.3 Within 14 days prior to starting the therapy: 
a.  Chem 20 equivalent: (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, LDH, Total Protein, Total CK, Uric 
Acid). 
b. TSH 
c. CBC with differential and TBNK 
d. PT/PTT 
e. Beta-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
f. ECOG performance status assessment 
2.3 
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 here. 
2.3.1 Treatment assignment and randomization procedures: 
Cohorts 
Number Name 
Description 
1 
Patients 
Patients with vulvar HSIL 
Arms 
Number Name 
Description 
1 
Arm 1 
1x1011 E7 TCR T cells will be administered 
intravenously over 20 to 30 minutes on day 0. 

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18 
Arm Assignment 
Patients in Cohorts 1 will be directly assigned to Arm 1. 
2.4 
BASELINE PROCEDURES 
2.4.1 Within 14 days prior to starting therapy (unless otherwise indicated): 
a. Complete history and physical examination 
a. Chem 20 equivalent: (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, LDH, Total Protein, Total CK, Uric 
Acid). 
b. TSH 
c. CBC with differential and TBNK 
d. PT/PTT 
e. Beta-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
f. ECOG performance status assessmentBaseline photographs and biopsies of HSIL 
lesions to be performed under local anesthetic in the clinic within 8 weeks prior to 
therapy. Patients will be required to sign a separate consent for all biopsies conducted 
during the study.  Refer to Section 5.4 for guidelines for handling specimens. 
Peripheral blood lymphocytes (PBLs), plasma, and serum collected at time of 
baseline biopsy. As noted in 5.1.3, Biopsies will not be performed if they are not 
technically feasible, if they will interfere with response assessment, or if a patient 
declines consent. Replication Competent Retrovirus (RCR) testing.Leukapheresis as 
described in section 3.1.2. 
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a single arm phase II clinical trial using a Simon minimax two-stage design. Twelve 
patients will be treated initially, which  will be expanded to sixteen patients if one or more 
patient(s) have a complete response in the initial 12 patients.  

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19 
3.1.1 Protocol Schema 
 
 
1 month 
Enrollment 
Leukapheresis, Biopsy & Baseline Photography 
E7 TCR Cells (1x1011 cells)     
Safety 
Safety Visit, Leukapheresis & Biopsy (10-14 days) 
1 week 
1 week 
Response Assessment 
& Biopsy (27-34 days) 
Response Assessment (2 months) 
Response Assessment (3 months) 
2 weeks 
1 month 
NR 
Standard of 
Care 
CR or PR 
Response Assessment q 1 
month x 3 (4, 5 and 6 month) 
PR
CR 
Standard of 
Care Treatment 
Followup every 3 months for 2 
visits, then every 6 months for 2 
visits (2 years of followup total) 

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20 
3.1.2 Leukapheresis 
The patient will undergo a 10-15 liter leukapheresis (generally, 12 liters will be processed to target  
yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) Dowling 
Apheresis Clinic according to DTM standard operating procedures.  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. The leukapheresis collection will be obtained at least 21 
days prior to the cell infusion. Leukapheresis material that is not required for clinical use will 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 this study and protocol 16-C-0061 (ETIB Tissue 
Procurement Protocol) if the subject coenrolled on that study. Patients previously treated on 
protocol 17-C-0116 will not undergo leukapheresis to generate a cell product.  
3.1.3 E7 TCR T cell preparation 
After cells are obtained by apheresis, further cell processing to generate E7 TCR cells will occur 
in the DTM according to standard operating procedures and the E7 TCR investigational new drug 
application.  E7 TCR cells can be produced in approximately 21 to 27 days. Cell products may be 
cryopreserved during production to accommodate patient 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 (2-3 vials at 3-4.5 x 109 cells/vial) will be retained in the DTM; the remaining 
cells will first be frozen in 10 vials at 100 x 106 cells per vial with excess frozen at 300 x 106 
cells/vial. Cells will be frozen in the DTM and then transferred to ETIB the following day.  The 
ETIB preclinical core contact is Jeremy Rose (301-594-5339).    
Before infusion, the percentage of T cells expressing the E7 TCR will be determined by flow 
cytometry. Successful TCR gene transfer will be defined as greater than 20% TCR positive cells. 
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 patient is no longer eligible for 
retreatment (see section 3.4)on this protocol due to meeting any of the off-study criteria listed in 
Section 3.6.2, any remaining pretreatment PBMC collected on this protocol and cryopreserved as 
described in Section 3.1.2 will be transferred from the Department of Transfusion Medicine to the 
Principal Investigator of this protocol for storage in the ETIB PDCMF and possible use in research 
and banked according to protocol 16-C-0061 (ETIB Tissue Procurement Protocol) if the subject 
coenrolled on that study. Cell products for patients treated on protocol 17-C-0116 will be generated 
from previously collected PBMC products retained in the DTM.   
3.1.4 Treatment Phase 
E7 TCR T cells will be infused while the patient is admitted to the hospital on treatment day 0. A 
central line catheter may be placed for cell infusion. Patients will be observed overnight as 
inpatients following administration of cells, and will not be discharged until cleared by the 
treating physician. Patients will receive one course of treatment unless eligible for retreatement 
as discussed in section 3.4.   

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21 
3.1.5 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 E7 TCR T cells. 
2. If 2 of the first 6 patients or the fraction of patients > 33%after the initial 6 patients 
develop grade 4 or greater adverse events (except lymphocyte count increased) possibly 
related to E7 TCR Tcells. 
 
3.2 
DRUG ADMINISTRATION 
3.2.1 Cell infusion and other drug Administration 
Inpatient treatment will be according to the following schedule. Cell infusions may be slowed or 
delayed as medically indicated. Administration of diuretics, hydration, and electrolyte 
monitoring and replacement will be performed as clinically indicated. 
Day 0  
E7 TCR cells 
The E7 TCR cells (1x1011 cells) will be delivered to the patient 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) and an identification of the product and 
documentation of administration are entered in the patient’s chart (as is done for blood 
banking protocols). E7 TCR T cells (1x1011 cells) will be administered intravenously 
over 20 to 30 minutes via non-filtered tubing, gently agitating the bag during infusion to 
prevent cell clumping. A peripheral IV may be used if access is adequate (in general, two 
18 gauge or larger IVs should be established). A PICC line or other central line may be 
used if peripheral access is not adequate. 
 
 
 

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22 
3.3 
STUDY CALENDAR 
 
Procedure 
Screening/ 
Baseline 2 
Day 
0 
Day 
1  
Day 
2 
Day 
3 
 
 
 
 
 
 
Daily 
until d/c 
Follow-up Period 
1 wk 
(Days 5-8) 
2 wk   
(Days 10-14) 
 
 
 
 
Monthly f/u 7 
(Month 1 is also 
End of Treatment 
Visit) 
 
 
 
 
Annual 
Followup 
for 5 
years 
after 
infusion 
History, physical exam, and review of systems1 
X 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
X 
X 
X 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Screening labs: HIV, HBV serology, HCV 
serology, thyroid panel, PT/PTT, Beta-HCG 
pregnancy test in women of childbearing 
potential, HLA-A typing for HLA-A*02:01 allele 
positivity  
X 
 
 
 
 
 
 
 
 
 
 
HPV-16 verification and pathology review for 
confirmation of diagnosis3 
X 
 
 
 
 
 
 
 
 
 

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Procedure 
Screening/ 
Baseline 2 
Day 
0 
Day 
1  
Day 
2 
Day 
3 
 
 
 
 
 
 
Daily 
until d/c 
Follow-up Period 
1 wk 
(Days 5-8) 
2 wk   
(Days 10-14) 
 
 
 
 
Monthly f/u 7 
(Month 1 is also 
End of Treatment 
Visit) 
 
 
 
 
Annual 
Followup 
for 5 
years 
after 
infusion 
Cervical high-risk HPV testing 
 
X 
 
 
 
 
 
 
 
 
 
Cardiac stress test and/or pulmonary function 
tests11 
X 
 
 
 
 
 
 
 
 
 
 
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, 
CK, uric acid, CBC with differential and TBNK 
X 
 
 
 
 
 
X 
X 
X 
 
HSIL measurements, vulvar biopsy, and 
photographs4 
X 
 
 
 
 
 
 
X 
X 
 
Leukapheresis12 
X 
 
 
 
 
 
 
X 
 
 
Replication Competent Retrovirus (RCR) testing5 
X 
 
 
 
 
 
 
 
X5 
 

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24 
Procedure 
Screening/ 
Baseline 2 
Day 
0 
Day 
1  
Day 
2 
Day 
3 
 
 
 
 
 
 
Daily 
until d/c 
Follow-up Period 
1 wk 
(Days 5-8) 
2 wk   
(Days 10-14) 
 
 
 
 
Monthly f/u 7 
(Month 1 is also 
End of Treatment 
Visit) 
 
 
 
 
Annual 
Followup 
for 5 
years 
after 
infusion 
Research samples: peripheral blood lymphocytes, 
plasma, and serum6 
X 
 
X 
 
X 
X6 
X 
X 
X 
 
E7 TCR T cells 
 
X 
 
 
 
 
 
 
 
 
E7 TCR assay10 
X 
 
X 
 
 
 
X 
X 
X 
 
Response Evaluation  
 
 
 
 
 
 
 
 
X 
 
NIH Advance Directives Form8 
X 
 
 
 
 
 
 
 
 
 
HSIL and patient status update9 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1  Patients will have a full history and physical at screening, on admission to the hospital, and on follow-up visits. While inpatient, patients will have a daily review of 
systems and physical exam 
2 Exact timeline is indicated in Sections 2.2 and 2.4 
3 Vulvar HSIL must be HPV-16+ by PCR, RNA, or in situ hybridization test from a CLIA certified laboratory prior to treatment. 

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25 
4 Vulvar biopsies will be performed as a punch biopsy under local anesthetic in the outpatient clinic within 8 weeks prior to starting therapy, at 2-week follow-up (day 
10-14), and at 1-month follow-up (day 27-34) for all patients. An additional biopsy will be obtained at the time a patient comes off-treatment (e.g. at time of 
progression, at time of complete response, or at 6-month visit for patients with continuing partial response). Biopsies will be performed only if technically feasible, if 
they do not interfere with response assessment, and if the patient provided consent. The investigators may elect not to perform biopsies at their discretion (i.e. safety 
concerns, patient concerns, etc.). HSIL photographs will occur at each follow up visit. HSIL measurements will occur at baseline and at each monthly follow-up visit.   
5 Patients’ blood samples will be obtained and undergo analysis for detection of replication competent retroviruses (RCR) by PCR prior to cell infusion and at 
approximately 3, 6, and 12 months post cell administration.  Blood samples will be archived annually thereafter if all previous testing has been negative with a brief 
clinical history.  The ETIB preclinical core staff will cryopreserve 2 vials of cells if possible. If less than 10 million cells are available, only 1 vial of cells will be 
cryopreserved. 
6 Research samples will be collected pre-treatment (within four weeks prior to cell infusion); posttreatment on post-therapy day 1, post-therapy day 3, thereafter any 
MWF while still an inpatient for one week, and thereafter weekly while still inpatient; and post-treatment at each research visit. For each time point, six 8mL CPT 
tubes will be drawn (5 for PBMC and 1 for plasma) and one 8mL SST tube (for sera). Processing and storage are as described in section 5. 
7 All patients will follow-up at 1, 2, and 3 months after cell infusion (+/- 7 days).Patients with no response at the 3-month evaluation will be referred for standard of 
care therapy. Patients with a partial or complete response at the 3-month evaluation will continue to follow up at 4, 5, and 6 months for safety, response, and research 
evaluations (+/- 7 days). After the 6-month response assessment patients with partial response will be referred for standard of care therapy and patients with a 
complete response will continue to have follow-up every 3 months (+/- 30 days) for 2 visits, then every 6 months (+/- 30 days) for 2 visits (2 years of follow up total). 
8As indicated in section 10.4, all subjects ≥ age 18 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. 
9Subjects or local treating physician will be contacted to collect information annually for five years after the date of cell infusion:1) procedures or treatments for 
vulvar HSIL, 2) procedures or treatments for cervical, vaginal, or anal intraepithelial neoplasia, 3) occurrence of vulvar, cervical, or anal cancer. This followup can be 
conducted via telephone. 
10Clinical assay may be performed at these time points by the NCI Flow Cytometry Laboratory in the Laboratory of Pathology. 
11If applicable, see section 2.1.2.6. 
12Except for patients previously treated on protocol 17-C-0116.

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3.4 
POTENTIAL REPEAT TREATMENT  
Patients may be retreated if an E7 T cell product can be generated from cells collected prior to 
any T cell gene therapy treatment. Patients eligible for retreatment include those who had partial 
or complete response to E7 TCR T cell therapy that subsequently progress. Patients must  meet 
the original eligibility criteria to be considered for retreatment. Research assessments will be 
performed at the same time intervals used for initial treatment. Patients 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 until at least 12 weeks after initial T cell therapy but must be 
within 5 years from the date of progressive disease. 
Note: Response data for all treatments will be captured in the database however only the 
response data from the first treatment with E7 TCR T cells will be used in determination of 
response.  
3.5 
ON-STUDY EVALUATIONS 
Please see the study calendar in Section 3.3 for details regarding on-study evaluations. 
3.5.1 Long-term Follow-Up: 
Long-term follow-up of patients receiving gene transfer is required by the FDA and must 
continue even after the patient comes off the study. Long-term follow-up will be done under a 
different long-term gene therapy follow-up protocol (20C0051).   
3.6 
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 30 days following the last dose of study therapy.   
3.6.1 Criteria for removal from protocol therapy 
Note: Subjects removed from protocol therapy may still be eligible for up to one course of 
retreatment per section 3.4.  The same off treatment criteria apply after the second potential 
course as for the first. Data collection and assessments required while off therapy are addressed 
in sections 6.1 and 3.3 respectively. 
• Completion of protocol therapy 
• Positive pregnancy test 
• Progression of disease 
• Participant requests to be withdrawn from active therapy 
• Investigator discretion 
• Unacceptable toxicity 
 
3.6.2 Off-Study Criteria 
• Screen failure 
• Completed study follow-up period 

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27 
• Inability to generate a cell product. A second attempt may be made to generate a cell 
product from the patient.   If the second attempt fails, that patient will be removed 
from the study and replaced with another patient.    
• Participant requests to be withdrawn from study 
• There is significant noncompliance 
• The investigators decide to end the study 
• The investigators decide it is in the patient’s best interest 
• Death 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
PROHIBITED MEDICATIONS 
Patients needing systemic steroid therapy greater than the equivalent of 5 mg of 
prednisone may not participate in this study.   
4.2 
BLOOD PRODUCT SUPPORT  
Patients are unlikely to require blood product support as a side effect of therapy. However, 
any patient on study may receive platelets and packed red blood cells (PRBC’s) in clinically 
needed.  As a general guideline, patients may be transfused for:  
• Hemoglobin < 8 gm/dl 
• Platelets < 10,000/mm3  
All blood products will be irradiated and leukocyte filters will be utilized to decrease 
sensitization to transfused WBC’s. 
4.3 
 OTHER CONCOMITANT MEDICATIONS/MEASURES 
 
Concomitant medications to control side effects of therapy may be given.  Meperidine 
(25-50 mg) will be given intravenously if severe chilling develops.  Other supportive therapy 
will be given as required and may include acetaminophen (650 mg q4h), indomethacin (50-75 
mg q8h) and ranitidine (150 mg g12h). If patients require steroid therapy they will be taken off 
treatment.  Patients who require transfusions will receive irradiated blood products.  Ondansetron 
will be administered per standard dosing instructions as needed for nausea and vomiting.  
Additional antiemetics will be administered as needed for nausea and vomiting uncontrolled by 
ondansetron.    
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
The amount of blood that may be drawn from adult patients for research purposes shall not 
exceed 10.5 mL/kg or 550mL; whichever is smaller, over any 8-week period.   
5.1.1 Pre cell infusion evaluations 
• The following samples may be drawn for research and sent to the ETIB preclinical core 
within 4 weeks prior to cell infusion. Send to Pre-Clinical Core lab; Attention Jeremy 
Rose, Bldg 10, room 12C216 contact phone: 301-594-5339. 

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o 6 CPT tubes (8mL each). One CPT tube per time point 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 
o 1 SST tube (8mL) for sera. Serum will be processed in the ETIB Pre-Clinical 
Core and aliquoted into vials of 0.5-1 mL each.  
5.1.2 Post cell infusion evaluations 
• The following samples may be drawn for research and sent to the ETIB preclinical core 
While the patient is inpatient, samples may be drawn on post-treatment day 1, post-
treatment day 3, thereafter every Monday/Wednesday/Friday x5 days, and then weekly 
until discharge. Samples may also be collected at each outpatient follow-up visit. Send to 
Pre-Clinical Core lab; Attention Jeremy Rose, Bldg 10, room 12C216 contact phone: 
301-594-5339. 
o 6 CPT tubes (8mL each). One CPT tube per time point may be used to collect 
4mL of plasma, which will be frozen in 4mL vials. PBMC from the remainder of 
the CPT tubes may be frozen in aliquots of 10 x 106 cells/vial 
o 1 SST tube (8mL) for sera. Serum will be processed in the ETIB Pre-Clinical 
Core and aliquoted into vials of 0.5-1 mL each.  
5.1.3 Optional vulvar Biopsies 
• Biopsies for research purposes will be obtained at baseline (within 8 weeks of starting 
treatment), 10 to 14 days after treatment, 27 to 34 days after treatment, and at the time the 
patient comes off-treatment (i.e. attains a complete response, experiences progression, or 
reaches the 6-month time point without a complete response). This biopsy schedule may 
be repeated for patients receiving retreatment. Clinically indicated biopsies may be 
obtained at any time by PI discretion if there is concern for invasive cancer. 
• Biopsies for research will be performed with a standard punch biopsy instrument of up to 
4 mm diameter. At each time point, up to 3 biopsies of HSIL lesions and up to 2 biopsies 
of adjacent normal tissue will be performed. A formalin-fixed paraffin embedded 
specimen will be transported to the NCI Laboratory of Pathology for review and 
archiving. The contact will be Scott Norberg, Bldg 10, Room 4B04, contact 301-275-
9668. Specimens will then be transported to the ETIB preclinical core for further 
processing and storage. They will be delivered to Pre-Clinical Core lab; Attention Jeremy 
Rose, Bldg 10, room 12C216 contact phone: 301-594-5339. 
• Processing of biopsies will depend upon the amount of tissue obtained. Examples of 
processing may include OTC blocks, formalin-fixed paraffin embedding, snap freezing, 
placing in RNAlater or other required laboratory processing technique.  
• Biopsies will not be performed if they are not technically feasible, if they will interfere 
with response assessment, or if a patient declines consent.   
• Samples will be stored for this protocol. Some of these samples may be archived and 
analyzed under another protocol 16-C-0061 (ETIB Tissue Procurement Protocol) if the 
subject also coenrolled on that study.  
5.1.4 Mandatory vulvar biopsies 

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• Biopsies of vulvar lesions for clinical purposes will be obtained within 8 weeks prior to 
starting treatment if clinically indicated to rule out invasive cancer. Biopsies will be 
performed in the outpatient clinic under local anesthetic.  
5.1.4 Immunological Testing 
• Leukapheresis will be performed prior to treatment (expect for patients previously treated 
on protocol 17-C-0116) and 10-14 days after treatment.   
• Processing of leukapheresis will be in the Department of Transfusion Medicine (DTM). 
Cell product may be frozen in 10 vials at concentration 100 x 106 cells/mL and additional 
vials at 300 x 106 cells/mL. Cells will be stored in a -80 degrees Celsius freezer in DTM 
overnight and transferred to the ETIB Preclinical Core the following day. Samples will be 
sent to Pre-Clinical Core lab; Attention Jeremy Rose, Bldg 10, room 12C216. Contact 
phone: 301-594-5339. 
• At other time points, peripheral blood lymphocytes (PBL) and plasma may be obtained 
from whole blood by purification using centrifugation. These samples will be transferred 
directly to the ETIB Pre-Clinical Core lab for processing. Plasma may be frozen in 4mL 
vials. PBL may be frozen in aliquots of 10 x 106  cells/vial. 
• The following tests may be used to evaluate immunologic correlates:  specific lysis and 
cytokine release, intracellular FACS of cytokine production, ELISPOT assays, 
engraftment of E7 TCR T cells and lymphocyte subset analysis.  
• Samples of all infused cell products will be cryopreserved, and retrospective analysis of 
infused cell phenotype and function may be performed including functionality measured 
by cytokine release in co-culture assays (ELISPOT, ELISA), cytotoxicity measured by 
cell impedance assay and characterization of T cell subsets by surface marker expression 
detected by flow cytometry and/or RNA sequencing.  
• Peripheral blood lymphocytes (PBL) may be tested by cytolysis assays, cytokine release 
and limiting dilution analysis.Immunological monitoring may consist of quantifying T 
cells reactive with tumor cells using established techniques such as intracellular FACS, 
cytokine release assays, and ELISPOT assays.  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.  
• Blood and tissue specimens collected in the course of this research project will be stored 
for this protocol and may be used in the future to investigate new scientific questions 
related to this study. If the patient is coenrolled on protocol 16-C-0061 (ETIB Tissue 
Procurement Protocol) their blood and tissue speciments may be used on that protocol as 
well. 
5.2 
SUMMARY OF SAMPLE COLLECTION 
Test/assay 
Volume blood   
(approx) 
Type of 
tube 
Collection point    
(+/- 48hrs) 
Location of specimen analysis 
Plasma/PBMC 
48 mL 
CPT  
<4 weeks prior to cell 
infusion 
Pre-Clinical core lab (PDCMF)  
(Jeremy Rose)  

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30 
Serum 
8 mL 
SST 
<4 weeks prior to cell 
infusion 
Pre-Clinical core lab (PDCMF) 
(Jeremy Rose) 
Plasma/PBMC 
48 mL 
CPT 
Post cell infusion day 1, 
3, every Mon/Wed/Fri x 
5 days, weekly until 
discharge 
Pre-Clinical core lab (PDCMF) 
(Jeremy Rose) 
Serum 
8mL 
SST 
Post treatment days 1 & 
3, then every 
Mon/Wed/Fri x 5 days, 
then weekly until 
discharge 
Pre-Clinical core lab (PDCMF) 
(Jeremy Rose) 
 
Vulvar Biopsy 
N/A 
N/A 
< 8 weeks prior to 
treatment, 10-14 days 
after treatment, 27-34 
days after treatment, and 
when patient comes off 
treatment. 
Processed in Christian Hinrichs Lab, 
then transported to Pre-Clinical core 
lab (PDCMF) (Jeremy Rose) 
 
 
5.3 
GENE-THERAPY-SPECIFIC FOLLOW-UP  
•  Patients will be enrolled on the Long Term Followup Gene Therapy Study in order to 
collect information to meet current FDA requirements.  All followup as required by the 
FDA will occur via the 20C0051 protocol.  
5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.4.1 Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF) 
• Samples will be ordered in CRIS and tracked through the 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 the NIH without 
appropriate approvals and/or agreements, if required.  
• Patient blood and tissue samples, collected for the purpose of research under IRB 
approved protocols of the Experimental Transplantation and Immunotherapy Branch 
(ETIB), may be archived by the ETIB Preclinical Development and Clinical Monitoring 
Facility (PDCMF). All data associated with archived clinical research samples is entered 
into LabMatrix. Access  is limited to PDCMF staff and ETIB clinical staff, requiring 
individual login and password. All staff in the PDCMF laboratory receive annually 
updated NIH/CIT training and maintain standards of computer security. 
• The data recorded for each sample includes the patient ID, trial name/protocol number, 
date drawn, treatment cycle/post-transplant time point, cell source (e.g. peripheral blood, 
marrow,) as well as box and freezer location. Patient demographics that correlate 
treatment outcomes and therapies with the samples can be obtained only through the 

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31 
NCI/ETIB clinical records. As of January 2007, all newly received samples receive a 
unique bar code number, which is included in the sample record in the PDCMF database. 
Only this bar code is recorded on the sample vial and the vials will not be traceable back 
to patients without authorized access to the PDCMF database. All non-coded samples 
previously archived will be stripped of identifiers prior to distribution for any use other 
than as a primary objective of the protocol under which they were collected. 
• Samples are stored in freezers.  All samples will be labeled solely with a bar code (which 
includes the date, and serially determined individual sample identifier). The key will be 
available to a restricted number of ETIB investigators and associate investigators on the 
protocol. Coded samples will be stored frozen at -20°, -80° or liquid nitrogen vapor phase 
to -180 C according to the stability requirements in a single location under the restricted 
control of the PDCM Facility of ETIB.  
These freezers are located onsite at the Preclinical Service laboratory (12C216) (-85° 
freezer) or in ETIB common equipment space (CRC/3-3273). Access to samples from a 
protocol for research purposes will be by permission of the Principal Investigator of that 
protocol in order to be used (1) for research purposes associated with protocol objectives 
for which the samples were collected, or (2) for a new research activity following 
submission and IRB approval of a new protocol and consent, or (3) for use only as unlinked 
or coded samples under the OHSRP Exemption Form guidelines stipulating that the 
activity is exempt from IRB review. Unused samples must be returned to the PDCMF 
laboratory. Samples, and associated data, will be stored permanently unless the patient 
withdraws consent. If researchers have samples remaining once they have completed all 
studies associated with the protocol, they must be returned to the PDCMF laboratory. 
5.4.2 Storage/Track in the Christian Hinrichs lab 
Blood, plasma, serum, and tissue samples will be processed, labeled, and stored in the ETIB 
Pre-Clinical Core. Samples will be requested and transferred to Dr. Hinrichs’ lab as needed 
for analysis. The contact will be Scott Norberg, Bldg 10, Room 4B04, phone 240-858-3303 
Once received, the samples will be coded utilizing LabMatrix.  The bar-coded samples will 
be stored at -80oC or in liquid nitrogen until time of use. Any unused samples will be 
returned to the PDCMF laboratory at the completion of all studies associated with the 
protocol.  
Samples transferred to the Hinrichs laboratory will be barcoded and tracked with 
LabMatrix. 
Laboratory research data will be stored on the NCI secure server in the Hinrichs 
laboratory folder 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 patient and their samples 
5.4.3 Protocol Completion/Sample Destruction  
• Once research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB 

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32 
approved protocol and patient consent or an OHSRP exemption indicating that the 
activity is exempt from IRB review. 
• The PDCMF staff will report to the Principal Investigators any destroyed samples, if 
samples become unsalvageable because of environmental factors (ex. broken freezer or 
lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a 
researcher.  
• The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section 7.2. 
  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) 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. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant.   
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.  
Document AEs from the first study intervention, Study Day 0 through  28 days after removal 
from the study treatment, or until off-study, or until they initiate a new treatment, whichever 
comes first. Beyond 28 days after the last intervention, or  initiation of  new treatment as 
applicable, only adverse events and serious adverse events that are at least possibly related to E7 
TCR T cells will be recorded. Grade 1 adverse events will not be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only 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 patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  

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Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
  x__ Coded and linked data in an NIH-funded or approved public repository.   
_x__ Coded and linked data in BTRIS (automatic for activities in the Clinical Center) 
_x__ Coded and linked or identified data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
  x__ An NIH-funded or approved public repository.  Insert name or names:ClinicalTrials.gov. 
_x__ BTRIS (automatic for activities in the Clinical Center) 
_x__ Approved outside collaborators under appropriate individual agreements. 
_x__ Publication and/or public presentations. 
When will the data be shared 
_x__ Before publication. 
_x__ At the time of publication or shortly thereafter. 
6.3 
RESPONSE CRITERIA 
6.3.1 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension as > 5 mm.  All measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <5 mm), are considered non-measurable disease.   
Target lesions.  All measurable lesions will be identified as target lesions and recorded and 
measured at baseline.   
Non-target lesions.  All other lesions (or sites of disease) will 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 will be noted throughout 
follow-up.  

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34 
6.3.2 Methods for Evaluation of Measurable Disease 
Lesions will be photographed, described in detail, and measured at each response evaluation. 
Measurements will be recorded in metric notation using a ruler or calipers. Baseline evaluations 
will be performed no more than 8 weeks before starting treatment. 
The same method of assessment will be used to characterize each identified and reported lesion 
at baseline and during follow-up. Lesions will be documented by digital color photography at 
each response evaluation. 
6.3.3 Response Criteria 
6.3.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. No appearance of new lesions. 
Partial Response (PR): A ≥ 50% decrease in the sum of the product of the longest perpendicular 
diameters of target lesions, taking as reference the baseline measurements. No appearance of 
new lesions. No increase of greater than 25% of any index lesion. 
Progressive Disease (PD): A ≥ 25% increase in sum of the product of the longest perpendicular 
diameters of target lesions, taking as reference the smallest product on study (this includes the 
baseline product if that is the smallest on study).  In addition to the relative increase of 25%, 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 progression). 
Non-CR/Non-PD: Neither sufficient decrease to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest product of diameters while on study. 
Note: In the event of lesion regression with a residual abnormality of unclear significance, a 
biopsy may be obtained. If HSIL is present in the pathology specimen the response will be 
considered less than complete. If HSIL is not present the response will be considered complete.  
6.3.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of non-target lesions. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  It must be representative of the overall non-target 
disease rather than an increase in a single lesion.     
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
6.3.3.3 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).   
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall Response 

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35 
CR 
CR 
No 
CR 
CR 
Non-
CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
Non-
CR/Non-
PD 
Non-
CR/Non-
PD/not 
evaluated 
No 
Non-CR/Non-PD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients 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. 
 
6.3.4 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) 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). 
Duration of overall CR: 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. 

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36 
Duration of overall non-CR/non-PD:  Non-CR/non-PD 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.  
6.4 
TOXICITY CRITERIA 
Careful evaluation to ascertain the toxicity, immunologic effects and anti-HSIL efficacy of the 
treatment regimens will be performed. This study will utilize the CTCAE version 5.0 for toxicity 
and adverse event reporting.  A copy of the CTCAE version 5.0 can be downloaded from the 
website http://ctep.cancer.gov.  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 here. 
7.2 
OHSRP OFFICE OF COMPLAINCE 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 here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem 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 here. 
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of E7TCR transduced PBL 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 E7 TCR transduced PBL, 
but are not fatal or life-threatening, much be reported to the NIH IBC as soon as possible, but not 

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37 
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. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the i IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the 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. 
7.4.2.1 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.  
7.4.2.2 Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• 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.  

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38 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a weekly basis when patients are being actively treated 
on the trial to discuss each patient.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expediated reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC).  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.   For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. 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. 
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient 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. 

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39 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient 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 patient 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 patient 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) 
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 

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40 
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. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
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.  
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/pages/viewpage.action?pageId=157942842  
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 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreement with Kite Pharma (CRADA #03022).  
8.5 
REPORTING PREGNANCY  
8.5.1 Maternal exposure 
If a patient 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 become 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 (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
8.6 
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 expedited 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 

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41 
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. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESES 
10.1.1 Primary Efficacy endpoints 
The primary efficacy endpoint of this trial is to determine the complete response rate for E7 TCR 
T cells in the treatment of patients with vulvar HSIL. 
10.1.2 Secondary Efficacy endpoint 
The secondary objective of this trial is to characterize the safety profile of E7 TCR T cells 
administered in a low intensity setting without conditioning or systemic aldesleukin. 
10.1.3 Sample Size Determination 
This trial will be conducted using a Simon minimax two-stage phase II trial design(25) to rule 
out an unacceptably low CR rate of 5% (p0=0.05) in favor of an improved complete response 
rate of 25% (p1=0.25). With alpha=0.10 (probability of accepting a poor treatment=0.10) and 
beta = 0.20 (probability of rejecting a good treatment=0.20), the first stage will enroll 12 
evaluable patients, and if 0 of the 12 have a complete response, then no further patients will be 
accrued.  If 1 or more of the first 12 patients have a complete response, then accrual would 
continue until a total of 16 evaluable patients have been treated. As it may take up to several 
months to determine if a patient has experienced a complete response, a temporary pause in the 
accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 
1-2 patients with a complete response out of 16 patients, this would be an uninterestingly low 

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42 
complete response rate. If there were 3 or more of 16 (18.75%) who experienced a complete 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (5% complete response rate), the probability of early termination is 54.0%. In 
patients that undergo retreatment, only the first response to E7 TCR T cell treatment will be used 
in the calculation of complete response rate.  
Since patients will be screened on this protocol, to allow for patients who enroll but are not 
evaluable for the primary endpoint, as well as screen failures, up to 200 patients total may be 
enrolled. It is expected that up to 10-12 treated patients can be enrolled within one year; thus, up 
to 18 months may be required to accrue 16 evaluable patients. Up to 16 patients may be treated 
in order to allow for a small number of inevaluable, treated patients. 
10.1.4 Populations for Analyses 
Toxicity Analysis: All patients will be evaluable for toxicity from the time of E7 TCR T cell 
infusion.  Toxicity data will be collected for all patients. 
Response Analysis - Intention to treat: any subjects who enroll onto the trial and provide consent 
and who receive at least one cycle of treatment will be included in analyses. 
10.2 STATISTICAL ANALYSES 
10.2.1 General Approach 
The fraction of patients who experience a complete response will be reported along with 
confidence intervals. Only the first treatment course with E7 TCR T cells will be used for this 
analysis.  
10.2.2 Analysis of the Primary Endpoints 
The fraction of patients who experience a complete response will be reported along with 80% 
and 95% two-sided confidence intervals. 
10.2.3 Analysis of the Secondary Endpoint 
The safety of the E7 TCR T cells will be monitored and any toxicities identified will be reported 
by type and grade. All treatment courses with E7 TCR T cells will be considered in this analysis. 
10.2.4 Safety Analyses 
If two of the first six patients develop any grade 4 event related to E7 TCR T cells or grade 3 
events (except lymphocyte count increased) that does not resolve to a grade 2 or less in 48 hours 
or the fraction of participants with these events is greater than or equal to 33% after the initial 6 
patients, then no further patients will be accrued as soon as this has been determined. Accrual 
may resume after appropriate treatment revision is described in approved amendment. All 
treatment courses with E7 TCR T cells will be considered in this analysis. 
10.2.5 Baseline Descriptive Statistics 
Baseline demographic characteristics will be reported. 

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10.2.6 Planned Interim Analyses 
 As indicated in the two-stage design, the number of complete responses noted after 12 evaluable 
patients have been treated will be noted and will be used to determine if enrollment to the second 
stage of accrual may proceed. 
10.2.7 Sub-Group Analyses 
None.  
10.2.8 Tabulation of individual Participant Data 
None. 
10.2.9 Exploratory Analyses 
Optionally, the following analyses may be done if appropriate and adequate data exist to perform 
them: 
• To evaluate a novel assay to genotype HPV using a ddPCR-based blood test. 
• Test for clearance of HPV infection from vulvar tissues. 
• Evaluate the expansion, survival, trafficking, phenotype, and function of E7 TCR cells 
following infusion. 
• Investigate the vulvar HSIL microenvironment including immune cell subsets and 
costimulatory/inhibitory molecules. 
• Assess circulating HPV DNA levels associated with treatment. 
 
Any exploratory evaluations which generate quantitative measures will be done using descriptive 
statistics including confidence intervals when appropriate. Any statistical tests performed for 
evaluation of exploratory objectives will be done without formal adjustment for multiple 
comparisons, but in the context of the number of tests performed.  
 
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (# 03022) between NCI and Kite Pharma is in place. Kite Pharma will be providing 
funding for this study. 
12  HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
The patients to be entered in this protocol have vulvar HSIL that is unable to be completely 
resected to negative margins without causing deformity. As only women develop vulvar HSIL, 
men will be excluded from the study. 
Subjects from 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.  If differences in outcome 
that correlate to ethnic identity are noted, accrual may be expanded or a follow-up study may be 
written to investigate those differences more fully. 

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12.2 STRATEGIES/PROCEDURES FOR RECRUITMENT 
Patients for this protocol will be recruited via standard CCR mechanisms. This protocol may be 
abstracted into a plain language announcement posted on NIH websites and on NIH social media 
platforms.  All advertisements, letters and other recruitment efforts will be submitted to the IRB 
for approval prior to their implementation.   
12.3 PARTICIPATION OF CHILDREN 
The efficacy of this treatment is unknown, and no safety data in children exist; children are 
therefore excluded from participation. In addition, vulvar HSIL is exceedingly rare in children so 
a small number of children, if any, would be eligible to participate. The protocol has defined 
risks based on prior studies with E7 TCR T cells.  
12.4 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.6), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
12.5 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has well-defined risks based on experience with the administration 
of E7 TCR T cells. The benefit of the treatment is unknown. The alternative to treatment on the 
protocol is surgical resection, which carries risks of disfiguration, pain, anesthesia complications, 
wound infections, functional impairment, and disease recurrence. 
The additional risks associated with potential study procedures have been outlined and described 
in detail in the consent form. 
12.6 RISKS/BENEFITS ANALYSIS(INCLUDING WHO ARE OR MAY BECOME UNABLE TO 
CONSENT) 
All patients in this protocol have vulvar HSIL, and therefore an increased risk of vulvar cancer. 
In addition, their standard treatment option is surgery with unacceptable cosmetic or functional 
results and a high risk of disease recurrence. The protocol has defined risks based on prior 
studies with E7 TCR T cells. The success of this effort cannot be predicted now. Because all 
patients in this protocol have vulvar HSIL and therefore an increased risk of vulvar cancer the 
potential benefit is thought to outweigh the potential risks.  

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12.7 CONSENT PROCESS AND DOCUMENTATION 
The patient, along with family members or friends, will be presented with a detailed description 
of the protocol treatment.  The specific requirements, objectives, and potential advantages and 
disadvantages will be presented.  The Informed Consent document is given to the patient who is 
requested to review it and to ask questions prior to agreeing to participate in the treatment 
portion of this protocol.  The patient will be reassured that participation on trial is entirely 
voluntary and that she can withdraw or decide against treatment at any time without adverse 
consequences. The research nurse, Principal Investigator or his designee is responsible for 
obtaining written informed consent from the patient. 
If new safety information results in significant changes in the risk/ benefit assessment, the 
consent form will be reviewed and updated as necessary. All subjects (including those already 
being treated) will be informed of the new information, be given a copy of the revised form, and 
asked to give their consent to continue in the study. 
For optional biopsies, patients will be required to sign a separate consent for all biopsies 
conducted during the study.  If the patient refuses the optional biopsy at that time, the refusal will 
be documented in the medical record and the research record. 
12.7.1 Telephone consent (for screening consent only) and re-consent 
13 CONSENT FOR SCREENING AND RE-CONSENT ON THIS STUDY MAY BE 
OBTAINED VIA TELEPHONE. TELEPHONE CONSENT WILL BE OBTAINED 
AND DOCUMENTED PER OHSRP/IRBO AND CCR POLICIES AND 
PROCEDURES.PHARMACEUTICAL AND INVESTIGATIONAL DEVICE 
INFORMATION   
13.1 DESCRIPTION OF THE INVESTIGATIONAL PRODUCT (IND #16959) 
13.1.1 Cell Preparation (E7 TCR Transduced PBL) 
The procedure for the expanding the human PBL is similar to those approved by the Food and 
Drug Administration, and used at the NCI in ongoing protocols.  The PBL will be transduced with 
retroviral supernatant containing the E7 TCR. 
13.1.2 Retroviral Vector Containing the E7 TCR gene 
The retroviral vector supernatant (PG13-MSGV1-E7-TCR) encoding a T cell receptor directed 
against HPV16 E711-19) was prepared and preserved following cGMP conditions in the Surgery 
Branch Vector Production Facility (SBVPF).  The E7 TCR vector was produced by the Surgery 
Branch 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 E7 TCR consists of 7,310 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 E7 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.     
 

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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 -80C at Surgery Branch, NCI, American Type Culture 
Collection (ATCC), Rockville, MD, and the NIH Clinical Center Department of Transfusion 
Medicine.  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 patient 
PBL.  There will be no re-use of the same unit of supernatant for different patients.  Retroviral titer 
has been shown to be stable after immediate thawing and immediate administration (coating the 
tissue culture wells previously coated with Retronectin).  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. 
13.1.3 Source 
After cells are obtained by apheresis, further cell processing to generate E7 TCR cells will occur 
in the DTM according to standard operating procedures and the E7 TCR investigational new 
drug applicationToxicities 
13.1.4 Storage and Stability 
There is a 4-hour expiration time from the point of harvest to the end of infusion. This is based 
on stability studies showing no changes in cell viability or cell count at 4 hours from cell harvest.   
13.1.5 Administration procedures 
Please see section 3.2. 
13.1.6 Potential Drug Interactions 
There are no known drug interactions.  

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14 REFERENCES  
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Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type-
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Srodon M, Stoler MH, Baber GB, Kurman RJ. The distribution of low and high-risk HPV 
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van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar 
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of invasive and in situ vulvar carcinoma. Obstet Gynecol. 2006;107(5):1018-22. 
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Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon 
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del Campo AB, Kyte JA, Carretero J, Zinchencko S, Mendez R, Gonzalez-Aseguinolaza 
G, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of 
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14. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, 
efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting 
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randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015;386(10008):2078-88. 

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15 APPENDICES 
15.1 APPENDIX A: 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. 
 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 

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