E7 T-cell Receptor (TCR) -T Cell Induction Therapy for Locoregionally Advanced HPV-associated Cancers

Study Overview
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Brief Summary
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The goal of this study is to determine the feasibility of administration of a single dose of E7 TCR-T cells as induction therapy prior to definitive treatment (chemoradiation or surgery) of locoregionally advanced HPV-associated cancers. The intent of E7 TCR-T cell treatment is to shrink or eliminate tumors and thereby facilitate definitive therapy and increase overall survival. This study seeks to determine 1) if E7 TCR-T cell can be administered without undue delay in definitive treatment, 2) the tumor response rate to E7 TCR-T cell treatment, 3) and the disease-free survival rate at 2 and 5 years. Participants will undergo an apheresis procedure to obtain T cells that will be genetically engineered to generate E7 TCR-T cells. They will receive a conditioning regimen, a single infusion of their own E7 TCR-T cells, and adjuvant aldesleukin. Participants will follow up to assess safety and determine tumor response and will return to their primary oncology team for definitive therapy.

Detailed Description
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This is a single-arm, single-cohort, single-center, feasibility study to determine the feasibility of E7 TCR-T cell induction therapy for locoregionally advanced human papillomavirus (HPV)-associated cancers (LAHPVC). Participants must have LAHPVC with HPV-16-positive cancer (tumor test) and the human leukocyte antigens (HLA)-A*02:01 allele (blood test). Participants will undergo apheresis for generation of autologous, gene-engineered, E7 TCR-T cells. One week after apheresis, they will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine. Conditioning will be followed by a single infusion of E7 TCR T cells and adjuvant high-dose aldesleukin. Participants will follow up 3 weeks and 6 weeks after treatment. Tumor response will be assessed by imaging studies at the 6-week time point. Participants will be referred back to their primary oncology team for definitive therapy after the 6-week assessment (or earlier if tumors do not appear to be responding). Participants will be followed to determine 2- and 5-year disease free survival.

Official Title
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A Feasibility Study of E7 TCR-T Cell Induction Therapy for Locoregionally Advanced HPV-Associated Cancers

Conditions
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HPV-Associated Cervical Carcinoma, HPV-Related Carcinoma, HPV-Related Malignancy, HPV Positive Oropharyngeal Squamous Cell Carcinoma, HPV-Related Adenocarcinoma, HPV-Related Adenosquamous Carcinoma, HPV-Related Squamous Cell Carcinoma, HPV-Related Anal Squamous Cell Carcinoma, HPV-Related Penile Squamous Cell Carcinoma, HPV-Related Vulvar Squamous Cell Carcinoma, HPV-Related Endocervical Adenocarcinoma, Cervical Cancer, Oropharynx Cancer, Anal Cancer, Vulvar Cancer, Penile Cancer, Vaginal Cancer

Intervention / Treatment
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* Drug: Conditioning, E7 TCR-T cells, and aldesleukin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed carcinoma of a primary tumor site and stage indicated in Table 3 of the protocol. Tumor with HPV16 genotype as determined by testing performed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. HLA haplotype that demonstrates the HLA-A*02:01 allele as determined by testing performed in a CLIA certified laboratory. Participants may be enrolled based on low resolution typing (i.e., HLA-A*02) but the HLA-A*02:01 allele type must be confirmed prior to apheresis. Measureable disease per RECIST Criteria Version 1.1 or PERCIST. Age > 18 years. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. Negative pregnancy test for women under 55 and all women who have had a menstrual period in the last 12 months. A pregnancy tests is not required for women who have had a bilateral oophorectomy or hysterectomy. Women of child-bearing potential must agree to use adequate contraception (i.e., intrauterine device, hormonal barrier method of birth control; abstinence; tubal ligation or vasectomy) prior to study entry and for four months after treatment. Should a women become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Seronegative for HIV antibody, hepatitis B surface antigen (sAg), and hepatitis C antibody. If a hepatitis C antibody test is positive, then testing for antigen by reverse transcription polymerase chain reaction (RT-PCR) must be negative. Participants must have organ and marrow function as defined below: Leukocytes > 3,000/Mantle cell lymphoma (mcL) Absolute neutrophil count > 1,500/mcL Platelets > 100,000/mcL Hemoglobin > 9.0 g/dL Total bilirubin within normal institutional limits except in participants with Gilbert's Syndrome who must have a total bilirubin < 3.0 mg/dL. Serum aspartate aminotransferase (AST) (SGOT)/ alanine transaminase (ALT)(SGPT) < 2.5 x upper limit of normal (ULN) Calculated creatinine clearance (CrCl) >50 mL/min/1.73 m2for participants with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation). international normalized ratio (INR) or activated partial thromboplastin time ( aPTT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy. Subjects on anticoagulant therapy must have a PT or aPTT within therapeutic range and no history of severe hemorrhage. Participants must be able to understand and be willing to sign the written informed consent document. Participants must agree to participate in protocol CINJ 192103 (Pro2021002307) for gene therapy long term follow up and in protocol Cancer Institute of New Jersey (CINJ) 192002 (Pro2021000281) for biospecimen collection study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-arm feasibility study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conditioning, E7 TCR-T cells, and aldesleukin<br>Participants will receive a conditioning regimen consisting of cyclophosphamide and fludarabine followed by E7 TCR-T cells cells IV x 1 dose, followed by aldesleukin every 8 hours for up to 3 doses. | Drug: Conditioning, E7 TCR-T cells, and aldesleukin<br>* Participants will receive induction E7 TCR-T cell therapy.<br>* Other names: TCR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of administering E7 TCR-T cell therapy as induction treatment for LAHPVC | Proportion of subjects who complete treatment without an event that meets criteria for feasibility failure | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective tumor response rate at 6-weeks after treatment | Tumor response as assessed by imaging using Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1 or PERCIST | 6 weeks | 
| 2-year and 5-year disease free survival (DFS) | DFS will be determined using the Kaplan-Meier method | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV, Cell therapy, Adoptive cell therapy, Immunotherapy, Radiation, Chemoradiation, CAR-T, cell therapy, Tumor infiltrating lymphocyte, TCR, T cell, Gene therapy, Cervical cancer, Oropharyngeal cancer, Anal cancer, Vulvar cancer, Vaginal cancer, Penile cancer, Induction therapy