E7 TCR-T Cell Immunotherapy for Human Papillomavirus (HPV) Associated Cancers

Study Overview
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Brief Summary
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This is a phase II clinical trial to assess the clinical activity of immunotherapy with E7 TCR-T cells for metastatic HPV-associated cancers. HPV-associated cancers in include cervical, throat, penile, vulvar, vaginal, anal, and other cancers. Participants will receive a conditioning regimen, E7 TCR-T cells, and aldesleukin. Clinical response to treatment will be determined.

Detailed Description
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This study will determine the tumor response rate for the treatment of HPV-associated cancers with E7 TCR-T cells. E7 TCR-T cells are autologous gene-engineered T cells that target HPV16 E7 through a T cell receptor (TCR). E7 is an HPV oncoprotein that is present in HPV-associated cancers. Participants must have the HLA-A*02:01 allele, which is required for tumor targeting by the E7 TCR. Treatment consists of a conditioning regimen (cyclophosphamide and fludarabine), a single infusion of E7 TCR-T cells, and adjuvant aldesleukin. Tumor response rate and response duration will be determined. Safety data will also be collected.

Official Title
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A Phase II Trial of T Cell Receptor Gene Therapy Targeting Human Papillomavirus ( HPV) 16 E7 for HPV-Associated Cancers

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

Intervention / Treatment
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* Biological: E7 TCR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic or refractory/recurrent HPV-16+ cancer. Tumor with HPV16 genotype as determined by testing performed in a CLIA certified laboratory. HLA-A*02:01 allele as determined by testing performed in a Clinical Laboratory Improvement Amendments (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. Measurable disease as assessed by RECIST Criteria Version 1.114. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at screening. Must have received prior first line standard therapy or have declined standard therapy. Standard treatment options for first and second-line therapy must be presented and formally declined (Appendix VII). Patients with three or fewer brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Patients must be fully recovered from surgery. 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. Men and 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 antigen, and hepatitis C antibody. If a hepatitis C antibody test is positive, then testing for antigen by RT-PCR for Hepatitis C (HCV) RNA must be negative. Participants must have organ and marrow function as defined below: Leukocytes > 3,000/microliter (mcL) Absolute neutrophil count > 1,500/mcL Platelets > 100,000/mcL Hemoglobin > 8.0 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 transferase (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. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the E7 TCR cells. Participants must be able to understand and be willing to sign the written informed consent document. Participants must agree to participate in protocol Cancer Institute of New Jersey (CINJ) 192103 (Pro2021002307) for gene therapy long term follow up and in protocol 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 phase II clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E7 TCR-T cells<br>Subjects will receive a conditioning regimen, E7 TCR-T cells, and aldesleukin. | Biological: E7 TCR-T cells<br>* Participants will receive a conditioning regimen (cyclophosphamide and fludarabine), E7 TCR-T cells as a single infusion, and adjuvant high-dose aldesleukin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response | Objective tumor response as measured by RECIST | Five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Adverse events as measured by CTCAE | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV, Chimeric antigen receptors (CAR-T), Tumor infiltrating lymphocyte, TCR-T, immunotherapy, T cell, adoptive cell therapy, cellular therapy, gene therapy, human papillomavirus, E7, T cell receptor, TCR, E7 TCR, lymphocyte, cell therapy, cervical cancer, oropharyngeal cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, tumor infiltrating lymphocytes (TIL), TIL therapy