E7 TCR T Cells for Human Papillomavirus-Associated Cancers

Study Overview
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Brief Summary
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Background: Human papillomavirus (HPV) can cause cervical, throat, anal, and genital cancers. Cancers caused by HPV have a HPV protein called E7 inside of their cells. In this new therapy, researchers take a person s blood, remove certain white blood cells, and insert genes that make them to target cancer cells that have the E7 protein. The genetically changed cells, called E7 TCR cells, are then given back to the person to fight the cancer. Researchers want to see if this can help people. Objective: To determine a safe dose and efficacy of E7 TCR cells and whether these cells can help patients. Eligibility: Adults ages 18 and older with an HPV-16-associated cancer, including cervical, vulvar, vaginal, penile, anal, or oropharyngeal. Design: Participants will list all their medicines. Participants will have many screening tests, including imaging procedures, heart and lung tests, and lab tests. They will have a large catheter inserted into a vein. Participants will have leukapheresis. Blood will be removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. The cells will be changed in the lab. Participants will stay in the hospital. Over several days, they will get: Chemotherapy drugs E7 TCR cells Shots or injections to stimulate the cells Participants will be monitored in the hospital up to 12 days. They will get support medicine and have blood and lab tests. Participants will have a clinic visit about 40 days after cell infusion. They will have a physical exam, blood work, scans, and maybe x-rays. Participants will have many follow-up visits with the same procedures. At some visits, they may undergo leukapheresis. Participants will be followed for 15 years.

Detailed Description
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Background: Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly palliated by standard therapies. HPV-16+ cancers constitutively express the HPV-16 E7 oncoprotein, which is absent from healthy human tissues. Administration of T cell receptor (TCR) gene engineered T cells can induce objective tumor responses in certain malignancies including HPV-16+ cancers. T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) display specific reactivity against HLA-A2+, HPV-16+ target cells. Objectives: Phase I Primary Objective - To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers. Phase II Primary Objective -To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers. Eligibility: Patients greater than or equal to 18 years old with metastatic or refractory/recurrent HPV-16+ cancer. Prior first line systemic therapy is required unless the patient declines standard treatment. Patients must be HLA-A*02:01-positive. Design: This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR cells. All patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by a single infusion of E7 TCR cells. Cell infusion will be followed by high-dose aldesleukin. Re-enrollment will be allowed for a small number of subjects.

Official Title
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A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers

Conditions
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Papillomavirus Infections, Cervical Intraepithelial Neoplasia, Carcinoma In Situ, Vulvar Neoplasms, Vulvar Diseases

Intervention / Treatment
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* Biological: E7 TCR cells
* Drug: Aldesleukin
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Measurable metastatic or refractory/recurrent HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test). Patients must be HLA-A*02 by low resolution typing, and HLA-A*02:01 by one of the high resolution type results. All patients must have received prior first line standard therapy or declined standard therapy. 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 with surgically resected brain metastases are eligible. Greater than or equal to 18 years of age. Able to understand and sign the Informed Consent Document. Clinical performance status of ECOG 0 or 1. Patients of both genders must be willing to practice birth control from the time of enrollment on this study up to four months after treatment. Patients must be willing to undergo testing for HPV-16 prior to becoming pregnant after this period. Women of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Women of childbearing potential are defined as all women except women who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least one year. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with E7 TCR transduced PBL, breastfeeding should be discontinued if the mother is treated with E7 TCR transduced PBL. These potential risks may also apply to other agents used in this study. Serology: 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 are less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative. a. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. WBC greater than or equal to 3000/mm^3 Platelet count greater than or equal to 100,000/mm^3 Hemoglobin > 8.0 g/dL b. Chemistry: Serum ALT/AST less than or equal to 2.5 times the upper limit of normal Calculated creatinine clearance (CCr) greater than or equal to 50 mL/min/1.73^2 using the Cockcroft-Gault equation Total bilirubin less than or equal to 1.5 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL c. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the E7 TCR cells. Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to Grade 1 or less. EXCLUSION CRITERIA: Active systemic infections (for e.g.: requiring anti-infective treatment), coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, severe obstructive or restrictive pulmonary disease. Patients with abnormal pulmonary function tests but stable obstructive or restrictive pulmonary disease may be eligible. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not exclusionary. Patients on immunosuppressive drugs including corticosteroids. With the exception of: intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) -Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; or, -Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin. Patients with a history of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test. Documented LVEF of less than or equal to 45% tested. The following patients will undergo cardiac evaluations Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or Age greater than or equal to 50 years old Any other condition, which would, in the opinion of the Principal Investigator, indicate that the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained. Subjects with baseline screening pulse oxygen level of < 95% on room air will not be eligible. If the underlying cause of hypoxia improves, then they may be reevaluated

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Phase I<br>Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 TCR Cells at escalating doses, followed by aldesleukin | Biological: E7 TCR cells<br>* T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells<br>Drug: Aldesleukin<br>* Following cell infusion the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 TCR cells after infusion.<br>Drug: Fludarabine<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>Drug: Cyclophosphamide<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>|
| Experimental: Arm 2: Phase II<br>1 x 10 e11 E7 Cells that was determined in Phase I + aldesleukin | Biological: E7 TCR cells<br>* T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells<br>Drug: Aldesleukin<br>* Following cell infusion the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 TCR cells after infusion.<br>Drug: Fludarabine<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>Drug: Cyclophosphamide<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Determine safety and effficacy of E7 TCR cells plus aldesleukin | Overall response rate (PR +CR) | At 12 weeks, every 3 months x 3, every 6 months x 5 years, then as per PI discretion thereafter | 
| Phase I: Determine a safe dose for E7 TCR cells plus aldesleukin | Number and type of AEs and/or UPs | 30 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess progression-free survival | time from start of treatment to disease progression or death | at time of last patient's progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Human Papillomavirus, Vulvar Intraepithelial Neoplasia, Vulvar High Grade Squamous Intraepithelial Lesion, Vaccine, HPV-related Malignancy, HPV-related Carcinoma, HPV-related Cervical Carcinoma, HPV-related Anal Squamous Cell Carcinoma, HPV Positive Oropharyngeal Squamous Cell Cancer