E7 TCR T Cells for treating HPV-related cancers

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

This study is testing if specially modified T cells can help treat cancers linked to HPV-16, like cervical and vulvar cancers, in patients whose cancer has spread or hasn't responded to other treatments.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 180 (estimated)
• Ages: 18 Years to 120 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (nih)
• Drugs / interventions: cyclophosphamide, fludarabine, prednisone, Chemotherapy
• Locations: 2 sites (Bethesda, Maryland and 1 other locations)
• Trial ID: NCT02858310 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the use of genetically engineered T cells, known as E7 TCR cells, to target and treat cancers associated with human papillomavirus (HPV), specifically HPV-16. The study aims to determine the safety and efficacy of these T cells in patients with metastatic or refractory HPV-16+ cancers, including cervical and vulvar cancers. Participants will undergo a preparative regimen followed by the infusion of E7 TCR cells and will be monitored for treatment responses and side effects. The trial includes both Phase I and Phase II components to assess optimal dosing and therapeutic outcomes.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with metastatic or refractory HPV-16+ cancers who have received prior standard therapy.

Not a fit: Patients with cancers not associated with HPV-16 or those who do not meet the HLA-A*02:01 requirement may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a novel and effective treatment option for patients with HPV-associated cancers that are currently difficult to treat.

How similar studies have performed: Other studies utilizing T cell receptor gene therapy for HPV-related cancers have shown promising results, indicating potential for success in this approach.

Eligibility criteria

* INCLUSION CRITERIA:

  1. Measurable metastatic or refractory/recurrent HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test).
  2. Patients must be HLA-A\*02 by low resolution typing, and HLA-A\*02:01 by one of the high resolution type results.
  3. All patients must have received prior first line standard therapy or declined standard therapy.
  4. 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.
  5. Greater than or equal to 18 years of age.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of ECOG 0 or 1.
  8. Individuals must be willing to practice birth control from the time of enrollment on this study up to twelve (12) months after treatment. Individuals must be willing to undergo testing for HPV-16 prior to becoming pregnant after this period.
  9. Individuals of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Individuals of childbearing potential are defined as all individuals except individuals who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as individuals over the age of 55 who have not had a menstrual period in at least one year. 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 individual is treated with E7 TCR transduced PBL. These potential risks may also apply to other agents used in this study.
  10. 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:

1. 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.
2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
3. 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).
4. 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.
5. 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)
6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin.
7. Patients with a history of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test.
8. Documented LVEF of less than or equal to 45% tested. The following patients will undergo cardiac evaluations

   1. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or
   2. Age greater than or equal to 50 years old
9. 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.
10. 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

Where this trial is running

Bethesda, Maryland and 1 other locations

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (RECRUITING)
• Rutgers Cancer Institute of New Jersey — New Brunswick, New Jersey, United States (COMPLETED)

Study contacts

• Principal investigator: Scott M Norberg, D.O. — National Cancer Institute (NCI)
• Study coordinator: Laura A Parsons-Wandell, R.N.

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