E7 TCR T Cells for Human Papillomavirus-Associated Cancers
- - 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. 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. 9. 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. 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. 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
Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical, vulvar,
vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly palliated by
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.
Phase I Primary Objective
To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of metastatic
Phase II Primary Objective
To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of
metastatic HPV-16+ cancers.
Patients greater than or equal to 18 years old with metastatic or refractory/recurrent
Prior first line systemic therapy is required unless the patient declines standard treatment.
Patients must be HLA-A*02:01-positive.
This is a phase I/II multicenter clinical trial that will test the safety and efficacy of E7
National Cancer Institute Center for Cancer Research (NCI CCR) will coordinate the study
across all participating sites. The NCI CCR and any Extramural Participating Site (EMPS) may
enroll patients and perform eligibility screening tests and procedures.
Eligible patients will undergo leukapheresis and cell manufacturing at the NCI CCR.
All eligible patients will be treated at the NCI CCR. Patients will receive a
non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and
fludarabine followed by a single infusion of E7 TCR cells and high-dose aldesleukin.
Post-treatment safety and response assessments may be performed at the EMPS where the subject
was initially screened or the NCI CCR.
Re-enrollment will be allowed for a small number of subjects.
Trial Phase Phase I/II
Trial Type Treatment
National Cancer Institute
Christian Sutter Hinrichs
- Primary ID 160154
- Secondary IDs NCI-2018-03362, 16-C-0154, NCI-2016-01170
- Clinicaltrials.gov ID NCT02858310