E7 TCR T Cells for Human Papillomavirus-Associated Cancers

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 human leukocyte antigen (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.

• E7 TCR cells (Biological), also known as E7 T Cell Receptor (TCR) cells: T cells genetically engineered with a T cell receptor (TCR) targeting human papillomavirus (HPV -16 E7 (E7 TCR) that display specific reactivity against human leukocyte antigen (HLA-A2+, HPV-16+ target cells.
• Aldesleukin (Drug), also known as Interleukin-2, IL-2, Proleukin: Following cell infusion, the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 T cell receptor (TCR) cells after infusion.
• Fludarabine (Drug), also known as Fludara: Part of the non-myeloablative lymphocyte-depleting preparative regimen.
• Cyclophosphamide (Drug), also known as Cytoxan, Neosar: Part of the non-myeloablative lymphocyte-depleting preparative regimen.
• EKG (Diagnostic test), also known as Electrocardiogram: Screening/Baseline. Follow-up (end of treatment).
• Biopsy (Procedure), also known as Bx: Screening/Baseline. Following treatment (6 weeks post treatment preferred) and at disease progression only.
• Chest CT and MRI or PET (Diagnostic test), also known as Chest computed tomography and magnetic resonance imaging and positron emission tomography: Screening/Baseline. Follow-up (end of treatment). 40 days (+/- 2 weeks) after cell infusion; additional visits as indicated.
• PFT (Diagnostic test), also known as Pulmonary function test: Screening/Baseline.
• Granisetron (Drug), also known as Kytril, Sancuso, Sustol: Supportive medication for nausea/vomiting/anorexia. 0.01 mg/kg intravenous (IV) every(q) day as needed (prn).
• Ondansetron (Drug), also known as Zofran: Supportive medication for nausea/vomiting/anorexia. Ondansetron 10mg intravenous (IV) every(q) 8 hours(hr) as needed (prn).
• Droperidol (Drug), also known as Inapsine, Droleptan, Dridol, Xomolix, Innovar: Supportive medication for nausea/vomiting/anorexia. 1mg intravenous (IV) at 4-6 hours(h) as needed (prn).
• Prochlorperazine (Drug), also known as Compazine: Supportive medication for nausea/vomiting/anorexia. 25mg per rectum (PR) as needed (prn) or 10mg intravenous (IV) every(q) 6hours(h) prn.
• Diphenoxylate HCL (Drug), also known as Diphenoxylate Hydrochloride: Supportive medication for diarrhea. 2.5mg by mouth (po) every(q) 3 hours(h) as needed (prn).
• Atropine sulfate (Drug), also known as Atropen: Supportive medication for diarrhea. 25mcg by mouth (po) every(q) 3 hours(h) as needed (prn).
• Codeine sulfate (Drug), also known as Codeine: Supportive medication for diarrhea. 30-60mg by mouth (po) every(q) 4 hours(h) as needed (prn).
• Loperamide (Drug), also known as Imodium A-D: Supportive medication for diarrhea. 2mg by mouth (po) every(q) 3 hours(h) as needed (prn).
• Indomethacin (Drug), also known as Indocin, Tivorbex: Supportive medication for fever. 50-75mg by mouth (po) every(q) 8 hours(h).
• Acetaminophen (Drug), also known as Tylenol: Supportive medication for fever. 650mg by mouth (po) every 4 hours (q) 4hr.
• Diphenhydramine HCL (Drug), also known as Diphenhydramine Hydrochloride, Benadryl, Unisom, ZzzQuil: Supportive medication for pruritis. 25-50mg by mouth (po) every 4 hours (q) 4hr as needed (prn).
• Hydroxyzine HCL (Drug), also known as Atarax: Supportive medication for pruritis. 10-20mg by mouth (po) every 6 hours(h), as needed (prn).
• Meperidine (Drug), also known as Demerol: Supportive medication for chills. 25-50mg intravenous (IV) every 1 hour (q1hr), as needed (prn).

Primary outcomes

• Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR) [At 12 weeks, every 3 months x 3, and every 6 months for approximately 5 years]: Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Compete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
• Phase I: Number of Dose Limiting Toxicities (DLT) [From the day of cell infusion (Day 0) to Day +30]: Adverse events were assessed by the Common Terminology Criteria for Adverse Events v4.0. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event. A DLT is defined as all Grade 3 and greater toxicities occurring within 30 days of the cell infusion with the exception of: Cytokine Release Syndrome (CRS) that resolves ≤ grade 2 within 14 days of the last dose of aldesleukin. Autoimmune toxicity that resolves to ≤ grade 2 within 14 days for starting symptom treatment (e.g. steroids). Cardiac, gastrointestinal, dermatological, hepatic, pulmonary, renal, hematologic, neurologic toxicity, or toxicity in Appendix C of the protocol attributable to aldesleukin that resolves to ≤ grade 2 within 14 days of the last dose of aldesleukin. Transient grade 3 hypoxia associated with cell infusion that corrects to ≤ grade 2 with supplemental oxygen and/or that resolves to ≤ grade 2 within 24 hours or before starting aldesleukin.

Secondary outcomes

• Progression-free Survival [From the time of cell infusion (Day 0) until documented progressive disease; a maximum of 12 months]: Progression-free survival is the time from start of treatment to disease progression or death from any cause. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Other outcomes

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [Adverse Events were monitored/assessed from the first study intervention, Study Day 0, through 40 days after the study therapy was last administered up to a maximum of 12 months]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to 120 Years

* INCLUSION CRITERIA:

  1. Measurable metastatic or refractory/recurrent human papillomavirus (HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test).
  2. Patients must be human leukocyte antigen (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 Eastern Cooperative Oncology Group (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 infant's secondary to treatment of the mother with E7 T cell receptor (TCR) transduced peripheral blood lymphocytes (PBLs), 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 human immunodeficiency virus (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 reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative.

  a. Hematology:
* Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim.
* White blood count (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 Alanine aminotransferase (ALT)/Aspartate aminotransferase (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., computed tomography (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 left ventricular ejection fraction (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

Participant flow

Outcome results

• Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR) (Primary), Count of participants, Participants: Phase II Cohort; Arm 2: Phase II: 1 x 10^11 E7 Cells 0
• Phase I: Number of Dose Limiting Toxicities (DLT) (Primary), Number, toxicities: Phase I:Dose Escalation Cohort; Arm 1:Phase I:DoseLevel 1: 1 x 10^9 E7 T-Cell Receptor (TCR) Cells 0; Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 2: 1 x 10^10 E7 T-Cell Receptor Cells 0; Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 3: 1 x 10^11 E7 Cells 1
• Progression-free Survival (Secondary), Median, Months: Phase I:Dose Escalation Cohort; Arm 1:Phase I:DoseLevel 1: 1 x 10^9 E7 T-Cell Receptor (TCR) Cells 5.5 (3 to 8); Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 2: 1 x 10^10 E7 T-Cell Receptor Cells 4 (1 to 9); Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 3: 1 x 10^11 E7 Cells 3.5 (1 to 8); Phase II Cohort; Arm 2: Phase II: 1 x 10^11 E7 Cells 2 (1 to 12); Participants Enrolled But Were Not Treated
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) (Other pre specified), Count of participants, Participants: Phase I:Dose Escalation Cohort; Arm 1:Phase I:DoseLevel 1: 1 x 10^9 E7 T-Cell Receptor (TCR) Cells 3; Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 2: 1 x 10^10 E7 T-Cell Receptor Cells 3; Phase I: Dose Escalation Cohort; Arm 1: Phase I; Dose Level 3: 1 x 10^11 E7 Cells 6; Phase II Cohort; Arm 2: Phase II: 1 x 10^11 E7 Cells 18; Participants Enrolled But Were Not Treated

Adverse events

Time frame: All-Cause Mortality was monitored/assessed from the time of consent for screening until participants were taken off study, a maximum of 1 year. Adverse Events (AEs) were monitored/assessed from the first study intervention, Study Day 0, through 40 days after the study therapy was last administered, a maximum of 12 months.

Serious adverse events by term

Other adverse events by term

106 more terms not shown.

• Draper LM, Kwong ML, Gros A, Stevanovic S, Tran E, Kerkar S, Raffeld M, Rosenberg SA, Hinrichs CS. Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6. Clin Cancer Res. 2015 Oct 1;21(19):4431-9. doi: 10.1158/1078-0432.CCR-14-3341. PMID 26429982
• Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, Restifo NP, Rosenberg SA, Hinrichs CS. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015 May 10;33(14):1543-50. doi: 10.1200/JCO.2014.58.9093. Epub 2015 Mar 30. PMID 25823737
• Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol. 2013 Nov;31(11):999-1008. doi: 10.1038/nbt.2725. Epub 2013 Oct 20. PMID 24142051
• Jin BY, Campbell TE, Draper LM, Stevanovic S, Weissbrich B, Yu Z, Restifo NP, Rosenberg SA, Trimble CL, Hinrichs CS. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight. 2018 Apr 19;3(8):e99488. doi: 10.1172/jci.insight.99488. eCollection 2018 Apr 19. PMID 29669936
• Results publication: Nagarsheth NB, Norberg SM, Sinkoe AL, Adhikary S, Meyer TJ, Lack JB, Warner AC, Schweitzer C, Doran SL, Korrapati S, Stevanovic S, Trimble CL, Kanakry JA, Bagheri MH, Ferraro E, Astrow SH, Bot A, Faquin WC, Stroncek D, Gkitsas N, Highfill S, Hinrichs CS. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021 Mar;27(3):419-425. doi: 10.1038/s41591-020-01225-1. Epub 2021 Feb 8. PMID 33558725

• Study Protocol and Statistical Analysis Plan (PDF, 2024-12-05)
• Informed Consent Form: Screening Consent (PDF, 2025-01-07)
• Informed Consent Form: Treatment, Affected Patient (PDF, 2025-01-07)

• Scott M Norberg, D.O., Principal investigator, National Cancer Institute (NCI)