Immunotherapy With E6 T Cell Receptor (TCR) T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
Condition: Human Papillomavirus; HPV-16; High Grade Squamous Intraepithelial Lesion
MeSH terms: Squamous Intraepithelial Lesions of the Cervix; Carcinoma, Squamous Cell; Carcinoma in Situ
Intervention: Aldesleukin; E6 T Cell Receptor (TCR)
Intervention description: Aldesleukin 720,000 IU/kg (based on total body weight) intravenous (IV) infused over 15 minutes approximately every 12 hours for a maximum of two doses.; On day 0, the E6 TCR cells will be administered one time, intravenously over 20 to 30 minutes
Intervention MeSH terms: Aldesleukin; Interleukin-2
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: Female
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HPV-16; Premalignancy; T Cell Therapy

Summary:

      Background:

      Vulvar high-grade squamous intraepithelial lesion (HSIL) is caused by infection of the vulva
      with human papillomavirus (HPV). In a small percentage of cases, vulvar HSIL can turn into
      cancer. The risk of cancer can be reduced by treating HSIL. A personalized immune treatment
      might rid the body of HPV infection and thereby cure vulvar HSIL. The immune treatment in
      this study is called T cell therapy. The cells are E6 T Cell Receptor (TCR) T cells.
      Participants will also get aldesleukin (IL-2) to help the cells last longer.

      Objective:

      To find a safe dose of E6 TCR T cells combined with aldesleukin to use in people with vulvar
      HSIL.

      Eligibility:

      Design:

      Participants will be screened with:

      Physical exam

      Medical history

      Blood, lab, and pregnancy tests

      Heart tests

      Chest x-ray

      Sample of tissue taken from the vulva (biopsy).

      Participants will have leukapheresis. Blood will be removed by a needle in one arm. A machine
      removes white blood cells from the blood. The rest of the blood is returned by needle in the
      other arm. The white blood cells will be changed into E6 TCR T cells and grown in a lab.
      About 3 weeks later, participants will be admitted to the hospital for about 5 days. They
      will get the cells through a tube placed in a vein. They will get IL-2 the same way.
      Participants will recover 1-3 days in the hospital. They will be monitored closely. They will
      have blood and lab tests. Participants will have follow-up visits with lab tests and a
      physical exam every few months for 5 years. At some visits they will also have leukapheresis,
      blood tests, or vulvar biopsy.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Patients must have vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) as
                  confirmed by pathology report from a Clinical Laboratory Improvement Amendments
                  (CLIA)-certified laboratory.

               2. Vulvar HSIL must be human papilloma virus (HPV)-16+ by a polymerase chain
                  reaction (PCR), ribonucleic acid (RNA), or in situ hybridization test from a CLIA
                  certified laboratory.

               3. Patients must have measurable lesion(s) as defined in section 6.3.2 and one or
                  more of the following criteria:

                    1. Failure of surgery to control disease (i.e. positive margins or recurrence
                       of HSIL after surgery).

                    2. Multifocal or extensive disease for which surgery would result in major
                       deformity that is not be acceptable to the patient.

                    3. Disease for which surgery would have a risk of functional impairment that is
                       not be acceptable to the patient (i.e. involve partial or complete excision
                       of the clitoris, anus, vagina, or urethra).

               4. Patients may have received any previous therapy, including surgical excision, but
                  must have histologically documented recurrence on new biopsy and a measurable
                  lesion that meets the above criteria.

               5. The presence of disease that can be biopsied for research purposes is not an
                  inclusion criterion.

               6. Patients must have the human leukocyte antigen (HLA)-A*02:01 allele

               7. Age greater than or equal to 18 years and less than or equal to 65 years. As age
                  increases, the ability to tolerate the toxicities of aldesleukin decreases, so
                  the patient population for this study will include up to and including 60 years
                  of age to increase safety.

               8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Able to
                  understand and sign the Informed Consent Document.

               9. Women of child-bearing potential must have a negative pregnancy test. Women of
                  child-bearing potential are defined as all women who are not post-menopausal or
                  who have not had a hysterectomy. Postmenopausal will be defined as women over the
                  age of 55 who have not had a menstrual period in at least 1 year.

              10. The effects of E6 T Cell Receptor (TCR) T Cells on the developing human fetus are
                  unknown. For this reason, women of child-bearing potential must agree to use
                  adequate contraception (hormonal or barrier method of birth control; abstinence)
                  prior to study entry and for the duration of study participation. Should a woman
                  become pregnant or suspect she is pregnant while she is participating in this
                  study, she should inform her treating physician immediately.

              11. 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
                  be less responsive to the experimental treatment.

              12. Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C
                  antibody test is positive, then the patient must be tested for the presence of
                  antigen by reverse transcription (RT)-PCR and be hepatitis C virus (HCV) RNA
                  negative.

              13. Must be willing to participate in Gene Therapy Long Term Followup Protocol
                  (15-C-0141), which will follow patients for up to 15 years per Food and Drug
                  Administration (FDA) requirements.

              14. Patients must have normal organ and marrow function as defined below:

          -  leukocytes greater than or equal to 3,000/mcL

          -  absolute neutrophil count greater than or equal to 1,000/mcL

          -  platelets greater than or equal to 150,000/mcL

          -  hemoglobin greater than or equal to 10.0 g/dL

          -  total bilirubin within normal institutional limits except in patients with Gilbert's
             Syndrome who must have a total bilirubin < 3.0 mg/dL

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase
             (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) Serum
             ALT/AST < 3 times ULN

          -  creatinine less than 1.5 times baseline, < 1.5 times upper limit of normal (ULN)

        OR

        -creatinine clearance less than or equal to 60 mL/min/1.73 m(2) for patients with
        creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology
        Collaboration (CKD-EPI) equation)

        EXCLUSION CRITERIA:

          1. Patients who are receiving any other investigational agents

          2. Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with E6 TCR, breastfeeding should be discontinued
             if the mother is treated with E6 TCR. These potential risks may also apply to other
             agents used in this study.

          3. Uncontrolled intercurrent illness including, but not limited to, any ongoing or active
             infection (e.g. requiring anti-infective therapy), coagulation disorders,
             cardiovascular disorders, respiratory disorders, cancer, or psychiatric illness/social
             situations (within the last six months) that would limit compliance with study
             requirements.

          4. Any form of systemic immunodeficiency, including acquired deficiency such as HIV or
             primary immunodeficiency such as Severe Combined Immunodeficiency Disease. 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
             treatment.

          5. Concurrent systemic steroid therapy if greater than the equivalent of 5 mg prednisone
             by mouth (PO) daily. Patients previously on steroids must be off steroids for four
             weeks prior to treatment.

          6. Any history of clinically significant cardiac arrhythmia, coronary revascularization,
             ischemic symptoms, or previously documented left ventricular ejection fraction (LVEF)
             of less than or equal to 45%. A cardiac stress test is required for all patients
             greater than 50 years old. A cardiac stress test may also be performed for any
             clinical concern. Patients with cardiac ischemia are not eligible.

          7. Patients with any active invasive cancer are not eligible.

          8. Patients vulvar HSIL that is not HPV-16+ or is associated with multiple types of
             high-risk HPV are not eligible.