Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
Condition: Squamous Lntraepithelial Lesions of Vulva; Neoplasms, Squamous Cell; Vulvar HSIL
MeSH terms: Neoplasms, Squamous Cell
Intervention: E7 T Cell Receptor (TCR)
Intervention description: One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Human Papilloma Virus (HPV) Type 16; Retroviral Vector Supernatant; Leukapheresis; T Cell Receptor; Premalignant Epithelial Lesion

Summary:

      Background:

      Human papillomavirus (HPV) can cause vulvar high-grade squamous intraepithelial lesions
      (HSIL). Sometimes, this can become cancer. Researchers want to see if T cell therapy can
      treat vulvar HSIL. In this therapy, a person s immune cells are genetically modified so they
      can attack the HPV.

      Objective:

      To test if a personalized immune treatment can cure vulvar HSIL.

      Eligibility:

      People ages 18 and older with vulvar HSIL that cannot be removed with surgery, or for which
      surgery has failed

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      HPV testing

      Venous assessment

      Chest x-ray

      Heart and pulmonary tests

      Participants will have a baseline visit. They may have a vulvar biopsy. Photographs will be
      taken of their lesions.

      Participants will have leukapheresis: Blood is removed from a needle in the arm and
      circulated through a machine that takes out the white blood cells. The other blood cells are
      returned through a needle in the other arm. The white blood cells will be used to grow
      treatment cells.

      Participants will receive the treatment through a tube inserted into an arm, neck, or chest
      vein. They will recover in the hospital for 1 to 2 days. They will have blood tests and take
      supportive medications.

      Participants may have one more treatment.

      Participants will have 5 follow-up visits in the first 3 months after treatment. They may
      have more visits if their disease is growing. Visits will include blood tests. They may
      include vulvar biopsies or leukapheresis.

      Participants will have an annual physical exam for 5 years after treatment that can be done
      at home or at the National Institutes of Health (NIH). Then they will have an annual phone or
      email questionnaire for another 10 years....
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) as
             confirmed by pathology report from a Clinical Laboratory Improvement Amendments
             (CLIA)-certified laboratory.

          -  Vulvar HSIL must be human papillomavirus (HPV)-16+ by a polymerase chain reaction
             (PCR), Ribonucleic acid (RNA), or in situ hybridization test from a CLIA certified
             laboratory.

          -  Patients must have measurable lesion(s) as defined in one or more of the following
             criteria:

               -  Failure of surgery to control disease (i.e. positive margins after surgery or
                  recurrence of HSIL after surgery).

               -  Multifocal or extensive disease for which surgery would result in disfigurement
                  that is not be acceptable to the patient.

               -  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).

          -  Patients may have received any previous therapy, including surgical excision. Patients
             with recurrent disease must have histologically documented recurrence on new biopsy
             and a measurable lesion that meets the above criteria.

          -  Patients must have the human leukocyte antigen (HLA)-A*02:01 allele

          -  Age greater than or equal to18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Able to understand and sign the Informed Consent Document.

          -  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.

          -  The effects of E7 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.

          -  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.

          -  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.

          -  Must be willing to participate in Gene Therapy Long Term Followup Protocol
             (20-C-0051), which will follow patients for up to 15 years per Food and Drug
             Administration (FDA) requirements.

          -  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 100,000/mcL

               -  hemoglobin greater than or equal to 9.0 g/dL

               -  total bilirubin within 1.5X 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 < 3X upper limit of normal (ULN)

               -  creatinine < 1.5X baseline, < 1.5X ULN OR

               -  creatinine clearance greater 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:

          -  Patients who are receiving any other investigational agents

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with E7 TCR, breastfeeding should be discontinued
             if the mother is treated with E7 TCR. These potential risks may also apply to other
             agents used in this study.

          -  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.

          -  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 maybe less responsive to the
             treatment.

          -  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.

          -  Cardiac stress test and pulmonary function tests maybe required for patients with a
             clinical history of significat cardiopulmonary disease. Patients with active cardiac
             ischemia or severe chronic obstructive pulmonary disease are not eligible.

          -  Patients with any active invasive cancer are not eligible.

          -  Patients with vulvar HSIL that is not HPV-16+ or is associated with multiple types of
             high-risk HPV at the time of eligibility assessment are not eligible.