Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
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....
Background:

 -  Vulvar high-grade squamous intraepithelial lesion (HSIL) is a premalignant epithelial
 lesion that is frequently multifocal and/or recurrent.

 -  The primary treatment is surgery, which may result in disfigurement and compromise of
 the urethra, anus, or clitoris. Recurrence after surgery is common and primarily treated
 with additional surgery.

 -  Vulvar HSIL is caused by chronic infection with the human papillomavirus (HPV) type 16
 infection. In this clinical trial the HPV-16 infection is targeted with a single
 infusion of autologous T cells that have been genetically engineered to express a HPV-16
 E7-specific T cell receptor (E7 TCR T cells).

 Objective:

 -Determine the complete response rate for E7 TCR T cells in the treatment of vulvar HSIL.

 Eligibility:

 -  Histologically confirmed diagnosis of HPV-16+ vulvar HSIL.

 -  Expression of the human leukocyte antigen (HLA)-A2*02:01 allele.

 -  Measurable lesion(s) that are recurrent or cannot be resected with acceptable cosmetic
 or functional results.

 -  Age greater than or equal to 18 years old.

 -  Eastern Oncology Cooperative Group Performance Score of 0 or 1.

 Design:

 -  This is a phase II clinical trial

 -  Simon minimax two-stage design with initial enrollment of 12 patients and expansion to
 16 patients if one or more complete response(s) is/are observed in the initial patients.

 -  Subjects will receive 1x10^11 E7 TCR T cells

 -  No conditioning regimen or aldesleukin will be given

 -  Re-enrollment will be allowed for a small number of subjects.
-  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.