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.
To find a safe dose of E6 TCR T cells combined with aldesleukin to use in people with vulvar
Participants will be screened with:
Blood, lab, and pregnancy tests
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.
- 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 an
T cell receptor (E6 TCR T cells).
-Determine the safety of E6 TCR T cells for the treatment of vulvar HSIL.
- 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 and less than or equal to 65 years old.
- Eastern Oncology Cooperative Group Performance Score of 0 or 1.
- This is a phase I clinical trial with a 3+3 dose escalation design.
- Subjects will receive E6 TCR T cells followed by up to two doses of aldesleukin 720,000
IU/kg intravenous (IV).
- No conditioning regimen will be given, aldesleukin will be capped at a maximum of two
doses, and E6 TCR T cell dosing will begin at dose level -1 from the previously
determined safe dose.
- INCLUSION CRITERIA:
1. Patients must have vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) as
confirmed by pathology report from a Clinical Laboratory Improvement Amendments
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
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
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
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)
-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)
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
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
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.