Immunotherapy With E6 T Cell Receptor (TCR) T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

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 an
HPV-16 E6-specific

T cell receptor (E6 TCR T cells).

Objective:

-Determine the safety of E6 TCR T cells for the treatment of vulvar HSIL.

Eligibility:

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

- Expression of the 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.

Design:

- 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 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 CRITIERA:

1. Patients must have vulvar HSIL as confirmed by pathology report from a
CLIA-certified laboratory.

2. Vulvar HSIL must be HPV-16+ by a PCR, 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 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. 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 E6TCR 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 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 RT-PCR and be 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

- AST(SGOT)/ALT(SGPT) Serum ALT/AST < 3 times ULN

- creatinine less than 1.5 times baseline, < 1.5 times ULN

OR

-creatinine clearance less than or equal to 60 mL/min/1.73 m2 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
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 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.