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

Phase 1

Terminated

Conditions: Human Papillomavirus
HPV-16
High Grade Squamous Intraepithelial Lesion

Interventions: Drug: Aldesleukin
Biological: E6 T Cell Receptor (TCR)

Registration Number: NCT03197025

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed Description: 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 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.

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 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 1

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1/Arm 1 - Dose Escalation	E6 T Cell Receptor (TCR)	Patients will undergo leukapheresis, then treatment with E6 T Cell Receptor (TCR) cells (at escalating doses) + aldesleukin
2/Arm 2 - Maximum Tolerated Dose (MTD)	E6 T Cell Receptor (TCR)	Patients will undergo leukapheresis, then treatment with E6 T Cell Receptor (TCR) cells (at the MTD) + aldesleukin
2/Arm 2 - Maximum Tolerated Dose (MTD)	Aldesleukin	Patients will undergo leukapheresis, then treatment with E6 T Cell Receptor (TCR) cells (at the MTD) + aldesleukin
1/Arm 1 - Dose Escalation	Aldesleukin	Patients will undergo leukapheresis, then treatment with E6 T Cell Receptor (TCR) cells (at escalating doses) + aldesleukin

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of E6 T Cell Receptor (TCR) T Cells for the Treatment of Vulvar High-Grade Squamous Intraepithelial Lesions (HSIL)	within 30 days of cell infusion	MTD is defined as the highest dose at which a maximum of 1 of 6 participants has a dose limiting toxicity (DLT). A DLT is defined as all treatment related Grade 3 (i.e. severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL)) and greater adverse events occurring within 30 days of the cell infusion with the exception of Grade 3 fever or chills responsive to symptomatic treatment that resolve to ≤ grade 2 in 48 hours. Grade 3 hypotension or oliguria responsive to ≤ 1.5L of intravenous fluid boluses in 24 hours that resolves to ≤ grade 2 in 48 hours. Grade 3 dyspnea/hypoxia that improves to ≤ grade 2 or less with supplemental oxygen and resolves to ≤ grade 2 without supplemental oxygen in 48 hours. Grade 3 creatinine or electrolyte abnormalities that resolve to ≤ grade 2 in 48 hours.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Clinical Response Treated With E6 T Cell Receptor (TCR) T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions (HSIL)	3 months	Complete Response (CR) is disappearance of all target lesions. No appearance of new lesions. Partial Response (PR) is a ≥50% decrease in the sum of the product of the longest perpendicular diameters of target lesions, taking as reference the baseline measurements. No appearance of new lesions. No increase of greater than 25% of index lesion. Progressive disease is a ≥25% increase in the sum of the product of the longest perpendicular diameters of target lesions, taking as reference the smallest product on study (this includes the baseline product if that is the smallest on study). In addition to the relative increase of 25%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progression. Non-CR/Non-PD is neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest product of diameters while on study.
Number of Participants With Serious and Non-Serious Adverse Events	Date treatment consent signed to date off study, approximately 4 months and 17 days.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.