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Clinical Trial Summary

Background:

In gene transfer therapy, cells are taken from a person s tumor to isolate mutations. White blood cells are then taken from the person's body, changed with a type of virus to attack the tumor cells, and returned to the person.

Objective:

To see if gene transfer therapy shrinks tumors.

Eligibility:

People with certain metastatic cancer for which standard treatments have not worked

Design:

Participants will complete screening and stages 1-3 under another protocol. Screening includes:

Undergoing a biopsy or surgery at the NIH to obtain pieces of tumor in order to grow tumor cells

Medical history

Physical exam

Scans

Blood, urine, heart, and lung tests

The study has 7 stages:

1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. An IV catheter will be placed in the chest.

2. Care at home over 6-12 weeks.

3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.

4. Hospital stay for 1 week to get chemotherapy by IV.

5. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.

6. Recover in the hospital for 1 2 weeks. Participants will get drugs and have blood and urine tests.

7. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined.


Clinical Trial Description

Background:

- The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in 20-25% of patients with metastatic melanoma. Recent studies have shown that these TIL predominantly recognize unique mutated neoantigens expressed by the cancer not shared by other melanomas.

- Administration of bulk autologous TIL to patients with a variety of other solid cancers, including cancers of the gastrointestinal tract and genitourinary tract, have little if any therapeutic impact.

- Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown that TIL from non-melanoma solid cancers can also contain T-cells reactive against non-shared unique mutated neoantigens expressed in the cancer. The frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to isolate and grow mutation reactive T-cells to levels required for effective therapy.

- In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to grow a relatively pure population of neoantigen reactive TIL and administration of these cells mediated a near-complete regression of all metastatic disease now lasting 2.5 years.

- We have developed approaches to identify these rare neoantigen reactive T-cells from common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the autologous cancer in vitro.

- We are now proposing a clinical protocol to treat patients with refractory solid cancers using the adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize unique mutated neoantigens expressed by the cancer.

Objectives:

-Primary objective:

--Determine the rate of objective response (using RECIST v1.1 criteria) of patients with solid cancers who receive autologous PBL that have been transduced with genes encoding T-cell receptors that recognize mutated neoantigens in the autologous cancer.

Eligibility:

-Patients must be/have:

- Age greater than or equal to 18 years and less than or equal to 70 years

- Measurable solid cancer with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured, that falls into one of four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma. Metastatic disease is required for cohorts 1-3, but not for cohort 4.

- Evaluable solid cancer that has recurred following standard chemotherapy or standard systemic therapy

- Normal basic laboratory values.

- At least one lesion suitable for surgical resection for the preparation of the cell product

- No allergies or hypersensitivity to high-dose aldesleukin administration

- No concurrent major medical illnesses or any form of immunodeficiency.

Design:

- Patients will undergo resection or biopsy to obtain tumor for generation of autologous TIL cultures. This will be conducted under the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

- Patients will be entered into four cohorts: (1) gastrointestinal and genitourinary cancers, (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma. Exomic sequencing, and often RNA-Seq will be performed to identify the mutations expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and tested for reactivity against mutations from the autologous tumor using assays we have developed that involve the exposure of autologous antigen-presenting cells to long peptides containing the mutation or tandem mini-genes encoding the mutation.

- T-cell cultures with reactivity against mutations will be identified and the individual T-cell receptors that recognize the mutation will be synthesized and used to create a retrovirus for transduction of the TCR into the patient s autologous PBL.

- Transduced autologous PBL will then be expanded to large numbers using our standard rapid expansion protocol and administered to the patient following a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine. Patients will then begin high-dose aldesleukin after the infusion of autologous transduced PBL. At the discretion of the Principal Investigator (PI), patients enrolled in Cohort 3 may receive low-dose aldesleukin.

- Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion and periodically thereafter.

- It is anticipated that approximately one patient per month may enroll on the trial for each of the four histologic groups. Thus, accrual of up to 4 x 50=200 total evaluable patients may be completed in approximately 2-4 years. In order to allow for a small number of inevaluable patients, the accrual ceiling will be set to 210. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT03412877
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact Ellen Bodurian
Phone (866) 820-4505
Email IRC@nih.gov
Status Recruiting
Phase Phase 2
Start date September 6, 2018
Completion date March 23, 2028

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