Metastatic HPV-16 Positive Squamous Cell Anal Cancer Clinical Trial
Official title:
Single Patient Protocol: A Study Using the Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated or Viral Neoantigens in a Patient With Metastatic Cancer Plus the Administration of Pembrolizumab
Background: A cancer treatment has been developed called "gene transfer" or "gene therapy." It involves taking white blood cells from a person (called apheresis), genetically modifying the cells in a lab to recognize cancer, and then giving the cells back to the person. Researchers want to see if this treatment can help people with metastatic squamous cell anal cancer. Objective: To see if treating cancer with a person s own white blood cells that have been genetically modified can cause tumors to shrink. Eligibility: People who have metastatic squamous cell anal cancer for which standard treatments have not worked. Design: Participants will have had a tumor biopsy and apheresis to collect white blood cells under a separate protocol. Participants will stay at the hospital for 3 to 4 weeks. They will have an intravenous (IV) catheter placed in a large vein in the upper chest. Participants will get chemotherapy drugs (fludarabine and cyclophosphamide), the cell infusion, and aldesleukin through the IV. Pembrolizumab is given before and for three doses given every three weeks after the cell infusion. Aldesleukin will help the cells grow. Participants will take an antibiotic, antiviral, and antifungal by mouth. They will get an injection of filgrastim. It will stimulate the formation of white blood cells. Participants will have blood and urine tests. They will have physical exams. Their symptoms will be reviewed. They will have imaging scans. About 6 and 12 weeks after they finish treatment, participants will have safety follow-up visits. These visits will take 1 to 2 days. Participants will return to the Clinical Center every 3 to 6 months for 3 years, and then as determined by their doctor. They will be followed long term for up to 15 years on a separate study.
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 or viral 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 nonshared unique mutated neoantigens expressed in the cancer. The frequency of these Tcells 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 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. - In addition to reactivity to neoantigens derived from nonsynonymous mutations, T-cells can recognize human papilloma virus (HPV) epitopes in patients with HPV-induced cancers. The TCR from these reactive cells can be isolated and retrovirally-transduced into autologous PBL with high efficiency. This clinical protocol will treat a single patient with refractory anal cancer using the adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize unique mutated or viral neoantigens expressed by the cancer. Objective: -Under a single-patient IND, to treat a patient with metastatic HPV-16 positive squamous cell anal cancer with autologous peripheral blood lymphocytes (PBL) that have been transduced with genes encoding T-cell receptors that recognize mutated or viral neoantigens in the autologous cancer. Eligibility: - Must have measurable, metastatic disease as assessed per RECIST v1.1 criteria. - Must sign the informed consent document. - Willing to sign Durable Power of Attorney Form. - Must have all regulatory approvals prior to start of treatment. Design: - This patient will have already undergone resection or biopsy to obtain tumor for generation of autologous TIL cultures. This will have been conducted under the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols). - Exomic sequencing and 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 mutated and viral neoantigens will be identified and the individual T-cell receptors that recognize the neoantigens will be synthesized and used to create retroviral supernatants for transduction of the TCR into the patient s autologous PBL. - The patient will be treated with a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine, followed by the infusion of autologous transduced PBL and then high-dose aldesleukin. The patient will also receive pembrolizumab on Day -2 prior to cell administration and three additional doses every three weeks following the cell infusion. - Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion and periodically thereafter. ;