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:

• 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.