Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations in Conjunction With a Vaccine Directed Against These Antigens in Participants With Metastatic Cancer

Background: * The majority of cancer deposits from patients with melanoma or solid epithelial cancers contain tumor infiltrating lymphocytes (TIL) that can recognize unique mutated neoantigens expressed by the cancer. * Administration of autologous TIL to patients with metastatic melanoma can mediate complete durable regression in up to 24% of patients with metastatic melanoma. The administration of TIL from patients with solid epithelial cancers mediate far fewer clinical responses probably because the frequency of these anti-tumor T cells in solid epithelial cancers is very low (often less than 0.1%). * We have developed approaches to adoptive cell transfer (ACT) therapy that involves isolating T-cell receptors (TCR) that recognize mutated cancer neoantigen. These TCRs are transduced into autologous peripheral lymphocytes to express these TCRs with high efficiency. These neoantigen TCR gene-modified cells can recognize and destroy the autologous cancer in vitro. * In a single patient with chemo-refractory metastatic colon cancer, we identified a rare population of neoantigen reactive TIL targeting the KRAS G12D hotspot mutation and administration of these TIL mediated a near-complete regression of all metastatic disease now lasting over 5 years. The administration of cells genetically modified to express anti KRAS G12D receptors obtained from this patient have now been used to mediate regression of metastatic pancreatic cancer in a patient containing a G12D mutation. Using targeted screening and in vitro sensitization of PBL and TIL, we have now identified a library of TCRs capable of recognizing the KRAS G12D or KRAS G12V shared mutations restricted by a variety of Class I or Class II MHC restriction elements. * In murine experiments utilizing T-cell receptors against mutated antigens, we have shown that cells bearing these receptors are far more effective in mediating anti-tumor responses against established tumors when cell administration is combined with a vaccine targeting the same antigen targeted by the T cells. * Gritstone bio has developed a prime boost adenoviral/mRNA vaccine targeting KRAS G12D and G12V shared mutations. * The clinical protocol described here will treat participants with chemorefractory solid cancers that express G12D or G12V KRAS mutations using the adoptive transfer of autologous lymphocytes transduced with genes encoding TCRs that recognize these mutations in conjunction with the administration of an anti-KRAS vaccine. Objectives: -Primary objective: --Determine the safety and efficacy of administering autologous T cells transduced to express receptors targeting KRAS G12D or G12V mutations in conjunction with an anti-KRAS vaccine to participants with metastatic solid cancers that contain KRAS G12D or G12V mutations. Eligibility: -Participants must be/have: * Age \>= 18 years and \<= 72 years * Metastatic cancer that expresses either the KRAS G12D or KRAS G12V hotspot mutation for which the Surgery Branch has identified TCRs capable of recognizing these antigens with appropriate MHC restriction. * Evaluable solid cancer that has recurred following standard systemic therapy. * Adequate basic laboratory values. * No concurrent major medical illnesses or any form of immunodeficiency. Design: * Participants who have cancers demonstrated to contain KRAS G12D or G12V genetic mutations in the autologous cancer will be included. * T-cell receptors that recognize KRAS G12D or G12V mutations will be inserted into participant PBL and used for cell transfer immunotherapy. Participants will also receive a KRAS prime-boost vaccine that expresses G12D and G12V hotspot mutation epitopes. * Participants will be enrolled into one of four cohorts: (1) G12D KRAS mutations treated with TCRs recognizing these mutations restricted by Class I MHC molecules, (2) G12D KRAS mutations treated with TCRs recognizing these mutations restricted by Class II MHC molecules, (3) G12V KRAS mutations treated with TCRs recognizing these mutations restricted by Class I MHC molecules, (4) G12V KRAS mutations treated with TCRs recognizing these mutations restricted by Class II MHC molecules. * Clinical and immunologic responses will be evaluated about 4-6 weeks after cell infusion and periodically thereafter. * It is anticipated that approximately 3 participants may enroll on the trial each month. There will be an initial limit of 21 evaluable participants per cohort for a total of 84 evaluable participants. Thus, the initial accrual may be completed in approximately 3 years. Any group moving to a second-stage evaluation would accrue an additional 29 evaluable participants over approximately two years for a potential total of 200 evaluable participants.