Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

Background: * We generated an human leukocyte antigen (HLA)-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the Glycine(G) to Aspartic Acid(D) substitution at codon 12 (G12D)-mutated variant of Kirsten rat sarcoma virus (KRAS) (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into peripheral blood lymphocytes (PBL). * In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR transduced T-cells lyse target cells and secrete interferon (IFN)-gamma with high specificity. Objectives: -Primary objectives: * Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin). * Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the rat sarcoma (RAS) G12D mutation. Eligibility: * Patients must be/have: * Age greater than or equal to 18 years and less than or equal to 72 years * HLA-A\*11:01 positive * Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). * Patients may not have: * Allergies or hypersensitivities to high dose aldesleukin, cyclophosphamide, or fludarabine. Design: * This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A\*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. * PBMC obtained by leukapheresis will be cultured in the presence of anti-cluster of differentiation 3 (CD3) Ortho-Kung T-cell 3 (OKT3) and aldesleukin in order to stimulate T-cell growth. * Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. * All patients will receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine. * On Day 0, patients will receive their PBL transduced with the anti-KRAS G12D mTCR and will then begin high dose aldesleukin. * A complete evaluation of lesions will be conducted approximately 6 weeks (plus-minus 2 weeks) after treatment. * The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. * A total of up to 70 patients may be required; approximately 24 patients in the Phase I portion of the study and 46 (21, plus an allowance of up to 2 non-evaluable per Phase II cohort) patients in the Phase II portion of the study.