This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients who express the KRAS G12V mutation and HLA-A*11:01 allele. The theoretical basis of this study is that mutant KRAS antigen-specific TCR transduced autologous Tcells will target and kill HLA-matched mutant KRAS cancer cells but not normal cells.

Hotspot KRAS mutations exist in various cancers, especially pancreatic, lung and colorectal cancer. Mutations in KRAS are implicated in the development of pancreatic cancer and are associated with poor prognosis of the patients. KRAS is an attractive target for cancer treatment because it is a driver mutation and is likely expressed by all cells in a tumor. Recently,T cells targeting mutant KRAS have been identified in patients with epithelial cancers, and these T-cell receptors (TCR) have been characterized. For example, TCRs that target mutant KRAS G12D peptides presented by HLA-C*08:02, and a TCR that targets a KRAS G12V peptide presented by HLA-A*11:01 have been identified. Mutant KRAS-reactive T cells appear capable of inducing tumor regression as highlighted in a patient with metastatic colorectal cancer who experienced regression of metastatic tumors after infusion of HLA-C*08:02-restricted KRAS-G12D reactive tumor-infiltrating lymphocytes (TIL). The investigators will test the safety and activity of adoptive transfer of autologous T cells genetically engineered to express a TCR that targets mutant KRAS G12V in the context of HLA-A*11:01 in HLA-matched patients with advanced pancreatic cancer that express mutant KRAS G12V. The investigators will also measure the in vivo survival of engineered T cells.

Inclusion Criteria:

• Patients with measurable and pathologically confirmed advanced pancreatic cancer, including metastatic pancreatic cancer (who have received standard chemotherapy) and recurrent pancreatic cancer (who have received surgery and adjuvant chemotherapy previously).

• Patient's tumor must express the KRAS G12V mutation, or a G12V mutation in HRAS or NRAS, as determined by DNA or RNA sequencing methods.

• Patients must be HLA-A*11:01.

• Patients with brain metastasis may be eligible if they are asymptomatic and there are fewer than 3 brain lesions that are each less than 1 cm in diameter.

• Patients between 18 to 75 years old are eligible.

• Patients should have good clinical performance status (ECOG 0 or 1).

• Patients must practice birth control once enrolled into the study and for up to four months after therapy.

• Patients must be seronegative for HIV antibody.

• Patients must be seronegative for hepatitis B surface antigen and core antibody (or HBV non-detectable by QPCR).

• Patients must be seronegative for hepatitis C antibody (or HCV non-detectable by QPCR).

• Baseline hematology criteria:

  • Absolute neutrophil count of at least 1000/mm^3.
  • White blood cell count of at least 3000/mm^3.
  • Platelet count of at least 100,000/mm^3.
  • Hemoglobin > 8.0 g/dL.

• Baseline chemistry criteria:

  • Serum ALT/AST less than or equal to 3.0 x ULN.
  • Total bilirubin less than or equal to 1.5 mg/dL, unless the patient has Gilbert's Syndrome in which case total bilirubin must be less than or equal to 3.0 mg/dL.
  • Serum creatinine less than or equal to 1.6 mg/dL.

• Anticipated lifespan greater than 12 weeks.

• Patients must be willing and able to comply with all study-related procedures and follow-up requirements.

• Patients must be able to understand and sign a written Informed Consent Document as well as a durable power of attorney.

Exclusion Criteria:

• Women who are pregnant or breastfeeding.
• Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or HIV).
• Patients with active systemic infections, coagulation disorders, or any other major medical illnesses.
• Patients with concurrent opportunistic infections.
• Patients on concurrent systemic steroid therapy.
• Patients with a history of severe immediate hypersensitivity reaction to any of the medicines used in this study (e.g., cyclophosphamide, fludarabine).
• Patients with active coronary ischemic symptoms.
• Patients who are receiving any other investigational agents.