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

-INCLUSION CRITERIA:

1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancyexpressing G12D mutated KRAS as assessed by one of the following methods: RT-PCR ontumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. Patients shown to have tumors expressing G12D mutated NRAS and HRASwill also be eligible as these oncogenes share complete amino acid homology withG12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassingthe target epitope.

2. Patients must be HLA-A*11:01 positive as confirmed by the NIH Department ofTransfusion Medicine.

3. Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.

4. Patients must have:

-previously received standard systemic therapy for their advanced cancer and havebeen either non-responders or have recurred, specifically:

• Patients with metastatic colorectal cancer must have had at least two systemicchemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin,and irinotecan (or similar agents), or have contraindications to receivingthose medications.

• Patients with pancreatic cancer must have received gemcitabine, 5FU, andoxaliplatin (or similar agents), or have contraindications to receiving thosemedications.

• Patients with non-small cell lung cancer (NSCLC) must have had appropriatetargeted therapy as indicated by abnormalities in ALK, EGFR, or expression ofPDL-1. Other patients must have had platinum-based chemotherapy.

• Patients with ovarian cancer or prostate cancer must have had approvedfirst-line chemotherapy. OR

-declined standard treatment.

5. Patients with 3 or fewer brain metastases that are < 1 cm in diameter andasymptomatic are eligible. Lesions that have been treated with stereotacticradiosurgery must be clinically stable for one month after treatment for the patientto be eligible. Patients with surgically resected brain metastases are eligible.

6. Age greater than or equal to 18 years and less than or equal to 72 years.

7. Clinical performance status of ECOG 0 or 1

8. Patients must be willing to practice birth control from the time of enrollment onthis study and for 12 months after the last dose of combined chemotherapy for womenand for four months after treatment for men..

9. Women of child-bearing potential must be willing to undergo a pregnancy test priorto the start of treatment because of the potentially dangerous effects of thetreatment on the fetus. NOTE: Certain malignancies may secrete hormones that produce false positivepregnancy tests. Serial blood testing (e.g. HCG measurements) and/ or ultrasound maybe performed for clarification.

10. Serology

-Seronegative for HIV antibody. (The experimental treatment being evaluated in thisprotocol depends on an intact immune system. Patients who are HIV seropositive mayhave decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)

-Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. Ifhepatitis C antibody test is positive, then patient must be tested for the presenceof antigen by RT-PCR and be HCV RNA negative

11. Hematology

• ANC > 1000/mm^3 without the support of filgrastim

• WBC greater than or equal to 2500/mm^3

• Platelet count greater than or equal to 80,000/mm^3

• Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off.

12. Chemistry

• Serum ALT/AST less than or equal to 5.0 x ULN

• Serum creatinine less than or equal to 1.6 mg/dL

• Total bilirubin less than or equal to 2.0 mg/dL, except in patients withGilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL.

13. Patients must have completed any prior systemic therapy at the time of enrollment. Note: Patients may have undergone minor surgical procedures or limited fieldradiotherapy within the four weeks prior to enrollment, as long as related majororgan toxicities have recovered to less than or equal to grade 1.

14. Ability of subject to understand and the willingness to sign a written informedconsent document.

15. Willing to sign a durable power of attorney.

16. Subjects must be co-enrolled on the protocol 03C0277.

EXCLUSION CRITERIA:

1. Women of child-bearing potential who are pregnant or breastfeeding because of thepotentially dangerous effects of the treatment on the fetus or infant.

2. Concurrent systemic steroid therapy.

3. Active systemic infections requiring anti-infective treatment, coagulationdisorders, or any other active or uncompensated major medical illnesses.

4. Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

5. Concurrent opportunistic infections (The experimental treatment being evaluated inthis protocol depends on an intact immune system. Patients who have decreasedimmune-competence may be less responsive to the experimental treatment and moresusceptible to its toxicities.)

6. History of severe immediate hypersensitivity reaction to cyclophosphamide,fludarabine, or aldesleukin.

7. History of coronary revascularization or ischemic symptoms.

8. For select patients with a clinical history prompting cardiac evaluation: last knownLVEF less than or equal to 45%.

I. For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50%.

j. Patients who are receiving any other investigational agents.