Background:
A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells.
Objective:
To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors.
Eligibility:
Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors.
Design:
In another protocol, participants will:
Be screened
Have cells harvested and grown
Have leukapheresis
In this protocol, participants will have the procedures below.
Participants will be admitted to the hospital.
Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest.
A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter.
For up to 3 days, participants will get a drug to make the cells active.
A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin.
Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests.
Participants will take an antibiotic for at least 6 months.
Participants will have visits every few months for 2 years, and then as determined by their doctor.
Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn.
Participants will have blood collected over several years.
Measurable (per RECIST V1.1 criteria, metastatic, or unresectable malignancy expressing G12V mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.
Patients must be HLA-A*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.
Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
Patients with metastatic colorectal cancer must have had at least two systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin, and irinotecan (or similar agents), or have contraindications to receiving those medications.
Large volume pulmonary irradiation.
Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
Concurrent systemic steroid therapy.
Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
Sequential
Cyclophosphamide
DrugDays -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
Fludarabine
DrugDays -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Anti-KRAS G12V mTCR PBL
Biological/VaccineDay 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes (2-4 days after the last dose of fludarabine).
Aldesleukin
DrugAldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).
Response rate
Percentage of patients who have a clinical response (PR+CR) to treatment (objective tumor regression)
Frequency and severity of treatment-related adverse events
Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT
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