Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.
Name: Cyclophosphamide
Description: Days -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.Type: Drug1/Phase I 2/Phase II
Name: Fludarabine
Description: Days -7 to -3: Fludarabine 25 mg /m^2/day IVPB daily over 30 minutes for 5 days.Type: Drug1/Phase I 2/Phase II
Name: Aldesleukin
Description: Aldesleukin 720,000 IU/kg (based on total body weight) IV over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).Type: Drug1/Phase I 2/Phase II
Name: anti-KRAS G12D mTCR PBL
Description: Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes.Type: Biological1/Phase I 2/Phase II
Description: Aggregate of all adverse events, as well as their frequency and severity
Measure: Frequency and severity of treatment-related adverse events Time: 5 years following cell infusionDescription: Percentage of patients who have a clinical response to treatment (objective tumor regression)
Measure: Response rate Time: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per PI discretionDescription: TCR and vector presence will be quantified in PBMC samples using established PCR techniques
Measure: In vivo survival of mTCR geneengineered cells Time: Batched and assayed at the conclusion of the studyAllocation: Non-Randomized
Parallel Assignment
There is one SNP
Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12D ---
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: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. --- G12D ---
It is called gene transfer using anti-KRAS G12D mTCR cells. --- G12D ---
Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. --- G12D ---
-INCLUSION CRITIERIA: 1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy expressing G12D 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. --- G12D ---
Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D ---
Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D --- --- G12D ---
2. Confirmation of G12D mutated KRAS, NRAS, or HRAS by the NCI Laboratory of Pathology. --- G12D ---
Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer Pancreatic Neoplasms Gastrointestinal Neoplasms Background: - We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of 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 PBL. --- G12D ---
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). --- G12D ---
- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D ---
- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D --- --- G12D ---
Eligibility: - Patients must be/have: - Age greater than or equal to 18 years and less than or eqaul to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). --- G12D ---
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-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D ---
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-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D --- --- G12D ---
- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. --- G12D ---
- On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin. --- G12D ---
- 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. --- G12D ---
- 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. --- G12D --- --- G12D ---