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.
Name: Cyclophosphamide
Description: Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mlD5W with Mesna 15 mg/kg/day X 2 days over 1 hr.Type: Drug1/Phase I 2/Phase II
Name: Fludarabine
Description: Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.Type: Drug1/Phase I 2/Phase II
Name: anti-KRAS G12V mTCR
Description: Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.Type: Biological1/Phase I 2/Phase II
Name: Aldesleukin
Description: Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).Type: Drug1/Phase I 2/Phase II
Description: 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, every 6 months x2 years, then per PI discretionDescription: Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels.
Measure: Maximum Tolerated Cell Dose (MTD) Time: Before progression to next higher dose levelDescription: TCR and vector presence will be quantitated in PBMC samples using established PCR techniques
Measure: In vivo survival of mTCR gene engineered cells Time: Batched and assayed at the conclusion of the studyAllocation: Non-Randomized
Sequential Assignment
There is one SNP
A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12V ---
Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients 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. --- G12V ---
This therapy is called gene transfer using anti-KRAS G12V mTCR cells. --- G12V ---
Eligibility: Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors. --- G12V ---
A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter. --- G12V ---
- INCLUSION CRITERIA: - Measurable metatstatic 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. --- G12V ---
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. --- G12V ---
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. --- G12V --- --- G12V ---
Patients who are receiving any other investigational agents - INCLUSION CRITERIA: - Measurable metatstatic 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. --- G12V ---
Patients who are receiving any other investigational agents Pancreatic Cancer Gastric Cancer Gastrointestinal Cancer Colon Cancer Rectal Cancer Pancreatic Neoplasms Gastrointestinal Neoplasms Background: - We generated an HLA-A*11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12V-mutated variant of KRAS (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains its alpha and beta chains that confers recognition of this antigen when transduced into PBL. --- G12V ---
Objectives: Primary objectives: - Phase I: determine the safety of administering PBL transduced with anti-KRAS G12V mTCR in concert with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin). --- G12V ---
- Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12V mutation. --- G12V ---
- Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12V mutation. --- G12V --- --- G12V ---
Eligibility: Patients must be/have: - Age greater than or equal to 18 years and less than or equal to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12V-expressing cancer which has progressed after standard therapy (if available). --- G12V ---
Design: - This is a Phase I/II, single center study of PBL transduced with anti-KRAS G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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. --- G12V ---
Design: - This is a Phase I/II, single center study of PBL transduced with anti-KRAS G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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. --- G12V --- --- G12V ---
- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12V mTCR. --- G12V ---
- On day 0 patients will receive their PBL transduced with the anti-KRAS G12V mTCR and will then begin high-dose aldesleukin. --- G12V ---
- 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 pancreatic cancer and Cohort 2b: all other RAS G12V non-pancreatic cancers - A total of 110 patients may be required; approximately 24 patients in the phase I portion of the study and 86 (41, plus an allowance of up to 2 non-evaluable per phase II cohort) patients in the phase II portion of the study. --- G12V ---