Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Malignancies
- Conditions
- Malignancy, HematologicNeoplasms, HematologicNeoplasms, HematopoieticBlood CancerHematological NeoplasmsHematopoietic MalignanciesDysmyelopoietic SyndromesHematopoetic MyelodysplasiaMyeloid Leukemia, AcuteNonlymphoblastic Leukemia, Acute
- Interventions
- Biological: Individual Patient TCR-Transduced PBLDevice: TruSight Oncology (TSO) 500
- Registration Number
- NCT06904066
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Blood cancers (such as leukemias) can be hard to treat, especially if they have mutations in the TP53 or RAS genes. These mutations can cause the cancer cells to create substances called neoepitopes. Researchers want to test a method of treating blood cancers by altering a person s T cells (a type of immune cell) to target neoepitopes.
Objective:
To test the use of neoepitope-specific T cells in people with blood cancers
Eligibility:
People aged 18 to 75 years with any of 9 blood cancers.
Design:
Participants will have a bone marrow biopsy: A sample of soft tissue will be removed from inside a pelvic bone. This is needed to confirm their diagnosis and the TP53 and RAS mutations in their cancer cells. They will also have a skin biopsy to look for these mutations in other tissue.
Participants will undergo apheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein.
The T cells will be grown to become neoepitope-specific T cells.
Participants receive drugs for 3 days to prepare their body for the treatment. The modified T cells will be given through a tube inserted into a vein. Participants will need to remain in the clinic at least 7 days after treatment.
Participants will have 8 follow-up visits in the first year after treatment. They will have 6 more visits over the next 4 years. Long-term follow-up will go on for 10 more years.
- Detailed Description
Background:
* Many difficult-to-treat hematologic malignancies carry mutations in the tumor suppressor gene TP53 or the oncogenes NRAS and KRAS (shortened to RAS).
* Missense mutations in TP53 and RAS result in immunogenic peptides (neoepitopes) that can be presented by human leukocyte antigens (HLA) to initiate an immune response.
* The NCI Surgery Branch has previously identified T-cell receptors (TCRs) that selectively recognize p53 or Ras neoepitopes.
* We propose to evaluate 3 TCRs targeting p53 neoepitopes and 4 TCRs targeting Ras neoepitopes in participants with hematologic malignancies.
* Several of these TCRs have already been evaluated in clinical trials enrolling subjects with solid tumors.
* We have shown that the TCRs have activity against hematologic malignancy cell lines in vitro and in vivo and have high specificity for only cells expressing the targeted mutation and the correct HLA.
Primary Objective:
-To determine the safety of administering neoepitope-specific T cells targeting p53 or Ras neoepitopes in combination with preparative conditioning chemotherapy and aldesleukin in participants with hematologic malignancies
Eligibility:
Participants must be/have:
* Myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, T-cell acute lymphoblastic leukemia/lymphoma, or multiple myeloma
* Age \>=18 and \<=75 years old
* The malignant cells must have a mutation in TP53 or RAS at a location targeted by one of a panel of TCRs.
* The participant must have the HLA type capable of presenting the targeted neoepitope.
* Recipients with relapsed or persistent malignancy after previous HLA-matched sibling or matched unrelated donor allogeneic hematopoietic stem cell transplant (alloHSCT) are eligible.
* AlloHSCT recipients must not have evidence of acute graft-versus-host disease (GVHD).
* AlloHSCT recipients must have no chronic GVHD or mild chronic GVHD as defined by NIH Consensus Development Project Criteria.
* Circulating malignant cells (blasts or plasma cells) must be 1% or less of peripheral white blood cells.
Design:
* This is an open-label, single center, non-randomized phase I trial
* Peripheral blood mononuclear cells (PBMCs) will be harvested by leukapheresis and cultured with anti-CD3 (OKT3) and aldesleukin to stimulate T-cell growth.
* The T cells will be genetically modified using a replication-incompetent gamma-retrovirus encoding a TCR.
* All participants will receive a chemotherapy conditioning regimen of cyclophosphamide and fludarabine.
* After the chemotherapy ends, participants will receive an infusion of the neoepitope-specific T cells and begin aldesleukin infusions.
* Following neoepitope-specific T-cell infusion, there is a mandatory inpatient hospitalization to monitor for toxicity.
* Frequent outpatient follow-up and malignancy assessment is planned after treatment.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 86
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Experimental: No allo-HSCT aldesleukin Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin. 1/Experimental: No allo-HSCT cyclophosphamide Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin. 1/Experimental: No allo-HSCT fludarabine phosphate Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin. 1/Experimental: No allo-HSCT Individual Patient TCR-Transduced PBL Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin. 1/Experimental: No allo-HSCT TruSight Oncology (TSO) 500 Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin. 2/Experimental: prior allo-HSCT aldesleukin Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin. 2/Experimental: prior allo-HSCT cyclophosphamide Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin. 2/Experimental: prior allo-HSCT fludarabine phosphate Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin. 2/Experimental: prior allo-HSCT Individual Patient TCR-Transduced PBL Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin. 2/Experimental: prior allo-HSCT TruSight Oncology (TSO) 500 Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin.
- Primary Outcome Measures
Name Time Method Safety From time of the lymphodepleting chemotherapy through 5 years after neoepitope-specific T cell infusion or until off study. Adverse Events (AE) per CTCAE v5.0, by type, grade, and frequency
- Secondary Outcome Measures
Name Time Method Overall response rate up to 5 years Defined by the Overall Response Rate (CR+PR) and the CR rate, duration of response. Duration of response will be calculated from the first date of a response until relapse, progression, or initiation of a new anti-malignancy therapy
Feasibility of manufacturing and administering neoepitope-specific T cells 30 days post treatment completion Feasibility will be measured as the fraction of participants with successful infusion of neoepitope-specific T-cell. Successful neoepitope-specific T-cell infusion will be achieved when at least 1x10\^10 total cells are infused
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Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States