Trials / Recruiting

RecruitingNCT06904066

Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Malignancies

A Phase I Study of Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Other Hematologic Malignancies

Status: Recruiting
Phase: Phase 1
Study type: Interventional
Enrollment: 86 (estimated)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 18 Years – 120 Years
Healthy volunteers: Not accepted

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.

Conditions

Interventions

Type	Name	Description
DRUG	aldesleukin	Aldesleukin 600,000 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 4 days (maximum 10 doses).
DRUG	cyclophosphamide	300 mg/m\^2 IV infusion over 30 minutes. Daily x 3 doses on days -5, -4, -3.
DRUG	fludarabine phosphate	30 mg/m\^2 IV infusion over 30 minutes administered immediately following cyclophosphamide on day -5, -4, -3. Participants with renal dysfunction receive a lower dose of fludarabine.
BIOLOGICAL	Individual Patient TCR-Transduced PBL	Up to 1.5x10\^11 total cells for non-transplant subjects. 1x10\^10 total cells for post-alloHSCT subjects.
DEVICE	TruSight Oncology (TSO) 500	TSO500 sequencing panel performed in the NCI Laboratory of Pathology to detect TP53 or RAS mutations

Timeline

Start date: 2026-04-22
Primary completion: 2029-04-30
Completion: 2029-04-30
First posted: 2025-04-01
Last updated: 2026-04-17

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study
FDA-regulated device study

Source: ClinicalTrials.gov record NCT06904066. Inclusion in this directory is not an endorsement.