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

NCT06904066 | Recruiting Phase 1 FDA Drug FDA Device

• 2 other identifiers: 10002088002088-C
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

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.

Conditions

Malignancy, Hematologic; Neoplasms, Hematologic; Blood Cancer; Hematopoietic Malignancies; Neoplasms, Hematopoietic; Hematological Neoplasms; Dysmyelopoietic Syndromes; Hematopoetic Myelodysplasia; Myeloid Leukemia, Acute; Nonlymphoblastic Leukemia, Acute; Leukemia, Lymphocytic, Acute

Keywords

Gene Therapy; T cell immunotherapy; Engineered T cell receptor; Hematologic Malignancies; Tumor-Associated Antigen; Myelodysplastic Syndrome; Neoepitope-specific T cells; T-cell acute lymphoblastic leukemia; Adoptive T Cell Therapy; Chronic Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Safety

  Adverse Events (AE) per CTCAE v5.0, by type, grade, and frequency

  From time of the lymphodepleting chemotherapy through 5 years after neoepitope-specific T cell infusion or until off study.

Secondary Outcomes (2)

• Overall response rate

  up to 5 years

• Feasibility of manufacturing and administering neoepitope-specific T cells

  30 days post treatment completion

Study Arms (2)

1/Experimental: No allo-HSCT

EXPERIMENTAL

Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin.

Drug: aldesleukin; Drug: cyclophosphamide; Drug: fludarabine phosphate; Biological: Individual Patient TCR-Transduced PBL; Device: TruSight Oncology (TSO) 500

2/Experimental: prior allo-HSCT

EXPERIMENTAL

Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin.

Drug: aldesleukin; Drug: cyclophosphamide; Drug: fludarabine phosphate; Biological: Individual Patient TCR-Transduced PBL; Device: TruSight Oncology (TSO) 500

Interventions

aldesleukin DRUG

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).

1/Experimental: No allo-HSCT; 2/Experimental: prior allo-HSCT

fludarabine phosphate DRUG

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.

1/Experimental: No allo-HSCT; 2/Experimental: prior allo-HSCT

cyclophosphamide DRUG

300 mg/m\^2 IV infusion over 30 minutes. Daily x 3 doses on days -5, -4, -3.

1/Experimental: No allo-HSCT; 2/Experimental: prior allo-HSCT

Individual Patient TCR-Transduced PBL BIOLOGICAL

Up to 1.5x10\^11 total cells for non-transplant subjects. 1x10\^10 total cells for post-alloHSCT subjects.

1/Experimental: No allo-HSCT; 2/Experimental: prior allo-HSCT

TruSight Oncology (TSO) 500 DEVICE

TSO500 sequencing panel performed in the NCI Laboratory of Pathology to detect TP53 or RAS mutations

1/Experimental: No allo-HSCT; 2/Experimental: prior allo-HSCT

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Malignancy diagnosis requirements:
• Eligible diagnoses include AML (acute myeloid leukemia), MDS (myelodysplastic syndrome), CMML(chronic myelomonocytic leukemia), CML (chronic myeloid leukemia), and T-ALL (T-acute lymphoblastic leukemia/lymphoma) meeting standard diagnostic criteria as described in the 5th edition World Health Organization Classification of Hematologic Tumors and/or the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Multiple myeloma participants meeting International Working Group diagnostic criteria are eligible. These diagnostic criteria can be met at any time during the course of the participant s malignancy. Atypical CML is not an eligible diagnosis.
• NOTE: Pathology reports are acceptable to confirm eligibility.
• Malignancy mutation and HLA requirements:
• Detection of at least one of the neoepitope-forming TP53 or RAS mutations that are listed in Table 3 in on the TruSight Oncology (TSO) 500 sequencing panel (NSR device) performed in the NCI Laboratory of Pathology is required. RAS mutations can be in NRAS, KRAS or HRAS as these oncogenes have the same amino acid sequence at the location of the targeted neoepitopes. A variant allele frequency (VAF) of at least 5% is required for a mutation to be eligible. This criterion can be met at any time within 60 days prior to apheresis regardless of treatment history during this 60-day period. DNA for sequencing comes from bone marrow.
• Presence of the correct HLA type needed to present one of the targeted neoepitopes as shown in Table 3. HLA typing data from any time-point prior to apheresis can be used to meet this requirement.
• Table 3: Eligibility requirements for the targeted mutation and HLA type
• Targeted mutation - TP53 R175H; HLA Type - A\*02:01
• Targeted mutation - TP53 Y220C; HLA Type - A\*02:01
• Targeted mutation - TP53 R248W; HLA Type - A\*68:01
• Targeted mutation - Ras G12V; HLA Type - A\*11:01
• Targeted mutation - Ras G12D; HLA Type - A\*11:01
• Targeted mutation - Ras G12D; HLA Type - C\*08:02
• Targeted mutation - Ras G12V; HLA Type - C\*01:02
• Malignancy burden requirements:

You may not qualify if:

• For alloHSCT recipients only, subjects receiving any systemic immunosuppressive drugs including corticosteroids at doses of greater than 5 mg/day prednisone or equivalent within 28 days prior to apheresis.
• NOTE: Topical corticosteroid preparations applied to the skin such as solutions, creams, and ointments are allowed. Inhaled corticosteroids are allowed, and corticosteroid eye drops are allowed.
• Corticosteroids given for any indication at doses greater than 5 mg/day of prednisone or equivalent within 14 days before either apheresis or start of protocol chemotherapy.
• Participants with MDS/Myeloproliferative neoplasia overlap syndromes are not eligible.
• Participants with acute promyelocytic leukemia are not eligible.
• Participants who received a mis-matched sibling or haploidentical transplant are not eligible.
• Tumor masses \>=10 cm in largest diameter
• Positive beta Human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test in IOCBP performed at screening.
• Human T-cell lymphotropic virus type 1/ 2 (HTLV-1/II) positive
• HIV infection, as measured by seropositivity for HIV antibody.
• Participants that require urgent therapy due to tumor mass effects on vital organ or tumor lysis syndrome.
• Any significant illness that, in the opinion of the principal investigator, may impair the participant s tolerance of the study treatment as evaluated by medical history, physical exam, assess for hepatosplenomegaly, and chemistry laboratory evaluations.
• Participants with a history of a previous malignancy are ineligible if the malignancy has not been in complete remission for at least 2 years or if the previous malignancy required treatment with surgery, radiation, or chemotherapy, including maintenance hormonal therapy, in the past 2 years. Exceptions to this requirement are participants who have had successful resection of the following types of skin cancer: nonmetastatic basal cell carcinoma or squamous cell carcinoma or stage 0 melanoma.
• Suspected or confirmed active uncontrolled infections defined as fevers of \>38 degrees within the past 24 hours without a known non-infectious source or participants requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours.
• Acti...

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hematologic Neoplasms; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

aldesleukin; Cyclophosphamide; fludarabine phosphate

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• James N Kochenderfer, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Genevieve C Fromm

CONTACT

(240) 858-3663; NCICAR@mail.nih.gov

James N Kochenderfer, M.D.

CONTACT

(240) 760-6062; kochendj@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2025
• First Posted: April 1, 2025
• Study Start (Estimated): April 21, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029
• Last Updated: April 16, 2026

Record last verified: 2026-03-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available until completion of the primary endpoint.
• Access Criteria: Clinical data will be made available with the permission of the study PI. Clinical data at NIH will also be available via subscription to BTRIS.

Locations

US (1)