T-cells with a single tumor antigen-specific T-cell receptor can be generated in vitro from clinically relevant stem...

Area of Science:

• Immunotherapy
• Hematology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for B-cell malignancies but lacks optimal targets for acute myeloid leukemia (AML).
• T-cell receptor (TCR)-redirected T-cells target intracellular antigens, expanding therapeutic options beyond surface antigens.
• Current adoptive TCR T-cell therapy using peripheral blood lymphocytes risks graft-versus-host disease due to TCR chain mispairing.

Purpose of the Study:

• To investigate the feasibility of generating tumor antigen (TA)-specific T-cells from hematopoietic stem and progenitor cells (HSPC).
• To develop a T-cell therapy for AML that avoids graft-versus-host disease by using TCR-transduced HSPC.
• To assess the efficacy of using adult HSPC from various clinical sources for T-cell generation.

Main Methods:

• Hematopoietic stem and progenitor cells (HSPC) were isolated from healthy donors, AML patients in remission, and diagnosed AML patients.
• TCR-transduction of HSPC was performed using an in vitro co-culture system (OP9-DL1) with agonist selection.
• Maturation of TCR-transduced HSPC into mature, tumor antigen-specific T-cells expressing a single TCR was analyzed.

Main Results:

• The study demonstrates the feasibility of generating TA-specific T-cells from adult HSPC obtained from clinically relevant sources.
• TCR-transduced HSPC developed into mature T-cells with a single TCR, mitigating the risk of mispairing.
• While feasible, adult HSPC showed slower maturation and lower cell yield compared to cord blood HSPC; cryopreservation did not impact cell numbers or functionality.

Conclusions:

• Generating TA-specific T-cells from HSPC of adult healthy donors and patients is feasible.
• This approach offers a potential strategy for patient-tailored T-cell immunotherapy in AML.
• Utilizing HSPC as the starting material circumvents the risk of graft-versus-host disease associated with peripheral blood lymphocyte-based therapies.