Toward safer haploidnetical hematopoietic stem cell transplantation

Area of Science:

• Hematopoietic Stem Cell Transplantation
• Immunology
• Oncology

Background:

• Haploidentical HSCT is increasingly used but faces challenges with myeloablative protocols or prolonged immunosuppression.
• These challenges can negatively impact graft-versus-leukemia (GVL) effects and anti-pathogen immunity.

Purpose of the Study:

• To evaluate a novel conditioning protocol for haploidentical HSCT combining megadose T-cell depleted HSCT with post-transplant cyclophosphamide (PTCY).
• To explore the potential of donor-type veto T cells and Veto-CAR T cells for safer conditioning and cancer therapy.

Main Methods:

• A stringent murine bone marrow (BM) allografting model was used to test the combination of megadose TCD HSCT and PTCY.
• Preclinical experiments involved administering donor-type anti-third party central memory veto T cells with megadose TCD HSCT.
• Murine studies demonstrated the survival of genetically engineered veto cells armed with cancer-specific receptors in allogeneic recipients.

Main Results:

• The combined megadose TCD HSCT and PTCY protocol enabled durable chimerism induction without graft-versus-host disease (GVHD) in the absence of post-transplant immunosuppression.
• Initial patient outcomes in multiple myeloma and Hodgkin's disease suggest this protocol is safe and effective for haploidentical HSCT.
• Donor-type veto T cells showed potential as an additional tool for safer conditioning protocols.
• Genetically manipulated veto cells armed with cancer-specific receptors survived long-term in allogeneic recipients.

Conclusions:

• The combination of megadose TCD HSCT and PTCY presents a promising, safer alternative for haploidentical HSCT.
• Veto T cells and Veto-CAR T cells offer potential advancements for conditioning protocols and off-the-shelf cancer immunotherapy.