TCR-like CARs targeting GvL mHAgs for the treatment of post-transplant AML relapse
Nicoletta Cieri
MD, PhDDana-Farber Cancer Institute
Project Term: July 1, 2024 - June 30, 2026
AML recurrence is a devastating event after allo-HCT. I hypothesize that it could be counteracted through targeting of leukemia-restricted mHAgs via TCR-like CARs. I will identify scFVs recognizing mHAg:HLA complexes using a cell-free nanobody screening platform, and test the anti-leukemia activity and safety of CAR-Ts bearing such scFVs in vitro and in vivo. Through this approach, I will build a library of CAR constructs able to provide population-scale coverage for at-risk allo-HCT patients.
While modern cancer immunotherapy has revolutionized the treatment paradigm of many hematologic malignancies, its application to acute myeloid leukemia (AML) has been lagging behind because of the lack of safe targets that could be exploited for treatment. As a result, allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially life-saving option for AML patients so far, yet post-transplant relapse accounts for >50% of treatment failures. The curative effect of allo-HCT relies on donor’s cells (the graft) perceiving the recipient’s cells (the host) as foreign and attack and destroy them. Depending on the recognition of determinants present on leukemic cells or healthy tissues, donor cells can elicit beneficial graft-versus-leukemia (GvL) or detrimental graft-versus-host (GvH) reactions. I have developed an analytic framework to predict starting from paired DNA sequences of patients and their donors those genetic determinants, called minor histocompatibility antigens (mHAgs), potentially able to elicit GvL – and not GvH – reactions. As naturally occurring donor cells recognizing GvL mHAgs might not be numerically sufficient to counteract disease outgrowth, I propose to develop a novel approach that targets these GvL mHAgs when exposed on the surface of the leukemic cells, with a chimeric antigen receptor (CAR)-based immunotherapy. To this aim, I will perform an in-depth proteomic analysis of the GvL mHAgs displayed on the surface of AML cells in the context of HLA molecules, and then identify antibodies that specifically recognize the GvL mHAg:HLA complexes. Such antibodies will be then employed to build CAR constructs to arm and redirect donor cells. I will assess the safety (lack of killing of non-leukemic cells) and efficacy (prompt recognition of AML cells) both in vitro and in animal models.
I anticipate this approach could serve the basis for creating a library of CARs targeting different mHAgs, thus able to provide a personalized immunotherapy for all at-risk AML patients treated with allo-HCT in need.