Wednesday, May 15, 2024
5/15/2024
PROJECT SUMMARY Post-transplant cyclophosphamide (PTCy) has substantially reduced the risk of lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (alloHCT). However, like other forms of GVHD prophylaxis, PTCy still relies upon passive graft-versus-leukemia (GVL) to prevent disease relapse. Progression-free survival after alloHCT is largely limited to 41-50%. Thus, concurrent GVHD and leukemia relapse prevention remains a critical unmet need in transplantation. Innovation in alloHCT must now maintain GVHD prevention at the level of PTCy and add tools to directly reduce relapse and not simply maintain or preserve GVL. Distinct from pharmacologic immune suppression, we have developed novel, human, CD83-targeted chimeric antigen receptor (CAR) T cells for concurrent protection against relapse of CD83+ leukemia as well as GVHD. CD83 is a member of the immunoglobulin superfamily. We show CD83 is expressed on human myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and alloreactive T cells implicated in GVHD. Importantly, we have demonstrated that CD83 CAR T cells kill leukemia in vivo and eradicate GVHD without impairing antiviral immunity. Further, CD83 is largely absent from hematopoietic stem cells, myeloid progenitors, and neutrophils, limiting the risk for on-target/off-tumor toxicity or myeloid aplasia. We also developed an ‘OR’ logic gated CD19/CD83 CAR T that can kill B cell ALL that expresses either CD19 OR CD83 via a shared activating endodomain. We show that our ‘OR’ gated CD19/CD83 CAR T can overcome CD19 antigen loss, which is clinically seen in 25% of ALL patients after treatment with CD19 mono- CAR T. In this application, we will (Aim 1, mouse experiments) test whether human CD83-targeted CAR T cells can concurrently prevent leukemia relapse and GVHD, as compared to standard PTCy. To parallel expected initial clinical trials, we will also investigate the sequential use of CD83 CAR T consolidation after PTCy to eliminate leukemia relapse and GVHD. Our preliminary data demonstrates that CD83 is expressed on CD4+ conventional T cells during acute GVHD, as well as B cells and T helper follicular cells during chronic GVHD. Thus, (Aim 2, biomarker validation study) we will investigate whether CD83 is a biomarker and therapeutic target among effectors of acute and chronic GVHD onset and therapeutic response. Successful completion of this work will guide the seamless transition from discovery to clinical translation of human CD83 CAR T cells to concurrently eliminate life-threatening relapse and GVHD after alloHCT.
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