Sunday, May 18, 2025
5/18/2025
Preventing Relapse After Non-myeloablative Stem Cell Transplantation: The Final Challenge - PROJECT SUMMARY / ABSTRACT - OVERALL The overall goal of this program project grant is to overcome disease relapse, which is the single-most important limitation of allogeneic hematopoietic cell transplant (HCT) in the treatment of older or medically infirm patients with myeloid malignancies and myeloma. Two principal approaches are proposed, understanding and enhancing graft-vs-tumor (GVT) effects after HCT and reducing the pre-HCT tumor burden by intensifying the conditioning regimen through innovative, first-in-human radioimmunotherapy (RIT) that has been entirely developed in our laboratories. Project 1 will lead to an understanding of how to enhance GVT effects using studies in a in vivo murine model and in a human in vitro model. Enhancing GVT effects will likely become an effective means of reducing the relapse problem. Projects 2 and 3 will employ novel first-in-human RIT technology using alpha- emitter astatine-211 (211At) conjugated to monoclonal antibodies that was first developed in murine and large animal models. This is now applied clinically in Phase I/II trials in patients with myeloid malignancies who have pre-HCT tumor including refractory disease and in patients with multiple myeloma. The principle addressed here is reducing the pre-transplant tumor burden, thereby shifting the balance in favor of the transplanted allogeneic donor lymphocytes. While RIT with an antibody to CD45, as proposed in Project 1, has been tolerated well in the ongoing dose-escalation trial, we expect that liver toxicity will be dose-limiting for myeloid malignancies. In order to get around that problem and to further minimize the toxicity profile of targeted RIT directed against CD45, Project 1 proposes to develop fully anti-human CD45 MAbs, with a series of MAb isotypes/variants, and then test the hypothesis that in vivo off-target toxicity of the RIT can be further minimized and 211At-anti-CD45 RIT be optimized by engineering of the MAb Fc portion to remove the potential to interact with Fc receptors, especially in the liver. Clinical trials in Project 3 will begin with a CD38 target for RIT and will next optimize the approach by switching to a B-cell maturation antigen (BCMA) target in order to achieve better efficacy of myeloma cell kill. In summary, work on the three projects will use a two-pronged approach at decreasing post-HCT relapse rates among patients with myeloid malignancies and multiple myeloma, reducing the pre-HCT tumor burden and enhancing post-HCT tumor kill through GVT effects. The outcomes of these studies have obvious bearings on allogeneic HCT in older patients with other hematologic malignancies.
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