Selective treatment of acute myeloid leukemia with radioimmunotherapies targeting the active conformation of integrin beta-2

PROJECT SUMMARY/ABSTRACT The Problem: Acute myeloid leukemia is a common blood cancer diagnosed in >20,000 Americans per year, but current therapies only lead to a dismal 5-year survival of ~30%. New treatments are urgently needed. While antibody-based immunotherapies targeting tumor surface proteins have made a great impact for other cancers, they have been stymied in AML due to a lack of targets with acceptable efficacy vs. safety profile. Our Solution to the Problem: In work recently published at Nature Cancer and funded by an NCI R21, we described a new proteomic technology allowing us to identify novel immunotherapy targets based on cell surface protein conformations. We used this approach to identify the open, active conformation of integrin β2 (aITGB2) as promising surface antigen in AML. We developed a conformation-specific antibody (clone 7065), that, when incorporated into CAR T cells, showed equal efficacy but much improved safety profile compared to other leading AML targets. For clinical translation, however, AML has been very challenging for CAR T. Here, we thus sought to leverage this antibody clone in an independent, highly promising therapeutic strategy: as a radioimmunotherapy (RIT) conjugate with 225Actinium. Similar agents against different targets have recently been FDA-approved in prostate cancer and neuroendocrine tumors. Though enthusiasm is high, this modality’s potential in other tumors must still be proven. In a collaborative study, our groups have recently demonstrated the promise of RIT for another blood cancer, multiple myeloma (Wadhwa et al, Clin Cancer Res (2024)). Our promising preliminary data here strongly supports the potential of treating AML with a 7065-based RIT. Hypothesis, Objectives, Aims, and Deliverables: Only one other similar RIT has gone into clinical investigation for AML, targeting the surface antigen CD33. Unlike aITGB2, however, CD33 is widely expressed on normal hematopoietic cells, leading to a narrow therapeutic index. Given the more tumor-selective nature of aITGB2, we hypothesize a 7065-based RIT will create a best-in-class therapeutic for AML with a promising efficacy vs. safety profile. Our objective is to complete a rigorous preclinical validation of this therapeutic using state-of-the- art model systems. We will complete this objective across three Aims, evaluating 7065 RIT’s 1) preclinical efficacy; 2) preclinical toxicity; 3) combination efficacy with a standard AML therapeutic, venetoclax, and potential mechanisms of resistance to 7065 RIT. This last Aim will motivate a future Phase I trial design as well as allow anticipation and mitigation of potential therapeutic failure modes. At the successful conclusion of this award, we will produce a data package highly supportive of near-term clinical translation of this approach. The Team: The PIs bring synergistic expertise in hematologic malignancy research, cancer immunotherapy, and radionuclide-based theranostics, enabling the rigorous preclinical evaluation of this innovative therapeutic. Impact: The findings here will directly motivate a near-term Phase I clinical trial of 7065-based RIT, ideally validating a best-in-class therapeutic option for AML patients urgently in need of new options.