Multi-functional cellular therapies to overcome tumor heterogeneity and limit toxicity in acute myeloid leukemia

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PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease with only 30% 5-year overall survival. As a blood cancer, AML appears poised to benefit from the revolution in engineered cellular therapies and bispecific antibodies. These agents are making an enormous impact in B-cell malignancies. However, extending this success to AML faces two significant hurdles: 1) lack of highly disease-specific targets, where engaging current AML therapeutic targets leads to severe cytokine release syndrome and severe myeloablation, precluding an effective therapeutic index; and 2) significant intratumoral heterogeneity, where targeting a single surface antigen is likely to lead to antigen-negative relapse. In practice, these two challenges leave few therapeutic targets sufficient to achieve cures in most patients. Here, my long-term goal is to develop a new therapeutic approach to overcome these hurdles. This proposal will be led by myself under the sponsorship of Dr. Arun Wiita, an expert in hematologic malignancies and drug resistance, with collaborative support from Dr. Kole Roybal, expert in advanced cellular engineering; and Dr. Jim Wells, expert in antibody engineering. Specifically, I hypothesize that employing SNIPR, the newly-described, next-generation, humanized platform based on the SynNotch cellular engineering technology (Zhu et al., Cell 2022), will enable development of a multi-functional T-cell therapy that can eliminate residual AML after induction chemotherapy, clearing relapse- driving leukemic stem cells and increasing cure rates, while avoiding toxicities of systemic therapeutics. My major design pillars include 1) develop engineered T-cells that home specifically to the leukemic stem cell niche; and 2) locally, but not systemically, have SNIPR T-cells secrete multiple protein therapeutics to ablate heterogenous leukemic stem cells and AML blasts in and near this niche. In Specific Aim 1, I test the feasibility and initial in vitro and in vivo potency of SNIPR engineered T-cells designed to simultaneously secrete functional bispecific antibodies against 3 AML targets. In Specific Aim 2, I use PDX models to test whether SNIPR T-cells can selectively home to the bone marrow niche, with CD70 as the optimal leukemic stem cell “trigger”. Successful completion of these Aims will set the stage for subsequent work, outside the scope of this proposal, to validate, using additional in vitro and in vivo models, the ability of CD70-sensing, multi-bispecific- secreting T-cells to eliminate AML more completely than other therapies while minimizing toxicities. Furthermore, this approach will ultimately enable delivery of other therapeutic payloads to the leukemic stem cell niche, ideally targeting this disease-driving cellular population with unprecedented precision. Success here may also outline a new therapeutic strategy for use across cancers, to eliminate heterogeneous tumor in the microenvironment while sparing normal cells. Completion of the work in this proposal in conjunction with the associated training plan will provide critical expertise and experience to support my goal of becoming an independent physician-scientist focused on translational immunotherapy research.