Combining immunotherapy with molecularly targeted radiation therapy

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PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICI) have limited single agent activity in metastatic castration resistant prostate cancer (mCRPC), in part related to the low number of tumor-infiltrating lymphocytes (TILs) relative to more responsive tumor types. Radiation therapy (RT) may enhance immunotherapy by either enhancing priming of an immune response and/or resetting the immunosuppressive tumor microenvironment to enhance effector function. Understanding the mechanisms by which RT can enhance immunotherapy in mCRPC is a significant unmet need. Using single cell RNA sequencing (scRNAseq), we have found that external beam RT induces the wholesale replacement of preexisting T cell clones with novel clonotypes in the prostate cancer tumor microenvironment consistent immunologic priming. This treatment, however, also induces novel myeloid states within the tumor microenvironment that may mediate immunosuppression and dampen the newly primed T cells. We hypothesize that molecularly-targeted radioligand therapy may induce immunologic priming without inducing the concomitant immunosuppression seen with external beam radiation. In prostate cancer, the beta- particle emitting 177Lu-PSMA-617, which targets prostate specific membrane antigen (PSMA), represents an emerging treatment of mCRPC. However, the optimal schedule and form of radioligand therapy to achieve an optimal immunogenicity remains to be elucidated. In Aim 1, we will use multi-omic single cell analyses (scRNAseq, T cell receptor sequencing, and single cell proteomics), to dissect the treatment induced changes in immune effectors and regulatory cell states both within the TME and circulation of mCRPC patients treated on our phase 1b trial with pembrolizumab and one dose of 177Lu-PSMA-617. In Aim 2, we will perform a prospective investigator-initiated phase 2 clinical trial combining pembrolizumab with repeated dosing of 177Lu- PSMA-617 where subsequent doses of 177Lu-PSMA-617 are triggered at the time of PSA progression to rescue anti-tumor immunity. In Aim 3, we define the immunogenic impact of beta- (177Lu) vs. alpha- (225Ac) particle emitting therapy and external beam radiation therapy to help guide future trials of radioimmunotherapy. With this proposal, we seek to advance the field of immunotherapy in prostate cancer in several important ways by: 1) determining the optimal schedule and form of radiation to prime anti-tumor immunity, 2) developing a novel approach to functionally and quantitatively visualize immune response through granzyme B PET, 3) understanding the role of treatment-induced myeloid cells in modifying T cell states, 4) developing biomarkers that will enable patient selection in future trials, and 5) identifying novel therapeutic targets on myeloid and/or T cells to enhance the efficacy of radioimmunotherapy.