PROJECT SUMMARY/ABSTRACT The objective of this research proposal is to maximize the cure rates of relapsed or refractory (R/R) non-Hodgkin lymphomas (NHL) by enhancing the capacity for targeted radionuclide therapies to comprehensively eliminate residual disease. NHL is the most commonly diagnosed hematologic malignancy in the United States and several subtypes portend poor outcomes, including so called “double hit” and “triple hit” disease. In addition, indolent lymphoma remains generally incurable. While CAR T (chimeric antigen receptor T cell therapy) offers promise for R/R diffuse large B cell lymphoma, durable complete response rates have been reported in only 30-40% of patients. NHL relapse is believed to result from the persistence of small tumor cell reserves that elude treatment. The notable heterogeneity of NHL contributes to malignant cell escape and complicates a uniform approach to therapy. Independent of responsiveness to other interventions however, virtually all NHL is exquisitely radiation sensitive, giving radionuclide based approaches a unique advantage. Radiolabeled anti-CD20 antibodies can achieve remissions in up to 95% of lymphoma patients failing conventional combination chemotherapy when myeloablative doses of the radioimmunotherapy (RIT) are administered with stem cell support. While these responses are encouraging, low tumor-to non-tumor ratios of absorbed radiation, toxicity, and unacceptable rates of relapse form the rationale for the ongoing work of this grant proposal. The proposed projects leverage novel RIT delivery methods developed during prior funding periods and shown to dramatically improve tumor-to- normal organ ratios of absorbed radiation. Clinical experience dictates that multi-agent combinations are generally most effective in the treatment of NHL. This proposal explores three RIT combination strategies with a goal of generating unvarying efficacy across NHL subtypes through targeting the presumptive cause of relapse, occult residual disease. To achieve this goal, Aim 1 will employ the rational pairing of two targeted radionuclides, first using the longer path length and modest linear energy transfer (LET) of β-emitter therapy to safely debulk NHL tumors, followed by an extremely high LET and short path length α-emitter to eliminate residual disease. Aim 2 will explore combining the ability of RIT to trigger tumor cell death with the pro-apoptotic efficacy of emergent BH3 mimetics. Aim 3 will examine RIT combined with rationally selected immune checkpoint inhibitors, in a novel tumor vaccine approach to eradicating residual disease. Collectively these proposed studies test the hypothesis that RIT combination approaches will reduce the total radiation dose required to effectively treat NHL, in a manner that facilitates rapid translation through our non-Hodgkin lymphoma clinical RIT program.