Precision next-generation radioimmunotherapies to Cure Non-Hodgkin Lymphoma

Progress has been made over the last decades in the treatment of non-Hodgkin lymphoma (NHL) with several therapies recently FDA-approved, including CD19 CAR-T cells, bispecific antibodies targeting CD20 and CD3, and anti-CD79b antibody-drug conjugates (ADC) but over 20,000 people will die of NHL in the US in 2024. There remains a critical unmet need for innovative, active and accessible therapies of NHL. Radioimmunotherapies (RITs) targeting CD20 (Zevalin® and Bexxar®) received FDA approval two decades ago in follicular and some transformed B-cell lymphomas. These first-generation RITs used immunogenic murine antibodies and were only administered in a single dose in non-myeloablative regimens. While safe, well-tolerated, and active, these treatments were not major commercial successes for several reasons, including economics. Also, 131I and 90Y are suboptimal due to unfavorable high-energy γ-emissions or a long β-particle path length poorly suited to low-burden residual disease, respectively. Given the continued unmet medical needs, additional treatment approaches must be obtained for NHL. To address these unmet needs, we will develop precision next-generation RIT for NHL that we anticipate will result in more cures. Our studies draw on our extensive experience in first-generation NHL radioimmunotherapy (of which the PI was an inventor) and our recent exciting preclinical work with next-generation fully-human anti-CD20 RITs. We will develop and evaluate novel, precision radiopharmaceutical therapies for NHL using preclinical models. In Aim 1), Next-generation anti-CD20 radioimmunotherapies for NHL will be evaluated using single agent and combined β-(Lu177) and α-particle-(Ac225)-emitting labeled ofatumumab in disseminated and solid tumor murine models. These studies will determine how to best utilize these α- and β-particle emitting RIT as single agents with single or multiple doses, or in combination to cure lymphoma. In Aim 2), New α-particle anti-CD20 RITs will be developed and assessed, evaluating both short- lived higher dose-rate (Pb212, t½ 10.6 hr) and long-lived, lower dose-rate (Th227, t½ 18.7 d) α-particle- emitters for NHL RIT in mouse tumor models. Comparative evaluation of multiple α-particle RITs is novel, significant, and clinically relevant. In Aim 3), a highly-innovative approach of combined dual-targeted therapy for NHL will be developed and evaluated for mechanism and for therapeutic efficacy, using an anti-CD79b antibody-drug conjugate, Polivy®, as a radiosensitizer for CD20-targeted RIT. This important, selective and novel dual- targeted approach, with mechanistic studies and therapeutic studies, should improve lymphoma curability and is expected to be broadly generalizable to other tumor types. Together, we expect our precision, next-generation RIT approaches to lead to human translation, facilitating more cures of patients with otherwise incurable NHL.