Friday, May 9, 2025
5/9/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).