Profound immunomodulatory effects of ²²⁵Ac-NM600 drive enhanced anti-tumor response in prostate cancer

Abstract

An immunosuppressive tumor microenvironment has hampered the efficacy of immunotherapy in prostate cancer. However, radiation-induced immunological effects can partly mediate anti-tumor effects by promoting a pro-inflammatory environment potentially responsive to immunotherapy. Herein, we examined the immunomodulatory properties of a radiopharmaceutical therapy (RPT) with NM600 radiolabeled with either a beta or alpha emitter in two prostate cancer models. 225Ac-NM600, but not 177Lu-NM600, promoted significant anti-tumor effects and improved overall survival. Immunomodulatory effects were dose, radionuclide, and tumor type-dependent. 225Ac-NM600 elicited an array of immunomodulatory effects such as increased CD8/Treg ratio, activation of effector and memory T cells, abrogation of infiltrating suppressor cells (e.g., Tregs and MDSCs), and increased levels of Th1 cytokine and pro-inflammatory chemokines. Importantly, we demonstrate the need to carefully characterize the immune responses elicited by RPT both pre-clinically and clinically to maximize tumor control and avoid potential counterproductive immunosuppressive effects.

Immunological effects of radiopharmaceutical therapy

“…They observed the highest decrease in CD8+ T cells at 19 days post-injection with 600 kBq/kg. However, no significant decrease in CD8+ T cells were observed in the Tramp-C1 TME after injection with 7.4 (∼300 kBq/kg) or 18.5 kBq (∼700 kBq/kg) of 225 Ac-NM600 (105). Moreover, 225 Ac-NM600 promoted a more active CD8+ T cell repertoire with increased expression of activation and proliferation markers such as CD44+, CD69+, and Ki67+ on CD8+ T cells, suggesting induction of an immunogenic TME by 225 Ac-NM600 which could be responsible for the antitumor response.…”

“…Ferreira et al showed that 225 Ac-NM600 abrogated the infiltration of Treg cells in the TME of murine prostate cancer (105). In this study, they compared the anti-tumor and immune modulatory effect of 225 Ac-NM600 and 177 Lu-NM600 in two different immunocompetent prostate cancer models MyC-Cap in FVB/NJ mice or Tramp-C1 in C57BL/6 mice.…”

“…The advantages of α-particles ensuing from their physical properties (short tissue range and high LET) and the regulatory approval of 223 RaCl 2 for patients with mCRPC have stimulated the development of several α-particle-emitter-based RPTs. Several reports indicate that α-particle irradiation elicits an immune activation (82,84,105). Herein, we will discuss some preclinical studies which have evaluated the effects of α-particles on specific immune cell populations.…”