Profound immunomodulatory effects of 225Ac-NM600 drive enhanced anti-tumor responsein prostate cancer
de Aguiar Ferreira, C.; Potluri, H. K.; Massey, C.; Grudzinski, J. J.; Carston, A.; Clemons, N.; Thickens, A. S.; Rosenkrans, Z.; Choi, C.; Pinchuk, A.; Kwon, O.; Jeffery, J. J.; Bednarz, B.; Morris, Z.; Weichert, J.; McNeel, D. G.; Hernandez, R.
Show 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. TeaserTargeted alpha therapy can create a pro-inflammatory tumor micro-environment that partly explains stronger anti-tumor responses in prostate cancer
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