[Research Articles] Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade

Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICI...

Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Patel, R. B., Hernandez, R., Carlson, P., Grudzinski, J., Bates, A. M., Jagodinsky, J. C., Erbe, A., Marsh, I. R., Arthur, I., Aluicio-Sarduy, E., Sriramaneni, R. N., Jin, W. J., Massey, C., Rakhmilevich, A. L., Vail, D., Engle, J. W., Le, T., Kim, K., Be Tags: Research Articles Source Type: research