Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade

Abstract

Low-dose targeted radionuclide therapy combined with immune checkpoint inhibition enhances complete response rates in preclinical tumor models. TRT-ing tumors Although some patients experience long-term cancer suppression from immune checkpoint inhibitors (ICIs), many patients experience limited response. Patel et al. tested the effects of targeted radionuclide therapy (TRT) with an alkylphosphocholine molecule (NM600) chelated to yttrium to deliver low-dose immunomodulatory radiation to tumor sites. Around half the mice carrying ICI-resistant tumors demonstrated complete response to TRT, and the combination of TRT with ICIs reduced metastases. The authors also combined TRT with external beam radiotherapy to augment response to ICIs in mice bearing multiple tumors and confirmed the safety of TRT in two canine companions with cancer. Further study is needed to assess TRT and ICIs in humans. 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 ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.