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

Abstract

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.

Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models

“…Because of the potent anti-tumor response elicited by CpG+OX40 in the A20 model, we sought to investigate its anti-tumor potential in the immunologically “cold” B78 melanoma model ( 32 , 34 ). Mice bearing B78 flank tumors (~150 mm 3 ) were randomized and treated with PBS, CpG, OX40, or CpG+OX40.…”

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy

“…Apart from individual therapeutic toxicities, the mechanistic interactions between radiation and immunotherapy and the potential common targets of both therapies can pose limits to either of the two therapies and these cells or organs might need to be modeled into the mathematical framework to optimize the dosage, interval, and number of cycles of either of these therapies. There is recent evidence to suggest that radiation can induce changes in the immune system and can stimulate a significant immune response for a better therapeutic efficacy [21][22][23]. Radiation therapy can act as a bridging therapy for immunotherapies yielding better therapeutic efficacies with immunotherapy [24][25][26].…”

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy

“…Apart from individual therapeutic toxicities, the mechanistic interactions between radiation and immunotherapy and potential common targets of both therapies can pose limits to either of the two therapies and these cells or organs might need to be modeled into the mathematical framework to optimize the dosage, interval and number of cycles either of these therapies can be administered. Additionally, there is recent evidence that radiation can induce changes in the immune system and can stimulate significant immune response for better therapeutic efficacy [17][18][19]. With a better understanding of the mechanistic basis and experimental data to support, the interactions between radiation and immunotherapy can be better modeled and additional interaction terms can be introduced in the mathematical formulation to account for toxicity.…”