Interactions of Antibody Drug Conjugate Anti‐Tubulin and Topoisomerase I Inhibitor Payloads with Radiotherapy to Potentiate Immunotherapy

Abstract The most effective treatments for locally advanced cancers rely on non‐targeted chemotherapies given with radiotherapy. Advances in cancer biology have identified vulnerabilities amenable to precision oncology approaches including antibody drug conjugates (ADCs). In theory, ADCs combine specificity of cancer cell receptor antibody targeting with potent cytotoxins. However, toxicities and resistance limit ADC clinical efficacy. Delivering ADCs with radiotherapy can improve their therapeutic index. Here, the combination of ADC payloads (anti‐tubulin monomethyl auristatin E (MMAE) or topoisomerase I inhibitors DXd and SN‐38) with radiotherapy is reported in immune‐competent murine models. To directly compare ADC payload effects and remove targeting bias, the payloads are tested as free drugs and as tumor‐targeted ADC or peptide‐drug conjugates in combination with ionizing radiation. Both DXd and MMAE induce anti‐tumor immune response that block re‐challenge tumor growth. As monotherapy, DXd is more potent than MMAE at inhibiting tumor formation. In contrast when combined with ionizing radiation at subtherapeutic doses, MMAE but not DXd radiosensitizes resulting in improved tumor control and greater immune activation with MMAE. The differential effects of anti‐tubulin versus topoisomerase I inhibitors when combined with ionizing radiation and immunotherapies can inform and optimize clinical development of ADC based chemo‐radio‐immunotherapy combinations for cancer patients.