Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY/ABSTRACT Locally advanced cancers remain a therapeutic challenge to eradicate. The most successful treatments for such patients continue to combine decades old classical cytotoxic chemotherapies with radiotherapy. While chemo-radiotherapy improves tumor control, using non-targeted drugs increases normal tissue damage in the irradiated field along with systemic toxicities precluding further treatment intensification. Targeted delivery approaches can improve the chemo-radiotherapy paradigm by restricting highly potent radiosensitizers specifically to irradiated tumor targets that activate anti-tumor immune responses while simultaneously avoiding normal tissues. To test this hypothesis, we leveraged antibody drug conjugate (ADC) technology for receptor-restricted radiosensitization. ADCs split the roles of tumor targeting and killing into two distinct molecular tasks. Targeting is achieved by the antibody portion recognizing cell surface receptors preferentially found on tumor cells. Following cell surface receptor binding, ADCs are endocytosed and the attached drug payload warhead intracellularly released specifically within target cells. ADCs have been exclusively built by linking cytotoxic drugs to tumor targeting antibodies. The potent anti-tubulin drug monomethyl auristatin E (MMAE) is the most common ADC warhead. We discovered MMAE could also radiosensitize. Advancing to syngeneic murine models using our novel drug delivery vehicles, we have now provided the first demonstration that MMAE produces durable irradiated tumor control which is dependent on CD8 T cells and is enhanced by immune checkpoint inhibition. While antibody coupled, MMAE is target restricted. However once released, MMAE has dose limiting toxicities. To achieve increasingly precise tumor radiosensitization, we used orthogonal strategies and rationally constructed a first-in-class radiosensitizing ADC designed to inhibit DNA damage repair. As proof of concept, we conjugated anti-EGFR antibody cetuximab to ATM inhibitor AZD0156 (cetux-AZD0156). Cetux-AZD0156 specifically bound and delivered drug to EGFR+ tumors while avoiding adjacent peri-tumoral normal tissue. Moreover, cetux-AZD0156 radiosensitized and increased irradiated tumor control. Based on these findings, we hypothesize that anti-ErbB ADCs coupled to radiosensitizing warheads improve spatial precision of radiosensitization and engage the tumor immune microenvironment (TIME). The goals of this proposal are to methodically test this hypothesis by evaluating radiosensitizing ADC warheads in murine tumor models using our innovative toolbox of tumor-targeted radiosensitizing ADC warheads. In Aim 1, we will test the ability of auristatins to sculpt the irradiated TIME and promote immunogenic tumor control. In Aim 2, we will test if immunotherapies potentiate radiosensitizing auristatins to achieve durable tumor control. In Aim 3, we will test first-in-class ADCs with ATM inhibitor warheads for tissue selective radiosensitization. Rigorously testing radiosensitizing ADCs in advanced murine models will provide rationale for moving away from non-targeted chemo-radiotherapy toward molecularly guided precision radio-chemo-immunotherapies.
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