Spatially precise radio-chemo-immunotherapy using antibody conjugates

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.

Grant Number: 5R01CA268513-03
NIH Institute/Center: NIH
Principal Investigator: Sunil Advani