PRCA-04 TARGETING A UNIQUE ACTIVATION RECEPTOR COMPLEX TO TREAT INTRACRANIAL BREAST CARCINOMA.

Abstract Despite enhanced therapies against primary breast carcinoma (BC), intracranial metastases remain incurable and are associated with a decreased quality of life. To address this unmet medical need, we developed a new therapy (ARL200CNS), representing a pivotal advancement in the field of cancer immunotherapy. ARL200CNS binds to a complex of activation receptors (CD200AR), priming a durable antitumor response when given with an antigen source such as tumor lysates, while simultaneously downregulating the inhibitory CD200 receptor (CD200R1), PD-1/PD-L1, and CTLA4. Moreover, ARL200CNS has demonstrated clinical and immunological responses and extended survival early in a phase 1 trial treating adults with recurrent glioblastoma. Although ARL200CNS educes anti-glioma and anti-breast cancer responses within the CNS, it exhibited little efficacy against primary BC. In contrast, the peptide ARL200Breast elicited an extra-CNS anti-BC response and failed against CNS tumors. However, despite the treatment location, both peptides induce a durable memory response. We hypothesize that targeting unique CD200AR complexes drives specific immune responses required for a peripheral or CNS anti-BC response. We revealed that ARL200CNS primarily binds to the CD200AR2&3 complex, signaling through a specific pathway downregulating NFkB and enhancing translocation of NFAT for the activation of an antitumor response. We now know that ARL200Breast does not signal through this pathway, however, ARL200Breast downregulates CD200R1, PD-1, and PD-L1 while eliciting a durable peripheral anti-BC response. Our overall objective is to demonstrate that the combination of radiotherapy and ARL200 enhances the elimination of tumor cells extending the durability of treatment. We are partnering with OX2 Therapeutics to elucidate immune responses elicited by the peptides in the periphery and CNS, filling the gap in knowledge involving the mechanism of and underlying the therapeutic effects of ARL200 with radiotherapy, enabling a vertical step to further clinical translation.