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The KRASG12D(ON) covalent tricomplex inhibitor RM-044 increases tumor antigen presentation and TCR repertoire diversity to promote anti-tumor immunity in a preclinical model of KRASG12D mutant cancer (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_583;
2 Here, we investigate the impact of RM-044, a KRASG12D(ON) preclinical tool compound, representative of the clinical candidate RMC-9805, on tumor antigen presentation and the tumor-specific TCR repertoire in vivo...Conclusions Direct inhibition of RAS signaling by RM-044 in tumor cells leads to increased anti-tumor immune response, including expansion of treatment-induced T cell clones that can be detected in both the tumor compartment and the blood, highlighting the interplay between RAS signaling in tumors and the immune system. These preclinical data suggest that the potential therapeutic impact of mutant KRAS inhibitors, particularly KRAS(ON) inhibitors, may be complemented by, and possibly enhanced by, combination with immunologic therapies including neoantigen targeting technologies.
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RMC-9805, a first-in-class, mutant-selective, covalent and orally bioavailable KRASG12D(ON) inhibitor, promotes cancer-associated neoantigen recognition and synergizes with immunotherapy in preclinical models (Valencia D - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5587;
TCR sequencing of T cells from tumors and blood harvested from treated mice revealed a significant increase in T cell diversity, as well as an increase in the number of shared TCR clones among all KRASG12D(ON) inhibitor-treated samples, suggesting cancer-associated antigen recognition.Overall, in these preclinical experiments, RMC-9805 exhibited direct anti-tumor effects and indirectly transformed the TME through inhibition of cancer cell-intrinsic KRASG12D oncogenic signaling. The increased antigen presentation, recognition, and T cell infiltration induced by inhibition of mutant KRAS may permit a more favorable environment for immune-directed
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Enhancement of anti-tumor immunity in immunogenic and immune-refractory RAS mutant tumors with tri-complex RAS(ON) inhibitors (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_303;
The covalent KRASG12D(ON) inhibitor, RMC-9805, had similar effects in KRASG12D cancer cells...The combination of RMC-6291 with RMC-6236, or with a SHP2 inhibitor, potentiated the functionality of cytotoxic T cells and improved anti-tumor activity over KRASG12C(ON) inhibition alone...Effective targeting of RASMUT in RAS-addicted cancers may enhance responses to immunologic therapies in immune-sensitive cancers such as NSCLC. In addition, it may rescue anti-tumor immune responses in classically immune-refractory RASMUT tumors where KRASG12D mutations predominate.
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These properties contribute to a favorable anti-tumor activity profile for RMC-6291, a KRASG12C(ON) inhibitor, compared to a first generation KRASG12C(OFF) inhibitor across a panel of preclinical NSCLC models. The RAS(ON) inhibitors are also designed to drive rational, mechanism-based combinations with approved drugs and investigational drug candidates, particularly in-pathway agents, to achieve optimal tumor suppression in diverse RAS-addicted cancers.
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