On November 10, 2022 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of orally delivered, small molecule allosteric therapies for the treatment of cancer and autoimmune diseases, reported the presentation of additional preclinical data on the Company’s Casitas B-lineage lymphoma proto-oncogene (CBL-B) program in two poster presentations at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, HotSpot Therapeutics, NOV 10, 2022, View Source [SID1234623866]).Due to its role as a gatekeeper in immune cell activation, CBL-B inhibition holds the potential to address several key mechanisms important in immuno-modulation. Translational data supports a role for CBL-B inhibition to address suboptimal response to current immunotherapies in certain cancers. Targeting CBL-B represents a novel therapeutic approach because inhibition of CBL-B has been shown to lower the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, potentially bringing benefit to patients with suboptimal conditions in the tumor microenvironment.
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"At HotSpot, we are generating preclinical data elucidating the central role of CBL-B inhibition to immune cell activation, providing strong biological rationale for this mechanism’s potential as a promising immuno-oncology treatment option," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer of HotSpot Therapeutics. "Our data in syngeneic mouse models underscore the broad range of immunostimulatory activity of CBL-B inhibition which, coupled with compelling data from the mixed lymphocyte reaction (MLR) assay, a clinical correlate for I-O agents, as well as clear synergistic activity with anti-PD-1, support the continued advancement of our CBL-B inhibitor program. We look forward to continuing to work toward advancing HST-1011, our lead CBL-B inhibitor development candidate, into the clinic."
The presentations describe compelling data for HotSpot compounds designed as novel, allosteric, small molecule inhibitors of CBL-B E3 ubiquitin ligase activity:
A HotSpot CBL-B inhibitor demonstrated immune-mediated tumor growth inhibition in multiple syngeneic mouse models. Gene expression profiling of the tumor microenvironment demonstrated upregulation of pro-inflammatory pathways in vivo. These effects were notable with CBL-B inhibition alone and further enhanced when combined with a PD-1 inhibitor.
In the MLR assay, a predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated robust effects on cytokine release and T cell proliferation as monotherapy. Additionally, CBL-B inhibition demonstrated synergistic activity in the MLR assay when combined with anti-PD1.