HC-5404

P1, N=23, Completed, HiberCell, Inc. | Recruiting --> Completed | Phase classification: P1a --> P1 | N=36 --> 23

By disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard of care therapies in RCC.

We hypothesized that inhibition of PERK would improve responses to ICI therapy by reprogramming TAM from immunosuppressive to immunoactivating cells. To investigate if ER-stress underlies resistance to PD-1/PD-L1 targeted therapies, we utilized ex vivo assays to investigate ER-stress regulation of macrophage phenotype, and in vivo syngeneic murine models of melanoma growth, with HC-5404 (PERKi), a selective and potent first-in-human small molecule PERK inhibitor currently in a phase 1 clinical trial for solid tumors (NCT04834778). Treatment with PERKi sensitized αPD-1/PD-L1 mAb-resistant melanoma tumors (Y1.7/YR1.7) to PD-1/PD-L1 blockade with concomitant increase in tumor infiltrating leukocytes, TH1- reprogrammed TAM, and cytotoxic CD8+ T cells... The combination therapy targeting PERK and PD-1/PD-L1 signaling increased adaptive immune responses, reprogramed TAMs and reduced tumor growth kinetics. Results from these studies highlight a role for ER-stress signaling in TAMs to maintain an immunosuppressive tumor microenvironment and demonstrate the potential therapeutic strategy of PERK inhibition in αPD-1/PD-L1 resistant tumors.

P1a, N=36, Recruiting, HiberCell, Inc. | Trial completion date: Jul 2023 --> Mar 2024 | Trial primary completion date: Jan 2023 --> Oct 2023

P1a, N=36, Recruiting, HiberCell, Inc. | N=24 --> 36 | Trial completion date: Apr 2022 --> Jul 2023 | Trial primary completion date: Mar 2022 --> Jan 2023

P1a, N=24, Recruiting, HiberCell, Inc.