Background Casitas B-lineage lymphoma proto-oncogene b (CBL-B) is an E3 ligase that serves as a master negative regulator of the immune system, indirectly controlling CD28, CTLA4 and other immunotherapy drug targets. CBL-B inhibition demonstrates anti-tumor immune responses as monotherapy and further enhances the effects of anti-PD-1 inhibition in pre-clinical models. HST-1011 is a novel, potent, selective, oral allosteric small molecule CBL-B inhibitor candidate currently being assessed in a multicenter Ph1/2 clinical trial (SOLAR1; NCT05662397).

Methods During HST-1011 dose escalation in patients with advanced solid tumors, peripheral blood samples were collected on days 1, 8 and 22 to assess changes in a range of immune-related gene expression signatures, including a specific CBL-B signature derived from common transcriptional effects of CBL-B inhibitors across pre-clinical models, using the Nanostring Immunology V2 panel (n=27/28 patients). Tumor biopsies (pre-treatment and day 15, when possible) were collected for whole transcriptome sequencing (WTS) using the Caris tissue next generation sequencing assay to measure gene expression changes in the tumor microenvironment (TME). WTS data from pre-treatment biopsies (n=16; 14 fresh, 2 archival) were also assessed using the Xerna TME panel - a machine learning based signature developed to assign the TME to 1 of 4 subtypes: Angiogenesis, Immune Active, Immune Desert, or Immune Suppressed.

Results Dose dependent changes in expression of a CBL-B derived signature were observed beginning on day 1 (compared to pre-treatment) as demonstration of peripheral pharmacodynamics consistent with CBL-B inhibition. Other immune-related pathways were also modulated, including but not limited to those involving the innate immune system, cytokine signaling, and type I Interferon signaling. These peripheral HST-1011-related transcriptional changes were maintained at day 22, supporting sustained pharmacology with repeated dosing. While limited by sample size, transcriptional changes in the TME indicative of tumor infiltrating lymphocytes were elevated in on-treatment biopsies for some patients, with greater levels noted in patients with clinical benefit (defined as tumor shrinkage or stasis) from HST-1011. Preliminary categorization of baseline TME subtypes showed a similar trend, with more patients with benefit from HST-1011 classified as high immune subgroups (Immune Active and Immune Suppressed) versus patients without clinical benefit.

Conclusions HST-1011 was associated with dose-dependent changes in peripheral blood pharmacodynamic measures that were sustained with repeated dosing and pre-treatment tumor WTS provided preliminary suggestion of a potential enrichment approach for a study population most likely to benefit from HST-1011. Monotherapy dose-optimization and combination with anti-PD-1 are ongoing.