Scientific Highlights for Saturday, Nov. 12, 2022
ELUCIDATING THE DEVELOPMENT AND FUNCTION OF CANCER-ASSOCIATED FIBROBLASTS
1450 TGF beta dependent LRRC15+ myofibroblasts dictate the tumor fibroblast setpoint to promote cancer immunotherapy resistance
Akshay Krishnamurty (Genentech, United States) presented results from a study to identify the origin and function of LRRC15+ cancer associated fibroblasts (CAFs). LRRC15+ CAFs support tumor growth through the expression immunosuppressive and extracellular matrix genes. Previous studies have shown that high expression of the LRRC15+ CAF gene signature corresponds to decreased survival and decreased response to anti-PD-L1 checkpoint blockade therapy. Mouse models of pancreatic cancer indicate that LRRC15+ CAFs develop from healthy DPT+ fibroblasts in a TGF beta-dependent manner. Novel LRRC15-Diphtheria toxin receptor (LRRC-15-DTR) was developed to specifically deplete LRRC15+ CAFs. Depletion of CAFs was associated with CD8+ T cell-dependent tumor control compared to wild type and a significant increase in the anti-tumor efficacy of anti-PD-L1 blockade. LRRC15+ CAFs suppress T cell function in the tumor microenvironment (TME), and depletion of CAFs enhanced T cell effector functions and decreased T cell exhaustion. This study provides a framework to address questions surrounding additional functions of CAFs in the TME. Therapies targeting LRRC15+ CAFs could potentially increase the efficacy of T cell-directed therapeutics and improve patient response to immunotherapy.
NEXT GENERATION ANTI-CTLA-4 BLOCKADE FOR IMMUNOLOGICALLY COLD SOLID TUMORS
778 Botensilimab, a novel innate/adaptive immune activator, plus or minus balstilimab (anti-PD-1) in “cold” and I-O refractory metastatic solid tumors
Breelyn Wilky (University of Colorado Cancer Center, United States) provided an update of Trial C-800-01, a phase I study of botensilimab (BOT) monotherapy or in combination with balstilimab (BAL) for immunologically cold or immunotherapy refractory metastatic solid tumors. The Fc enhancement of BOT strengthens engagement of T cells with antigen presenting cells, promoting T cell priming, activation, and memory formation. 125 patients were included in the study. 115 patients received combination BOT + BAL treatment, and 10 received BOT monotherapy. Patients were heavily treated and had 19 solid tumor types. Most tumors represented were immunologically cold tumors, but the few immunologically hot tumors were refractory to prior checkpoint inhibitor therapy. 10% of patients experienced treatment-related adverse events, and no new safety signals were observed, compared to CTLA-4 + PD-(L)1 combination therapy. Overall response rate (ORR) was 20%, and disease control rate (DCR) was 66%. Median overall survival has not been reached, and 66% of patients were alive at the 12-month check-in. In patients with microsatellite-stable colorectal cancer (n=59), ORR was 22%, and most responses were ongoing. DCR was 73%, and responses were observed regardless of PD-L1 status. In patients with ovarian cancer (n=19), ORR was 26%, and one patient achieved a durable complete response. For sarcoma (n=12) ORR was 42%, with 3 of 5 responses ongoing. For non-small cell lung cancer (NSCLC) refractory to PD-1 therapy (n=5), ORR was 60%, and 2 of 3 responses are ongoing. Combination therapy with BOS + BAL is safe and well tolerated and produces durable response across a broad range of immunologically “cold” solid tumors. The NSCLC cohort is actively enrolling patients, and three phase II trials of BOS are ongoing.
TARGETED DELIVERY OF IL-2 TO TUMORS INCREASES ANTI-CANCER ACTIVITY OF IL-2 AND REDUCES TOXICITIES
1329 Ultra-pH sensitive nanoparticles increase therapeutic index of IL-2-Fc
Qiang Feng (University of Texas Southwestern Medical Center, United States) presented preclinical data for ONM-405, an ultra-pH sensitive nanoparticle delivery system for increased half-life IL-2-Fc. ONM-405 is based on ON-BOARD technology, which consists of a pH-sensitive on/off switch. In the acidic tumor microenvironment (TME), ONM-405 is turned on, delivering IL-2-Fc to the TME. At physiological pH, ONM-405 is turned off and does not release IL-2-Fc to non-cancerous tissue. When ONM-405 was tested in mouse tumor models, there were no signals of IL-2 receptor binding at neutral pH, but IL-2-Fc bound to IL-2 receptors in acidic conditions. ONM-405 increased anti-tumor efficacy in both immunologically hot and cold tumor models, and toxicity was significantly reduced in mice, compared to IL-2-Fc. ONM-405 was also associated with decreased interferon gamma circulation. ON-BOARD technology provides a tumor-mediated on/off switch to administer IL-2 specifically to tumors with acidic environments, thus promoting anti-tumor activity. This targeted administration of IL-2 also minimizes toxicities in non-cancerous tissues.