Mendus has announced the publication of in vivo data demonstrating significant anti-tumor synergies between the company’s allogeneic dendritic cell-based immune primer program ilixadencel and immune checkpoint inhibition via CTLA-4 blockade in the peer-reviewed journal OncoImmunology.
“These preclinical data underpin the rationale behind our immune primer in playing multiple roles in overcoming immunosuppression and rewiring the TME rather than just providing for a simple inflammatory signal,“ says Alex Karlsson-Parra, Chief Scientific Officer at Mendus. “Taken together, these early-stage findings warrant further clinical investigation with our current generation allogeneic immune primer and future generation immune primers in cancer patients receiving anti CTLA-4 therapy and in indications where this immune checkpoint strategy has previously failed to make a substantial impact on patient outcomes.”
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an inhibitory checkpoint receptor and blocking has the potential to release the “brakes” on patients’ endogenous immune systems. The US Food and Drug Administration (FDA) approved the first anti CTLA-4 antibody, ipilimumab (Yervoy), for the treatment of late-stage melanoma in 2011 and several CTLA-4 targeting programs are in clinical development today. Despite achieving durable responses and improved overall survival using CTLA-4 blockade in many patients, it is estimated that up to 80% still do not respond possibly attributed to a lack of pre-existing immunity. Mendus’ current generation immune primer, ilixadencel, has been evaluated in a broad range of tumors and has demonstrated an excellent safety profile across all studies with encouraging signs of efficacy when combined with other treatment modalities including checkpoint inhibitor pembrolizumab and kinase inhibitors.
The preclinical study
In the preclinical study published, mice were transplanted subcutaneously with CT-26 colorectal cancer cells and were subsequently treated with an intratumoral injection of ilixadencel, an intravenously given antagonistic anti-CTLA-4 antibody, a combination of both or placebo. Neither ilixadencel, nor anti-CTLA-4 treatment alone affected tumor progression or prolonged survival significantly. However, combined treatment with ilixadencel and anti-CTLA-4 significantly delayed tumor progression and led to tumor remission with 7 out of 10 mice surviving longer than 70 days with no detectable tumor. All surviving mice were subsequently re-challenged with CT-26 cells and all mice rejected the newly inoculated tumors compared to the control mice, where none rejected the reintroduced CT-26 cells, indicating the establishment of an immunological memory response.
Several findings of the study demonstrated a profound remodeling of the initially immunosuppressive tumor microenvironment following the combined use of ilixadencel and the anti-CTLA-4 inhibitor. Changes to the TME were visible in gene set analyses of significant pathway signatures including upregulated pathways that affect the myeloid compartment, antigen presentation, the lymphoid compartment, and cytokines/chemokine regulation. On a cellular level, changes in the combination arm included intratumoral infiltration of immune cells with anti-cancer features, including host dendritic cells with high antigen-presenting capacity and activation phenotypes, macrophages with M1-like phenotype, activated neutrophils and inflammatory monocytes.
Combined, these changes led to a suitable TME for the expansion of CD8+ tissue-resident memory T cells which was positively correlated with elevated potential tumor-reactive CD8+ T cells in the tumor and “tumor-matching” CD8+ T cells in peripheral blood. Moreover, splenocytes from mice in the combination treatment group secreted significantly higher IFN-γ upon stimulation with a CT-26-derived model neoantigen, confirming the induction of a tumor-specific CD8+ T-cell response. Depletion of CD8+ T cells totally abolished the therapeutic benefit.