3/26/2023 0 Comments Elucidate gmbhNiraparib (PARP inhibitor) + nivolumab (PD-1) or Ipilimumab (CTL4-A) Nab-PTX + GEM +/- durvalumab (PDL-1) + tremelimumab (CTL4-A) Locally advanced/metastatic pancreatic cancerĭurvalumab (PDL-1) +/- tremelimumab (CTL4-A) The combination of ADH-503 with immunotherapy or standard-of-care chemotherapy significantly improved the therapeutic efficiency and survival rates in PDAC animal models, and its clinical relevance was investigated in a first phase I/II clinical trial (NCT04060342, Table 1). In a PDAC animal model, partial activation of CD11b resulted in the repolarization of immunosuppressive cells into a more proinflammatory phenotype, reduced cell invasion, and an improved T cell response. ADH-503 (GB1275) is a small-molecule agonist of CD11b and has shown benefits in pre-clinical studies in lung and pancreatic cancer by suppressing myeloid cell infiltration into sites of inflammation. CD11b mediates myeloid cell adhesion, trans-endothelial migration, and cell recruitment into sites of inflammation, negatively regulating proinflammatory pathways. CD11b/CD18 ( αM β2) is a heterodimeric integrin abundantly expressed on myeloid cells and can be therapeutically manipulated. For example, the migration of immunosuppressive myeloid cells into tumor tissue can be blocked to restore T cell functions. Hence, there is a strong interest in targeting individual components of the tumor-immune landscape in PDAC. Unfortunately, current clinical trials ( Table 1) harnessing tumor-infiltrating immune cells, such as PD-1 or CTL4-A immune checkpoint inhibition, have been disappointing in PDAC. Therapies manipulating mechanisms of immunosuppression to combat tumor growth have shown remarkable success in several malignancies, including melanoma, breast, and lung cancer. These cell infiltrates are associated with immunosuppression, T cell exclusion, exhaustion, and dysfunction, resulting in the inability of T cells to attack and destroy the tumor cells. Excessive amounts of myeloid cells, including monocytes, granulocytes, and macrophages, invade and populate the tumor tissue. ![]() In addition, PDAC has a diverse tumor-immune landscape. Within this complex tumor microenvironment (TME), mainly cancer-associated fibroblasts (CAFs) deposit and remodel the ECM, creating a desmoplastic milieu. Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, shows an aggressive phenotype, intratumoral heterogeneity, a characteristic deposition of extracellular matrix (ECM) and an abundance of stromal cells, all contributing to resistance to therapy and disease progression. In addition to a rising incidence, no improvement in survival has been achieved in decades. By 2030, it is predicted to be the second highest cause of cancer-related death. With an overall 5-year survival rate of around 10%, pancreatic cancer is one of the deadliest malignancies, with a steady increase in worldwide incidence. Combining the CD11b agonist ADH-503 with anti-PD-1 immunotherapy and chemotherapy leads to a significant reduction in tumor cell viability, proliferation, metabolic activity, immunomodulation, and secretion of immunosuppressive and tumor growth-promoting cytokines. Human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells are grown encapsulated in hydrogels to mimic key components of tumor tissues, and cell responses toward treatment are assessed. To address this limitation and explore the effects of immunotherapy in combination with chemotherapy, a multicellular 3D cancer model using a star-shaped poly(ethylene glycol)–heparin hydrogel matrix is developed. There is a lack of preclinical pancreatic cancer models that reconstruct the extracellular, cellular, and biomechanical elements of tumor tissues to assess responses toward immunotherapy. ![]() Resistance to therapy and disease progression are mediated by the tumor microenvironment, which contains excessive amounts of extracellular matrix and stromal cells, acting as a barrier to drug delivery. Standard-of-care therapy, including surgery and chemotherapy, is unsatisfactory, and therapies harnessing the immune system have been unsuccessful in clinical trials. ![]() Pancreatic cancer is a devastating malignancy with minimal treatment options.
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