A new study has shown that immunotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC) can be improved by agonism of an integrin molecule expressed on the cell surface of myeloid cell subsets.

Although successful in some cancers, checkpoint inhibitors have not led to a clinical benefit in PDAC. “One factor is the extensive infiltration of PDAC by multiple lineages of immunosuppressive myeloid cells,” explains co-senior author David DeNardo. “These cells, which include tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells, can drive T cell exclusion and dysfunction.” In the latest study, these cells were targeted to improve T cell-mediated immunity in PDAC.

Current myeloid-targeting strategies are prone to compensatory effects by untargeted cell subsets, suggesting that a nonselective approach for all tumour-infiltrating myeloid cells might be optimal. CD11b (integrin αM) is expressed on most myeloid cells and plays an important part in myeloid cell migration and function, but to achieve CD11b blockade requires antagonist doses not tolerable in humans. “To overcome this limitation, our team developed a small molecule, allosteric agonist of CD11b,” reports co-senior author Vineet Gupta. This agonist (ADH-503) results in a partially active CD11b conformation upon binding and suppresses myeloid cell infiltration by increasing adhesion to endothelium.

Using various mouse models and ex vivo assays, the team assessed the effect of treatment with ADH-503 on immune responses and the potential for immunotherapeutic synergy. “Our data demonstrate that CD11b agonism rapidly repolarizes TAMs to support antitumor immunity without the compensatory mechanisms seen from other myeloid-targeting agents,” says DeNardo. “The combination of CD11b-agonists with checkpoint immunotherapy leads to tumour regression, long-term survival and immunological memory in PDAC models that are otherwise resistant to immunotherapy.”

This work identifies CD11b agonism as an alternative approach for reprograming innate immunity in PDAC

This work identifies CD11b agonism as an alternative approach for reprograming innate immunity in PDAC. “We think the unique activity of CD11b agonism in altering tumour immunity is very exciting and warrants further study,” observes Gupta. “These studies have led to the development of ADH-503 for planned testing in human patients, although more studies are also needed to understand if the novel mechanisms of action observed in animals are similar in humans.”