The tumor microenvironment (TME) includes a host of cells (mesenchymal, immune, vascular), cytokines, and other signaling molecules that serve to abrogate the innate and adaptive immune responses against the tumor. This is appropriate to maintain tissue homeostasis, and to prevent autoimmunity after the rogue cancer cells have been eliminated. Cancer cells co-opt many of these pathways to terminate the effective immune response so that they are not wiped out, rather, proliferate, invade, metastasize and kill, Continue reading
The latest checkpoint inhibitor to be approved is AstraZeneca’s Imfinzi (durvalumab), a monoclonal antibody directed against PD-L1, which is expressed on cancer cells.
Immune checkpoint-directed therapy is producing unprecedented clinical results in many patients. So much so, that the FDA recently reversed its longstanding policy or approving cancer drugs based on site of origin, to the presence of a biomarker (microsatellite instability (MSI-H) or mismatch-deficient repair (dMDR) as the indication for therapy with pembrolizumab (Ketruda), and PD-1 blocker. Cancers expressing MSI-H or dMDR mutate at a rapid rate, presenting novel epitopes to the immune system, which is readily mobilized against them so that tumor infiltrating T-cells are reliably present. Blocking the PD-1/PD-L1 pathway in this context allows for prolongation of the immune response and better clinical results. Continue reading