Abstract IA17: PD-1 blockade therapy for cancer

Abstract

Abstract PD-1 and PD-L1 blockade therapy with therapeutic antibodies is providing unprecedented rates of durable tumor responses in a variety of cancers, including melanoma, lung, renal, bladder and ovarian cancers (1-5). A key question is defining in which settings blocking the PD-1/PD-L1 interaction will lead to tumor responses. PD-L1 expressed by cells in the tumor microenvironment engages PD-1 on T cells and triggers inhibitory signaling downstream of the TCR, blocking effector functions and reducing T-cell killing capacity. PD-L1 can be constitutively expressed on the surface of cancer cells through poorly characterized oncogenic signaling pathways, or more frequently alternatively, expressed in response to the presence of T cells producing immune-stimulating cytokines such as interferons (6, 7). The inducible process has been termed “adaptive immune resistance”, and represents a mechanism by which cancer cells attempt to protect themselves from immune-cell mediated cell killing. Based on this conceptual framework, we sought to determine whether pre-existing tumor-associated CD8+ T-cells with associated PD-1/PD-L1 engagement within tumors represented a key factor in determining clinical response to PD-1 blocking therapy. Our emerging data suggests that responses to PD-1 blockade indeed happen when PD-1/PD-L1 is the limiting step preventing a pre-existing clonal CD8 infiltrate from attacking the melanoma. The same process could be limiting T cell responses to many other cancer histologies in a significant proportion of patients. Releasing the PD-1 block would lead to durable tumor responses in them the same way that it happens in melanoma. Therefore, it is likely that in the near future, instead of relying on the status of estrogen receptor or Her2/neu in breast cancer, EGFR in lung cancer or BRAF in melanoma, for example, to decide on the front line therapy, oncologists will want to know if a patient is predisposed to respond to anti-PD-1/L1 antibody therapy as the initial decision point to select oncologic therapy. Such a predictive assay will likely need to take into account PD-L1 expression as well as other variables that quantitate tumor antigen-specific T cell infiltration leading to a dominant role of PD-1/L1 negative signaling in the cancer of a particular patient (8).