Improving the efficacy of anti-PD-1 antibody immunotherapy

Value Proposition

Despite the significant impact that the checkpoint inhibitor immunotherapies have generated in clinical oncology, the majority of our cancer patients still do not benefit from this treatment modality. While the PD-1/PD-L1 system plays an important role in appropriate immune system down-regulation, it is often hijacked by cancer cells to prevent recognition and attack by the T-cell mediated immune response. The preferred route to address this problem is administration of anti-PD-1 or PD-L1 antibodies to cancer patients, an option that has gained renewed and intense focus in light of recent technological advancements in the immunotherapy field. Indeed, six anti-PD-1/PD-L1 antibodies have already been FDA- approved to treat 14 different types of cancer and PD-1/PD-L1 inhibitors are currently being evaluated in thousands of additional clinical trials. However, it is well documented that PD-1/PD-L1 antibody treatments are prone to failure due to adaptive resistance. Accordingly, there is a great need to dissect the precise mechanisms of anti-PD-1 immunotherapy-induced signaling pathways in order to identify targets that can be leveraged to prevent resistance against these treatments.

Technology

Duke inventors have identified a novel pathway that significantly enhances responses to checkpoint inhibitor immunotherapy. This technology uses NLRP3 inhibitors as a treatment strategy with PD-1 checkpoint inhibitors to prevent adaptive resistance. Specifically, this is a newly identified mechanism whereby CD8+ T cell activation in response to PD-1 blockade induced a PD-L1-NLRP3 inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloidderived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMNMDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This technology has been demonstrated with several preclinical tumor models as well as clinical specimens.

Other Applications

In addition to improving oncology treatments, the inhibitors may also be used to prevent anti-PD-1 antibody induced autoimmune related side effects such as colitis. Apart from inhibiting the upstream activators, inhibitors of other members of the identified signaling axis may also be used in combination with anti-PD-1 / PD-L1 antibodies.

Advantages

• An identified pathway that represents a tumor-intrinsic adaptive resistance mechanism to anti-PD-1 checkpoint inhibitor immunotherapy that is a promising target for future translational research
• Inhibition of the upstream component of the signaling axis identified by the inventors will likely lead to higher specificity and lower toxicity
• Inventors have identified all components of the singling axis, each of which can be targeted in a multi-pronged approach to prevent anti-PD-1 immunotherapy resistance