Evince's initial focus is Innate Immunity


The opportunity: increase the response rate of breakthrough cures

Cancer immunotherapy is currently the hottest area of drug discovery and development. This has been driven in large part by the discovery of the class of agents known as checkpoint inhibitors, particularly those acting at the target PD-1 (programmed cell death protein 1). Therapeutic monoclonal antibodies like Keytruda that block the activity of this cell surface receptor can produce outright cures. Unfortunately, many patients don’t respond to treatment with these drugs. Both of these behaviors are apparent in the Kaplan-Meyer survival curves for patients with advance non-small cell lung cancer (at left). Keytruda treatment leads to a profound benefit in 15-20% of treated patients with little or no benefit for the remainder. Therefore, the current challenge is to identify new immunotherapies to combine with checkpoint inhibitors that substantially increase the number of patients that benefit from treatment.

Innate Immunity

The innate immune system can kickstart adaptive immune responses

Cancer Immunotherapy. At the turn of the century, Hanahan and Weinberg proposed six basic hallmarks of cancer - acquired abilities that allow cancer cells to survive, proliferate and metastasize. A decade later this list was expanded to highlight the nearly universal ability of tumors to avoid immune destruction. Today it is widely recognized that cancer immune evasion is the largest single stumbling block in designing effective anticancer therapeutic strategies. The invention of new medicines to artificially boost the body’s immune response against cancer is one of the most exciting advances in the treatment of this disease. Accordingly, the race to find new agents that unleash the immune system to fight cancer is the single most active area of drug discovery today.

The role of PD-1 on cancer cells is to trick the immune system so that the cancer cells are not recognized as threats, and thus can live and multiply without harassment by the immune system. This mechanism of immune evasion is called "checkpoint blockade". This specifically refers to the mechanism by which the cancer cells avoid recognition as disease by immune system T-cells, part of the well-known adaptive immune system. Checkpoint inhibitors like Keytruda restore the ability of T-cells to recognize cancer cells. Thus this class of drugs acts to restore normal immune status within the tumor environment.

In addition to adaptive immunity, there is another branch of the immune system that broadly senses threats and respond quickly but nonspecifically to danger signals, including tumor cells. This is the innate immune system. Some of the specific mechanisms induced are:

  • Activation of general anticancer cellular responses primed by chemokine and cytokine production

  • NK (natural killer) cell activation and enhanced antibody-mediated killing of tumor cells via antibody-dependent cellular cytotoxicity (ADCC), particularly with therapeutic mAbs.

  • CTL (cytotoxic T-cell) activation

This system provides time for adaptive immunity to come into play. More importantly, the innate immune system primes the adaptive system to respond to threats. Activators of innate immunity are thus the perfect complement to checkpoint inhibitors. Studies of the combination of checkpoint inhibitors and activators of innate immunity show substantially greater benefit than either therapy alone without increased toxicity in animal models of cancer.