Checkmate Pharma is developing a new approach for cancer immunotherapy, by specifically activating the immune system to recognize and kill tumor cells throughout the body, without harming normal tissues.
For decades, scientists and physicians knew that certain immune cells called Cytolytic T Lymphocytes (CTLs) are able to destroy cancer cells, yet they fail to play this key role for most patients suffering from cancer. Scientists and physicians now understand that tumors deploy “immune checkpoint proteins” to trick the CTLs to switch off before they can perform their cancer fighting role. The discovery of immune checkpoints led to the development of a new class of therapeutics, “checkpoint inhibitors,” that have ignited the immuno-oncology revolution.
Despite the promise of checkpoint inhibition, a limited number of patients currently benefit from this type of treatment. In a patient whose immune system is already activated and poised to kill their tumor, treatment with a checkpoint inhibitor can free the immune system to destroy the tumor (see example here). Unfortunately, most patients’ immune systems are not already activated so treatment with a checkpoint inhibitor does not provide any therapeutic benefit - and may actually worsen the patient’s condition by causing significant toxicity. In this case, the checkpoint inhibitor “takes the brakes off” the immune system, but fails to target it against the tumor, which continues to grow.
Many scientists believe that checkpoint inhibitors would have dramatically increased benefit if they were combined with an immune activator to stimulate the CTL attack against the tumor (for example, here). Many different immune activators have been tested and the Toll-like receptor 9 (TLR9) agonist CpG DNA has been the strongest at activating anti-tumor CTLs thus far. Checkmate Pharma believes that there is tremendous promise to the combination of two important cancer-fighting mechanisms: CpG DNA to activate the CTL response and checkpoint inhibition to release the tumor’s braking mechanism against the immune system. Checkmate’s founder and CEO, Dr. Art Krieg, discovered CpG DNA in 1994. Since then, CpG DNAs have been administered to thousands of humans showing potent immune activation and an excellent safety profile.
CTLs have the potential to kill tumor cells but normally do not because they do not receive adequate levels of the three required stimulatory signals; and/or, they are arrested by “checkpoints” or inhibitory signals that turn them off (e.g. through PD-1 and CTLA-4). To be fully activated and kill tumor cells, CTLs must receive each of the three stimulatory signals from a dendritic cell (DC): 1) a tumor antigen must be “presented” to the T cell receptor (TCR); 2) “costimulation” must be provided through CD28 on the T cell; and 3) type I interferons (IFN) must stimulate the DC and T cells through the type I IFN receptor. However, tumors can evade the immune activation and proliferate by preventing the CTL response. Tumors recruit immature plasmacytoid DC (pDC) that provide only weaker, non-activating stimulatory signals (small “+” signs), and promote dominant inhibitory effects (larger “-“ signs) through the “checkpoint” molecules CTLA-4 and PD-L1. Thus successful tumors induce an environment in which the “-“ signals to CTLs dominate over the “+” signals needed to kill the tumors.
Checkmate’s CpG DNA is the strongest stimulus known for pDCs, acting through the endosomal Toll-like receptor 9 (TLR9) to provide all three of the stimulatory signals (green “+” signs) required to induce a maximal anti-tumor CTL response. TLR9 signaling secondarily induces expression of the PD-1 checkpoint on T cells, which normally inhibits them. However, in the presence of a checkpoint inhibitor antibody to either PD-1 (shown) or to PD-L1, the fully activated T cells release cytolytic factors such as perforins and granzymes (granules in T cell) that act to effectively eliminate the tumor cells. Thus, combining a CpG DNA with a checkpoint inhibitor creates an environment with a dominant “+” effect, leading to tumor eradication by the CTLs.
Checkmate's team combines many decades of experience in all areas of drug development with a passion for innovation and execution.