Study Results Could Help Strengthen Response to Checkpoint Inhibitors

An animal study conducted at the Perelman School of Medicine, University of Pennsylvania (Penn), has identified a mechanism to strengthen the immune response of T cells in cancer patients who are treated with checkpoint inhibitors such as the programmed death-1 (PD-1) inhibitors.

With a study in a mouse model, the authors found that T cells, which are the body’s line of defense against an infection or against cancer, can become exhausted following an immune response. Blocking PD-1 can reinvigorate these cells, but whether the effect is durable is not known. The team of E. John Wherry, PhD, director of the Institute for Immunology at Penn, found that the exhausted T cells can be identified by their epigenetic profile, which is distinct from the effector or memory T cells that retain their immunogenic function.

The duration of response when using a PD-1 or a programmed death ligand-1 (PD-L1) inhibitor is determined by the strength of the T-cell response. According to Wherry, their research showed that the epigenetic profile of T cells changed only slightly following a PD-L1 blockade, which prevented the exhausted T cells from changing into more protective effector or memory cells. What the authors observed was that inhibition of the PD-1 signaling pathway caused transient, rather than permanent epigenetic reprogramming of T cells, which in the long run would not have a durable effect on the immune response.

This was quite opposite to what the authors had anticipated. They expected that T cells would not have a distinct epigenetic profile, but rather, would be flexible to obtain an immune memory. This clearly hints to limitations of existing immuno-oncology treatments like nivolumab and pembrolizumab that have been developed to block the PD-1 signaling pathway and could explain the low rate of response rate with these agents.

A potential strategy to combat this problem could be the use of combination therapies, such as combining PD-1 inhibitors with agents that target other immune pathways. Wherry’s group is collaborating with other research teams at Penn to study checkpoint inhibitors in multiple tumor types, and are combining the agents with radiation, in the hope of maintaining a durable response to treatment.

The paper has been published in Science.