Erik Ehinger

What if we can hijack the immune system’s rubbish-disposal system to toughen T cells against cancer?

Funded: January 2023
Funded By: The generosity of LJI Board Director Dave Rickey and the Rickey Family

Although immunotherapies have been successful in treating cancer patients, they are limited, especially in solid cancers, by a phenomenon known as T cell “exhaustion.” This term refers to the fact that tumor-infiltrating T cells are initially effective in destroying cancer cells, but later lose function and fail to destroy the tumor. Exhausted T cells upregulate inhibitory surface receptors, including PD-1. Treatment with antibodies to these receptors forms the basis for current approaches to cancer immunotherapy; however, blocking individual inhibitory receptors, or even combinations of inhibitory receptors, rarely achieves a complete cure.

In a quest to develop the next generation of cancer therapies, we are harnessing cells’ rubbish-disposal system to target the root cause of immune cell exhaustion, rather than current approaches that only target the peripheral receptors (expressed as a consequence of the exhaustion program).

We set up a mouse proof-of-concept system to show whether degrading exhaustion-causing proteins could counter T cell exhaustion. We found that by degrading each of our targets, we are able to substantially decrease the number of “terminally exhausted” T cells. These T cells regained their ability to secrete cytokines, which are paramount to their function in tumors. The remaining phase of this project will show whether our approach directly improves T cell tumor killing, and whether these targets are potent in humanized systems. In parallel, we are embarking on the beginning discovery stages of a lead compound that will unlock the totality of the entire immune system against solid cancers by using the rubbish-disposal system.

SPARKing Impact: Although newer cell therapy approaches are successful against blood cancers, these approaches don’t address the problem of T cell exhaustion which leads to incapacitated T cells in their fight against solid tumors. With this project, I plan to attack the problem of T cell exhaustion at its source by specifically targeting the intracellular proteins causing exhaustion.