Page 44 - The Hormel Institute 2024 Annual Report

44 | THE HORMEL INSTITUTE
// UNIVERSITY OF MINNESOTA
Cancer immunotherapy is a cornerstone of cancer-directed precision medicine. However, even in best case scenarios,
only 30-40% of treated patients show objective responses to any therapy regime. This reduced efficacy is further compounded by various resis- tance mechanisms, especially in solid tumors, including exhaustion of cancer specific effector T cells. My lab is dedicated to understanding these mechanisms and finding strategies to alleviate resistance so that anti-tumor efficacy of various therapeutics can be enhanced.
During the past year, my lab has focused on targeting the metabolic abnormalities in CD8
T cells that are a major source of immune cell exhaustion and associated therapy failure. Loss of mitochondria has been identified as a major contributor to immune cell exhaustion. However, no clinically viable strategy is available that can be used for preventing mitochondria related exhaustion in cancer specific effector cells.
My lab has developed and patented a pharmaco- logically viable strategy by targeting the metabol- ic enzyme PKM2 using a pharmacological small molecule TEPP46. We have found that mitochon- drial dysfunction can be prevented and lead to enhanced anti-tumor functions in CD8 T cells. We also found that TEPP46 can be combined with various FDA approved immune checkpoint block- er antibodies, leading to reversal of resistance to anti-tumor responses.
During the past year, my lab has also made head- way in defining resistance mechanisms in CAR-T cell therapy, one of the most promising anti-can- cer therapies against hematological malignan- cies. Several CAR-T cell products have been approved by the FDA for use in liquid tumors. However, due to lack of robust anti-tumor activity, none of the therapeutics have been approved for use in solid tumors. The reason for this inefficacy of CAR-T cells in solid tumors is not well defined. In one project, currently funded through Paint The Town Pink (PTTP) funds, we are defining the generation of a newly identified dysfunctional phenotype in CAR-T cells that has been found
to be induced after suboptimal activation in the tumor microenvironment. Establishment of this phenotype in CAR-T cells and its association with therapy failure opens a new avenue for targeting drug resistance and enhancing the outreach of CAR-T cells in broader population.
In summary, we have made significant prog- ress over the last year in defining the resistance mechanisms to some of the most promising an- ti-cancer drugs, opening up the way for develop- ment of newer strategies for their enhancement.