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Grant Information

Grant ID	RP220470
Awarded On	February 16, 2022
Title	Overcoming liver toxicity of anti-CD137 cancer immunotherapy
Program	Academic Research
Award Mechanism	Individual Investigator
Institution/Organization	The University of Texas Health Science Center at San Antonio
Principal Investigator/Program Director	Alexei Tumanov
Cancer Sites	Multiple Sites
Contracted Amount	$969471
Lay Summary	Novel antibody-based immunotherapies for cancer are having major clinical impact. However, accompanying immune-mediated adverse reactions, such as liver toxicity, remain the major obstacle of these therapies. Costimulatory molecule called CD137 is a powerful target for immunotherapy. Unfortunately, clinical trials of anti-CD137 antibody (Urelumab) in patients with advanced cancers revealed dramatic liver toxicity. Therefore, overcoming liver toxicity, a major roadblock of anti-CD137 and other checkpoint molecule targeted therapies is crucial. Our preliminary data identified an immune molecule, called lymphotoxin beta receptor (LTbR) as a critical regulator of anti-CD137 antibody induced hepa... Read More Novel antibody-based immunotherapies for cancer are having major clinical impact. However, accompanying immune-mediated adverse reactions, such as liver toxicity, remain the major obstacle of these therapies. Costimulatory molecule called CD137 is a powerful target for immunotherapy. Unfortunately, clinical trials of anti-CD137 antibody (Urelumab) in patients with advanced cancers revealed dramatic liver toxicity. Therefore, overcoming liver toxicity, a major roadblock of anti-CD137 and other checkpoint molecule targeted therapies is crucial. Our preliminary data identified an immune molecule, called lymphotoxin beta receptor (LTbR) as a critical regulator of anti-CD137 antibody induced hepatotoxicity. Our working hypothesis is that inhibition of LTbR will allow to uncouple protective anti-tumor immunity from hepatotoxicity mediated by cytotoxic CD8+ T cells. The output of this work is therefore anticipated to have major impact on developing effective and safe cancer immunotherapies. If successful, this study will be a game changer, as it will remove liver toxicity, a critical roadblock of anti-CD137 and other cancer immunotherapies which will be evaluated in follow up clinical trials. Fundamental knowledge obtained from our findings will be applicable to a variety of anticancer therapies by reducing liver toxicity and autoimmunity. Read Less