An adapted anti-CTLA4 therapeutic aimed at mitigating the toxicities of checkpoint inhibition
Jarushka Naidoo,1,2 Arbor Dykema,1,2 and Franco D’Alessio3
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,
2Bloomberg-Kimmel Institute for Cancer Immunotherapy, and
3Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Address correspondence to: Jarushka Naidoo, 300 Mason Lord Drive, Johns Hopkins Bayview, Baltimore, Maryland 21224, USA. Phone: 410.550.2646; Email: jnaidoo1@jhmi.edu.
Find articles by Naidoo, J. in: JCI | PubMed | Google Scholar
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,
2Bloomberg-Kimmel Institute for Cancer Immunotherapy, and
3Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Address correspondence to: Jarushka Naidoo, 300 Mason Lord Drive, Johns Hopkins Bayview, Baltimore, Maryland 21224, USA. Phone: 410.550.2646; Email: jnaidoo1@jhmi.edu.
Find articles by Dykema, A. in: JCI | PubMed | Google Scholar
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,
2Bloomberg-Kimmel Institute for Cancer Immunotherapy, and
3Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Address correspondence to: Jarushka Naidoo, 300 Mason Lord Drive, Johns Hopkins Bayview, Baltimore, Maryland 21224, USA. Phone: 410.550.2646; Email: jnaidoo1@jhmi.edu.
Find articles by D’Alessio, F. in: JCI | PubMed | Google Scholar
First published December 10, 2018 - More info
J Clin Invest. 2019;129(1):75–77. https://doi.org/10.1172/JCI125800.
Copyright © 2019, American Society for Clinical Investigation
Antibodies that target immune checkpoint molecules, such as CTLA4, provide robust antitumor effects in a subset of patients. Unfortunately, not all patients respond to immune checkpoint inhibition, and some develop life-threatening immune-related adverse events (irAEs). The mechanisms that underlie irAEs from immune checkpoint inhibition are not fully understood, and treatment strategies are currently limited to targeting inflammatory mediators. In this issue of the JCI, Pai et al. report on their development of a modified CTLA4 antibody that shields the inner CTLA4-binding domain until the antibody is within the protease-rich tumor microenvironment. In a lymphopenic murine model reconstituted with naive CD4+ T cells, adapted anti-CTLA4 reduced the occurrence of irAEs and enhanced antitumor effects. This thought-provoking study lays the groundwork for further exploration of this adapted antibody in immunocompetent hosts and introduction of this adaptation to other immune checkpoint molecules. It also suggests that this approach may reduce the incidence of irAEs.
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