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The effect of aging on OX40 agonist-mediated cancer immunotherapy

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Abstract

Agents that enhance T cell co-stimulatory signaling have emerged as promising cancer immunotherapies. Our laboratory has been evaluating the TNF receptor co-stimulatory molecule, OX40, which has the capacity to augment critical aspects of T cell function and induce tumor regression in animal models. Effective stimulation of OX40 expressing T cells was accomplished with agonist antibodies to OX40 that were eventually translated into a clinical trial for cancer patients. A recent attempt to assess the affect of immune senescence on OX40 therapy, revealed a dramatic loss of efficacy of the agonist therapy in older tumor-bearing mice. The deficiency in OX40-enhanced anti-tumor responses in older mice correlated with a decrease in the number of differentiated effector T cells. Further investigation suggests that the underlying age-related decline in the agonist OX40-mediated T cell responses was not inherent to the T cells themselves, but related to the host environment. Thus, effective use of immunotherapies based on T cell co-stimulatory molecules may require additional modifications, such as immune stimulants to increase innate immunity, to address age-related defects that reside outside of the T cell and within the host environment.

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Acknowledgments

The authors would like to thank Drs Walter Urba and Michael Gough for their critical reading of the manuscript.

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Correspondence to Carl E. Ruby.

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This article is part of the Symposium in Writing on “Impact of Ageing on Cancer Immunity and Immunotherapy”.

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Ruby, C.E., Weinberg, A.D. The effect of aging on OX40 agonist-mediated cancer immunotherapy. Cancer Immunol Immunother 58, 1941–1947 (2009). https://doi.org/10.1007/s00262-009-0687-6

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  • DOI: https://doi.org/10.1007/s00262-009-0687-6

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