The effect of aging on OX40 agonist-mediated cancer immunotherapy |
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Authors: | Carl E Ruby Andrew D Weinberg |
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Institution: | (1) Earle A Chiles Research Institute, Portland Providence Medical Center, 4805 NE Glisan Street, Portland, OR 97213, USA |
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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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