The effect of aging on OX40 agonist-mediated cancer immunotherapy

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.