Anti-CD40 monoclonal antibody therapy in combination with irradiation results in a CD8 T-cell–dependent immunity to B-cell lymphoma

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Abstract
The mechanisms of interaction between anti-CD40 monoclonal antibody (mAb) therapy and external beam irradiation were investigated in 2 syngeneic B-cell lymphoma models. We have established doses of anti-CD40 mAb and irradiation which, although ineffective when given singly, were capable of providing long-term protection when used in combination. Furthermore, such treatment was not only critically dependent on the dose of mAb and irradiation but also on tumor load, with greater efficacy only occurring at higher tumor burden. Using blocking antibody, the potency of treatment was shown to be totally dependent on CD8+ T cells, with protective levels of CD8+ cells occurring only in mice receiving the combination of anti-CD40 and irradiation. Interestingly, the ratio of T cells (CD8+) to tumor cells in mice receiving combination treatment was between 10 and 15 times that seen in animals given anti-CD40 or irradiation alone. In vivo tracking experiments revealed a 2-phase decrease in tumor burden, the first resulting directly from the external irradiation and the second, occurring 5 days later, concomitant with the rise in tumor-specific CD8+ cells. We suggest that the external irradiation induced an initial kill of lymphoma cells, probably by apoptosis, which releases tumor antigens and slows the progression of the malignancy to allow generation of a curative cytotoxic T lymphocyte (CTL) response promoted by the anti-CD40 mAb. Combining irradiation with immunomodulatory mAb as described here appears to provide a powerful new approach to the management of cancer.