Combined Anti-CD40 Conditioning and Well-timed Immunization Prolongs CD8+ T Cell Accumulation and Control of Established Brain Tumors

Abstract

Adoptive cell transfer has been shown to significantly reduce established tumors in both experimental models and cancer patients. Owing to the tolerogenic nature of cancer, approaches that lead to durable maintenance of functional T cells in tumor-bearing hosts are needed to maximize tumor regression. In this study, we investigated strategies to augment CD8+ T-cell (T-CD8)-mediated adoptive immunotherapy of mice bearing advanced-stage autochthonous brain tumors by targeting a weakly immunogenic epitope. We found that immunization enhanced the accumulation of adoptively transferred T-CD8 at the tumor site, but that the timing of immunization was critical for optimal T cell expansion. A more rapid accumulation of T-CD8 was achieved when mice were conditioned with agonist anti-CD40 antibody before adoptive transfer due to increased T cell activation against the endogenous tumor antigen. Both approaches led to an increase in the lifespan of SV11 mice due to decreased tumor progression. However, tumor-specific T-CD8 did not persist long term at the tumor site after administration of either regimen. Importantly, the combination of anti-CD40 conditioning followed by optimally timed immunization synergistically promoted long-term maintenance of T-CD8 in the brain and dramatically enhanced survival. A second round of combination immunotherapy resulted in a further increase in survival, suggesting long-term tumor sensitivity to CD8+ T-cell-based immunotherapy. These results demonstrate that even a weak antigen can be effectively targeted for control of established tumors using a combined adoptive transfer plus immune modulation approach and suggest that similar strategies may translate to clinical practice.