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. Due to the toleragenic 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 prior to 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 following 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.

Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors

“…We previously demonstrated that agonist αCD40 administration dramatically enhanced initial CD8 T cell priming against established T Ag-induced tumors, and resulted in either prolonged tumor control or tumor regression [7, 8, 23]. Increased T cell accumulation in vivo is consistent with the proposed mechanism of αCD40-enhanced antigen presentation and delivery of co-stimulatory and cytokine signals by professional APCs [24–26].…”

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

“…The combination of anti-CD40 with ACT was previously shown to enhance the magnitude of tumor-specific T-cell responses, but had only a minimal impact on tumor progression [18, 31, 33, 42] unless additional immune modulators, such as interleukin (IL)-2 or immunization, were provided [31–33]. Our results demonstrate that agonist anti-CD40 alone not only facilitates rapid, high-level donor CD8 + T-cell accumulation systemically and at the tumor site but also promotes regression of established autochthonous tumors.…”

“…Our results demonstrate that agonist anti-CD40 alone not only facilitates rapid, high-level donor CD8 + T-cell accumulation systemically and at the tumor site but also promotes regression of established autochthonous tumors. This robust response may be explained in part by the choice of target antigen, as targeting the weaker and less stable T Ag site V determinant with this approach previously failed to induce significant regression of choroid plexus tumors unless mice received multiple rounds of immunization [31]. Likewise, Cho et al found that using a combination of anti-CD40, tumor peptide, poly:ICLC, and recombinant IL-2 immune complexes with ACT was most effective against antigenic determinants expressed at relatively high levels on the tumor cells [32].…”

“…In particular, combination with ACT has yet to be translated to human cancer patients. Anti-CD40 conditioning promotes the in vivo expansion of adoptively transferred T cells capable of controlling solid tumor progression in experimental models [18, 31–33], however the effects on immune surveillance and tumor recurrence have not been thoroughly investigated. Thus, anti-CD40 conditioning could potentially broaden the use of ACT therapy to cancer patients for whom lymphodepleting chemotherapy or WBI is contraindicated.…”

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

“…Likely depending on one or more of the above-described mechanisms, targeting of CD40 has already been proven a promising strategy in several preclinical models and clinical trials against solid cancer ( 120 , 149 – 154 ). Also in preclinical models of ACT, agonistic CD40 antibodies promote tumor-specific T cell expansion and enhanced anti-tumor activity ( 155 , 156 ). Thus, clinical effectiveness in ACT has potential given that CD40 antibody-associated toxicity is managed ( 152 , 157 ).…”