The ability of T cells to destroy bacteria, viruses, or tumor cells necessarily depends on recognition of the offending cell. Tumor cells hide by leveraging the immune system’s own mechanisms, including immune checkpoints, such as cytotoxic T lymphocyte antigen-4 (CLTA-4) and PD-1, that serve to maintain self-tolerance and prevent the immune system from excessively damaging healthy cells when responding to pathogens.1 In general, tumors tend to express normal levels of receptors that regulate activation of T cells while overexpressing those that regulate T-cell effector functions. Using this adaptation, tumor cells evade the immune system and inhibit those T cells that do recognize them from mounting an effective immune response.1 Immunotherapy strategies to overcome this tumor cell survival strategy include CTLA-4 inhibition in melanoma (with ipilimumab) as well as research into PD-1, HSP90, and other checkpoint proteins.1,2
An innovative approach to cancer treatment stimulates tumor antigen presentation through vaccination, which in turn should provoke a robust immune response. Such an approach is now being used to treat advanced prostate cancer with sipuleucel-T, a dendritic cell (DC) vaccine that stimulates a specific T-cell response to an antigen overexpressed in prostate cancer.2
In preclinical studies, the delivery of tumor antigen to DCs using receptor-specific monoclonal antibodies (mAbs) plus DC-activating agents has elicited robust, antigen-specific immune responses. In a study reported in the journal Science and Translational Medicine in April, researchers sought to trigger robust humoral and cellular immunity by priming the immune system with a vaccine against NY-ESO-1, an antigen expressed by several tumor types. They further hypothesized that this approach might enhance response to subsequent therapy with checkpoint inhibitors, such as ipilimumab and the Toll-like receptor (TLR) inhibitor resiquimod.3
In this phase 1 study, 45 patients with advanced malignancies refractory to current treatment received escalating doses of CDX-1401 along with the TLR agonists resiquimod and hiltonol. The vaccine is composed of a fully human mAb-specific DEC-205, a molecule expressed on DCs, fused to a full-length NY-ESO-1 tumor antigen. Treatment-induced humoral and cellular immunity against NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors: anti-NY-ESO-1 antibody titers developed in 79% of evaluable patients, including 33% who developed very high titers (> 1:100,000). Although NY-ESO-1–specific T-cell responses were largely absent or low at baseline, they increased postvaccination in 56% of evaluable patients, with both CD4 and CD8 T-cell responses seen.