How do I steer this thing? Using dendritic cell targeted vaccination to more effectively guide the antitumor immune response with combination immunotherapy

Stefanie N. Linch, William L. Redmond

Mounting an immune response sufficient to eradicate a tumor is the goal of modern immunotherapy. Single agent therapies with checkpoint inhibitors or costimulatory molecule agonists are effective only for a small portion of all treated patients. Combined therapy, e.g., CTLA-4 and PD-1 checkpoint blockade, is a more effective treatment modality, but in preclinical studies OX40 agonism with CTLA-4 blockade using monoclonal antibodies (aOX40/aCTLA-4) failed to induce tumor regression of larger, more established tumors. We hypothesized that administration of a vaccine with a tumor-associated antigen targeted to the appropriate antigen presenting cell could make combined aOX40/aCTLA-4 therapy more effective. We administered an antibody-based vaccine targeting HER2 to the DEC-205 endocytic receptor on cross-presenting dendritic cells (anti-DEC-205/HER2; aDEC-205/HER2) and a potent adjuvant (poly (I:C)) to assist with maturation, along with aOX40/aCTLA-4 therapy. This therapy induced complete regression of established tumors and a pronounced infiltration of effector CD8 and CD4 T cells, with no effect on regulatory T cell infiltration compared to aOX40/aCTLA-4 alone. To be maximally effective, this therapy required expression of both OX40 and CTLA-4 on CD8 T cells. These data indicate that vaccination targeting cross-presenting dendritic cells with a tumor-associated antigen is a highly effective immunization strategy that can overcome some of the limitations of current systemic immunotherapeutic approaches that lack defined tumor-directed antigenic targets.