Combination CD40 agonist and PD-1 antagonist antibody therapy enhances vaccine induced T cell responses in non-immunogenic cancers
Hayley Ma, Evanthia Roussos Torres, Brian Christmas, Blake Scott, Tara Robinson, Todd Armstrong, Elizabeth Jaffee*
Dept of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
Our study asks the question of whether combining a T cell inducing vaccine and PD-1 inhibition with CD40 agonist antibody (Ab) can induce T cell priming and tumor infiltrating lymphocyte (TIL) activation in non-immunogenic solid malignancies. T regulatory cells and myeloid derived suppressor cells (MDSCs) dampen the immune response, and tumor antigen-specific T cell tolerance limits the efficacy of therapeutic cancer vaccines. CD40 signaling is critical to the decision of whether T cells become primed or tolerized, and administration of monoclonal CD40 agonistic Ab has been shown to promote CD8 activation in vivo.
We utilized an immune tolerant model of HER2/neu-expressing breast cancer to assess the effects of drug combinations on intratumoral immune responses. Tumor-bearing mice were treated with a granulocyte macrophage colony-stimulation factor secreting vaccine (GVAX) + anti-PD-1 Ab alone or in combination with CD40 Ab. Mice treated with GVAX + anti-PD-1 Ab + CD40 Ab had delayed tumor progression and increased median survival relative to CD40 Ab alone, although endogenous T cell infiltration remained low across treatment groups. However, adoptive transfer of neu-specific T cells revealed 100% tumor clearance in the combination-treated mice, along with significant T cell infiltration and activation as measured by IFNγ, Granzyme B and TNFα-secreting CD8+ T cells. In contrast, only 20% of mice treated with GVAX + anti-PD-1 Ab were able to clear tumor, and none of the mice receiving vehicle or CD40 Ab alone had long-term survival. Trends were also observed in monocytic and dendritic cell infiltration and maturation in the tumors of combination-treated mice, and warrant further investigation. In conclusion, GVAX, anti-PD-1 Ab and CD40 agonist Ab have potential synergy in modulating anti-tumor immunity in breast cancer.
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