Combination CD40 agonist and PD-1 antagonist antibody therapy enhances vaccine induced T cell responses in non-immunogenic cancers
Hayley Ma, Evanthia Roussos Torres, Bibhav Poudel, Tara Robinson, Brian Christmas, Kayla Cruz, Skylar Woolman, Blake Scott, 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 (Tregs) and myeloid derived suppressor cells (MDSCs) dampen the immune response, and the presence of extensive stromal networks within the tumor microenvironment (TME) can prevent T cell infiltration in many tumor types. CD40 is expressed on antigen presenting cells, and CD40 signaling is critical to the decision of whether T cells become primed or tolerized. Administration of monoclonal CD40 agonistic antibody (Ab) has been shown to promote CD8 activation in vivo, and likely alters the myeloid component of the TME.
We utilized mouse models of breast and pancreatic cancer to assess the effects of drug combinations on intratumoral immune responses. Tumor-bearing mice were treated with a GM-CSF secreting vaccine (GVAX) + anti-PD1 Ab alone or in combination with CD40 Ab. Mice treated with GVAX + anti-PD1 + CD40 Ab had delayed tumor progression and increased median survival. In both a subcutaneous and hemisplenectomy model of pancreatic cancer, 90-100% of mice treated with the combination were tumor free at day 120. In contrast, 70% of mice treated with GVAX + anti-PD1 succumbed to disease. The survival benefit was accompanied by significant tumor infiltration and activation of T cells as measured by IFNγ, Granzyme B and TNFα-secretion. Further characterization of immune populations was carried out by high dimensional flow cytometric analysis utilizing t-SNE dimensionality reduction and clustering algorithms. Changes were observed in monocytic and dendritic cell infiltration and maturation in the tumors of combination-treated mice. A significant decrease in granulocytic MDSCs was associated with response, as well as an increase in mature antigen presenting cells. In conclusion, GVAX, anti-PD-1 and CD40 agonist Ab have potential synergy in modulating anti-tumor immunity in non-immunogenic cancers.
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