Combination therapy with anti-CTLA4 and anti-PD1 leads to distinct immunologic changes in-vivo
Das, R., Verma, R., Sznol, M. et al.Combination therapy concurrently targeting PD1 and CTLA4 immune checkpoints leads to remarkable anti-tumor effects. While both PD1 and CTLA4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. In order to better understand biologic effects of therapy, we analyzed blood/tumor tissue from 45 patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA4, PD1 or combination of the two leads to distinct genomic and functional signatures in vivo in purified human T cells and monocytes. Therapy-induced changes are more prominent in T cells than in monocytes and involve largely non-overlapping changes in coding genes including alternatively-spliced transcripts, and non-coding RNAs. Pathway analysis revealed that CTLA4-blockade induces a proliferative signature predominantly in a subset of transitional memory T cells, while PD1-blockade instead leads to changes in genes implicated in cytolysis and natural killer cell function. Combination blockade leads to non-overlapping changes in gene expression including proliferation-associated and chemokine genes. These therapies also have differential effects on plasma levels of CXCL10, sIL2R and IL1α. Importantly, PD1 receptor occupancy following anti-PD1 therapy may be incomplete in the tumor T cells even in the setting of complete receptor occupancy in circulating T cells. These data demonstrate that in spite of shared property of checkpoint blockade, antibodies against PD1, CTLA4 alone or in combination have distinct immunologic effects in vivo. Improved understanding of pharmacodynamic effects of these agentsin patients will support rational development of immune-based combinations against cancer.
Das, R., Verma, R., Sznol, M. et al. "Combination therapy with anti-CTLA4 and anti-PD1 leads to distinct immunologic changes in-vivo" Journal of Immunology (2015): 950–9