Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGF beta and PD-1/PD-L1

摘要

IntroductionIn solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor beta (TGF beta) in diverse immunity is well-established; however, systemic blockade of TGF beta is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGF beta and PD-1/PD-L1 pathways.Areas coveredWe focus on TGF beta and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGF beta in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGF beta and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies.Expert opinionThe heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGF beta and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGF beta in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.