Combining Immune Checkpoint Inhibitors with Anti-Angiogenic Agents.

Paola Ciciola,Luigi Formisano,Roberto Bianco,Cataldo Bianco,Priscilla Cascetta

doi:10.3390/jcm9030675

Abstract

Immunotherapy has recently emerged as a novel strategy for treating different types of solid tumors, with promising results. However, still a large fraction of patients do not primarily respond to such approaches, and even responders sooner or later develop resistance. Moreover, immunotherapy is a promising strategy for certain malignancies but not for others, with this discrepancy having been attributed to a more immunogenic microenvironment of some tumors. As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs have already demonstrated their effectiveness both in preclinical and in clinical settings. By targeting abnormal formation of tumor vessels, anti-angiogenetic agents potentially result in an enhanced infiltration of immune effector cells. Moreover, crosstalks downstream of the immune checkpoint axis and vascular endothelial growth factor receptor (VEGFR) signaling may result in synergistic effects of combined treatment in tumor cells. In this review, we will describe and discuss the biological rationale of a combined therapy, underlying the modification in tumor microenvironment as well as in tumor cells after exposure to checkpoint inhibitors and anti-angiogenic drugs. Moreover, we will highlight this strategy as a possible way for overcoming drug resistance. By first discussing potential prognostic and predictive factors for combined treatment, we will then turn to clinical settings, focusing on clinical trials where this strategy is currently being investigated.

Highlights

IntroductionMultiple T cell checkpoint molecules have been described, and the blockade of either of of these two inhibitory proteins, cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1), has resulted in clinical benefit in several tumor types [3,4,5,6]
An increasing amount of preclinical data indicates that vessel normalization strategies can improve the aberrant structure and function of tumor blood vessels and can result in reduction of tumor hypoxia, reduction of function of suppressive cells, and promotion of antitumor activity of immune effector cells
Many studies are focusing on reprogramming tumor microenvironment to become more immune-stimulatory by combining anti-angiogenic drugs and immune check point inhibitors

Summary

Introduction

Multiple T cell checkpoint molecules have been described, and the blockade of either of of these two inhibitory proteins, cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1), has resulted in clinical benefit in several tumor types [3,4,5,6]. CTLA4 (CD152) is a membrane glycoprotein expressed by immunosuppressive T regulatory cells (Tregs) that inhibits early T cell activation and has an important role in the priming phase of the immune response [7,8]. The blockade of CTLA4 led to a 1.5- to two-fold increase in the proliferation of T cells, a six-fold increase in the production of interleukin-2 [9,10] and the depletion of T regulatory lymphocytes in the tumor microenvironment through a macrophage-dependent process [10,11]. PD1 (CD279) is an inhibitory co-receptor expressed on the cell surface of T lymphocytes CD8+ and CD4+, natural killer cells (NK), B lymphocytes, and tumor-infiltrating lymphocytes (TILs) [15]

Methods

Results

Conclusion