Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future.

Ece Esin

doi:10.1155/2017/1623679

Abstract

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

Highlights

“Natural forces within us are the true healers of disease” is a famous quote from Hippocrates which refers to the recent renaissance of cancer treatment
The encouraging results of ipilimumab in melanoma have been supported by trials with a PD-1 antagonist, and overall advantage of survival in addition to improvement in objective response rate [20] and progression free survival (PFS) were shown in randomized controlled phase III trials of PD-1 antagonists Nivolumab and pembrolizumab [21,22,23,24,25]
Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies and even in some refractory cases [31,32,33]. Despite these promising results and the characteristic response durability, ipilimumab, nivolumab, pembrolizumab, and atezolizumab as single agents only have a range of 10–35% response rates

Summary

Introduction

“Natural forces within us are the true healers of disease” is a famous quote from Hippocrates which refers to the recent renaissance of cancer treatment. Researchers found that the ignorance of self-proteins, which protect the body from autoimmune diseases (the “natural forces” in Hippocrates quote), acts as a key mechanism behind tumoral escape from destruction. The mechanism of the continuous guarding of progressive mutations happening in a single cell (immune-surveillance) was discovered; the production of new cancer cell antigens (neoantigens), the recognition of both cancer specific and malignancy associated antigens by the T-cells, and elimination of numerous tumors by immunoediting were understood in detail. The tumor associated antigens are recognised by Tcells, which leads to tumors being eradicated; tumoral cells escape from immunoediting by expressing programmed cell death ligand (PDL-1) and similar inhibitory gene products like IDO (indolamine 2,3 dioxygenase), TGFβ (transforming growth factor-β), and Interleukin-10 (IL-10). One of the mechanisms of cancer evolution to escape from antitumor guarding of immune system is the deactivation or silencing the effector T-cells. From the knowledge and experience of classical cytotoxic drugs, one of the solutions which have been put forth to overcome the challenges encountered in clinical practice is combination strategies

The Rationale and Scientific Background of Combinatorial Immunotherapies

Combination Strategies

Findings

Conclusion