The Heat-Stable Enterotoxin Receptor, Guanylyl Cyclase C, as a Pharmacological Target in Colorectal Cancer Immunotherapy: A Bench-to-Bedside Current Report.

Trevor Baybutt,Adam Snook,Allison Aka

doi:10.3390/toxins9090282

Trevor Baybutt, Adam Snook + Show 1 more

Open Access

https://doi.org/10.3390/toxins9090282

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Journal: Toxins	Publication Date: Sep 15, 2017
Citations: 5	License type: CC BY 4.0

Affiliation: Thomas Jefferson University

Abstract

Cancer immunotherapy is becoming a routine treatment modality in the oncology clinic, in spite of the fact that it is a relatively nascent field. The challenge in developing effective immunotherapeutics is the identification of target molecules that promote anti-tumor efficacy across the patient population while sparing healthy tissue from damaging autoimmunity. The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety. Here, we describe the current state of GUCY2C-directed cancer immunotherapy and the future directions of this work.

Highlights

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States, with the 5-year survival prognosis for patients with Stage IV disease being only 11% [1]
These two drug targets have been explored in myriad solid tumors, and the United States Food and Drug Administration (FDA) has recently granted fast track approval for the use of the PD-1 inhibitor nivolumab (Opdivo® ) for colorectal cancer patients with mismatch repair deficient and microsatellite instability positive (MSI+) disease (CheckMate-142 Trial, NCT02060188) [2]
T-cell response was sufficient to provide the help necessary for both B and CD8+ T cells to improve the GUCY2C response. This improved immune response conferred a substantial improvement in protection against colorectal cancer metastases in lungs, increasing survival 750% compared to the conventional GUCY2C vaccine [26]

Summary

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States, with the 5-year survival prognosis for patients with Stage IV disease being only 11% [1]. Of most recent success has been monoclonal antibody therapy directed against the T-cell inhibitory signaling molecules cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), collectively referred to as checkpoint inhibitors These two drug targets have been explored in myriad solid tumors, and the United States Food and Drug Administration (FDA) has recently granted fast track approval for the use of the PD-1 inhibitor nivolumab (Opdivo® ) for colorectal cancer patients with mismatch repair deficient (dMMR) and microsatellite instability positive (MSI+) disease (CheckMate-142 Trial, NCT02060188) [2]. It should be noted, that this therapy is effective in only a subset of MSI+. The intestinal epithelial, transmembrane cyclase, guanylyl cyclase C (GUCY2C), is an ideal immunotherapeutic target, because it occupies an endogenous, compartmentalized luminal niche protected from systemic autoimmune adverse events, whereas its depolarized expression on metastatic colorectal cancer can be targeted therapeutically

Guanylyl Cyclase C

Vaccines

Immunotoxins and Antibody-Drug Conjugates

Chimeric Antigen Receptor T Cells

Findings

Conclusions