Abstract
Simple SummaryLate-stage colorectal cancer treatment often involves chemotherapy and radiation that can cause dose-limiting toxicity, and therefore there is great interest in developing targeted therapies for this disease. Immunotherapy is a targeted therapy that uses peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer. Here, we discuss the preclinical and clinical development of immunotherapy for treatment of colorectal cancer and provide an overview of predictive biomarkers for such treatments. We also consider open questions including optimal combination treatments and sensitization of colorectal cancer patients with proficient mismatch repair enzymes.Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.
Highlights
Colorectal cancer (CRC) is a deadly disease with a 5 year survival rate of 13% when metastatic
As dendritic cells (DCs) are required for antigen presentation and activation of CD8+ T cells, their low numbers likely contribute to the resistance of liver metastatic CRC (mCRC) cell tumors
It is currently unclear if FDA-approved immune checkpoint blockade (ICB) treatments are more effective in the neoadjuvant or adjuvant setting, or if IT should be combined with chemotherapy or targeted treatments
Summary
Colorectal cancer (CRC) is a deadly disease with a 5 year survival rate of 13% when metastatic. CRC is classified based on genetic alterations present in the tumor such as mutations in APC, KRAS, BRAF, p53, and mismatch repair (MMR) enzymes [3]. Numerous preclinical studies have demonstrated promising results and have been translated into clinical trials While many of these trials are ongoing, some ITs are currently approved for CRC including mAbs that target cancer-associated antigens, namely panitumumab (anti-EGFR), cetuximab (antiEGFR), and bevacizumab (anti-VEGF) [7]. The clinical success of ICB therapy in specific CRC patient populations has made it highly relevant in the field of cancer IT. This review will discuss the molecular bases of ITs that have been investigated preclinically and clinically for treatment of CRC, provide an overview of current predictive biomarkers for IT in CRC, will consider future requisite topics of investigation including identification of optimal combination treatments and investigation of methods to sensitize MSS CRC to IT
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