Abstract

Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.

Highlights

  • Colorectal cancer (CRC) had 1.93 million new patients and caused 935,000 deaths worldwide in 2020, making it the third most common cancer and the second leading cause of cancer death in the world [1]

  • We provided the latest findings in immunotherapy of CRC

  • Approval of monoclonal antibodies (mAbs) such as Bevacizumab, Cetuximab, Panitumumab, and Ramucirumab as the first and second line of treatment with chemotherapy in metastatic CRC (mCRC) led to greater interest in CRC immunotherapy [5, 45]

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Summary

INTRODUCTION

Colorectal cancer (CRC) had 1.93 million new patients and caused 935,000 deaths worldwide in 2020, making it the third most common cancer and the second leading cause of cancer death in the world [1]. In 15% of CRCs, the high mutational burden (>12 mutations per megabase) is due to a defect in the genes of mismatch repair (MMR) systems such as MLH1, MSH2, MSH6, and PMS2, which causes transcriptional problems, especially in regions with repetitive nucleotides such as microsatellites. This group has microsatellite instability and is called deficient MMR/microsatellite instability-high (dMMR/MSI-H) CRCs. The second category, which comprises 85% of CRCs, has a much lower mutational burden (

CRC Microenvironment
Antibodies and Derivatives
Immune-Checkpoint Inhibitors
CRC HETEROGENEITY: A CHALLENGE OF IMMUNOTHERAPY
Efforts to Overcome CRC Heterogeneity
Cancer Vaccines
22 Montanide ISA-51 VG
Adoptive T Cell Therapy
30 BCG vaccine
Pembrolizumab Terminated
Role of the Microbiome in Personalized Immunotherapy
Combination Therapy
Findings
CONCLUSION
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