Immunotherapy for Colorectal Cancer

A Review of Current and Novel Therapeutic Approaches

Aaron J. Franke; William Paul Skelton IV; Jason S. Starr; Hiral Parekh; James J. Lee; Michael J. Overman; Carmen Allegra; Thomas J. George


J Natl Cancer Inst. 2019;111(11):1131-1141. 

In This Article

Abstract and Introduction


Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today's clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.


Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with an estimated 135 430 new cases and 50 260 cancer-related deaths annually.[1] Although the incidence and disease-specific mortality has gradually declined over the past two decades, recent studies describe a disturbing trend of an increased incidence in younger (<50 years) individuals.[2,3] The majority of patients diagnosed with metastatic colorectal cancer (mCRC) have incurable disease, with the exception of those with oligometastatic disease, for which successful surgical or ablative interventions and systemic therapy has yielded 5-year and 10-year survival rates of approximately 40% and 20%, respectively.[4–6] For all other patients with mCRC, the use of combination systemic therapies and optimal supportive care has produced meaningful improvements in mortality, with the median overall survival (OS) now exceeding 30 months.[7] However, with an overall 5-year survival of only approximately 20%, there remains much room for improvement with therapeutic strategies.

In recent years, there have been substantial advancements in our understanding of the intersection between host immune surveillance and tumorigenesis. As a result, clinically beneficial pharmacologic interventions have led to the approval of immunotherapeutic agents for all advanced microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) solid tumors, including mCRC (Table 1). The demonstration of durable clinical responses and improved survival outcomes in these select situations has spurred a renewed interest in using the immune system as an antineoplastic biological weapon. Unfortunately, for the vast majority of patients with mCRC whose tumors are not MSI-H:dMMR (>95%), immunotherapy currently offers little to no clinical benefit.

The aims of this comprehensive review are to examine what is known about the immunological microenvironment in mCRC and summarize the available evidence regarding the use of immunotherapy in current treatment paradigms. Moreover, through an updated analysis of the existing literature and anticipated results of ongoing clinical trials, we discuss pragmatic strategies for future investigation into novel immunotherapy targets and discuss current obstacles in navigating the immunological landscape of mCRC.