v
Search
Advanced Search

Publications > Journals > Exploratory Research and Hypothesis in Medicine > Article Full Text

  • Review Article
  • OPEN ACCESS

Immunotherapy in Colorectal Cancer: A Review

  • Alfredo Colombo1,* ,
  • Vittorio Gebbia2 and
  • Concetta Maria Porretto1
 Author information
Exploratory Research and Hypothesis in Medicine   2024;9(1):32-38

doi: 10.14218/ERHM.2023.00008

Abstract

The results of new randomized clinical trials show that immunotherapy is the preferred treatment for a small proportion of metastatic colorectal cancers (mCRCs). For microsatellite instability-high mCRC, pembrolizumab, nivolumab, and ipilimumab are currently authorized as first- and second-line immune checkpoint agents. However, the problem concerns tumors with microsatellite stability where the “cold” microenvironment does not allow immunotherapy to function properly. All efforts are now aimed at ensuring that this microenvironment is inflamed and “hot”. In this review, we examine recent studies on immunotherapy for mCRC and assess novel drivers of immunotherapy response.

Keywords

Colorectal cancer, Immunotherapy, Anti-PD-L1, Anti-PD-1

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths and the third leading cause of cancer overall. Treatment strategies for this disease constitute a global health problem.1 Morbidity and mortality rates are declining due to screening. At diagnosis, 25% of patients with CRC have advanced disease, and 25% to 50% of patients with early-stage disease may have already developed metastases.2–4 The 5-year survival rate for patients with metastatic disease is 4%, compared to 25% for patients with metastatic colorectal cancer (mCRC) after tumor resection and chemotherapy.5–8 Even if advantages have been obtained from chemical and targeted therapies, the 5-year prognosis remains poor. Therefore, efforts are being made to develop new drugs. Immunotherapy treats cancer by stimulating the immune system. For patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H), immune checkpoint inhibitors (ICIs) have demonstrated marked effectiveness. By modifying the interaction between T cells, antigen-presenting cells (APCs), and tumor cells, ICIs aim to reinvigorate suppressed immune responses.

Pembrolizumab and nivolumab (with or without ipilimumab) have gained approval from the U.S. Food and Drug Administration as treatments for these patients. However, comprehending the potential benefits of immunotherapy for patients without microsatellite instability (MSS) remains a challenge.9 This review outlines the present research endorsing the application of ICIs in CRC, emphasizes recent progress in the expanded use of ICIs in MSS/MSI-L CRC patients, and sheds light on emerging biomarkers that could predict the response to immunotherapy.

Methods

We searched PubMed (www.ncbi.nlm.nih.gov/pubmed ) for full-text articles published from 2017 to May 31, 2023, using the keywords immunotherapy, cancer, CRC, anti-programmed death ligand 1 (PD-L1), and anti-programmed death-1 (PD-1). The full-text articles found were carefully examined. In addition, all abstracts presented at international conferences between January 2020 and January 2023 were reviewed.

Microsatellites as biomarkers of reactions

DNA integrity relies on the essential function of mismatch repair (MMR).10 Immunohistochemical staining of MMR proteins—MLH1, MSH2, MSH6, or PMS2—allows the categorization of CRCs into two groups: those with dMMR and those with proficient mismatch repair MMR (pMMR).11 Microsatellite instability (MSI) can be detected by polymerase chain reaction or next-generation sequencing and may result from insertions or deletions.11

MSI refers to changes in microsatellite length resulting from alterations in MMR status. Within the cell surface, major histocompatibility complex class I-peptide complexes contain mutant peptides recognized as neoantigens that stimulate immune cell priming and infiltration. In the tumor microenvironment, circulating T helper 1 CD4+ T cells, macrophages, and CD8+ tumor-infiltrating lymphocytes release interferons, which exert antitumor effects. However, in dMMR/MSI-H tumor cells, immune evasion is facilitated by continuous upregulation of T-cell inhibitory ligands, such as the B7 family members PD-L1, CD80, and CD86.12–16 dMMR/MSI-H CRCs account for less than 15% of all CRCs, and their incidence correlates with tumor stage.17 Only 5% of stage IV patients have dMMR/MSI-H, compared to approximately 20% of patients with stage I or II disease and 12% of patients with stage III disease.18 As a predictive biomarker for patients at different stages, the dMMR/MSI-H status is important.18–21 In stages II and III, patients with dMMR/MSI-H tumors exhibit a more favorable prognosis than those with MSI-L tumors. However, intriguingly, even when treated with immune checkpoint inhibitors, stage IV dMMR/MSI-H patients still have a poor prognosis.22

Immunotherapy as a second-line treatment for mCRC

Pembrolizumab or nivolumab, with or without ipilimumab, received clinical authorization for use in 2017 as a second-line treatment for mCRC patients with dMMR/MSI-H. Pembrolizumab was administered in the phase II KEYNOTE 016 trial to treat patients with refractory mCRC.23 Patients with MSI-low achieved an objective response rate (ORR) of 0% and the disease control rate (DCR) was 50%, while patients with dMMR-MSI-H had an ORR of 16% and a DCR of 89%. The CheckMate142 study evaluated nivolumab, with or without ipilimumab, in mCRC and dMMR/MSI-H patients.24 After 13.4 months, 55% of the patients with MSI-H showed an ORR of 55% and a DCR of 80%, while patients with MSS had an ORR of 0% and a DCR of 16%. The study’s 119 participants were assessed for progression-free survival (PFS) and overall survival (OS) at the 12 months, which were 71% and 85%, respectively.25,26

Immunotherapy as a first-line treatment in mCRC

Due to the favorable outcomes observed in the second-line treatment of mCRC patients with dMMR/MSI-H tumors, there is growing interest in utilizing immunotherapy as a first-line therapy. Several randomized clinical trials have drawn significant attention (NIH-ClinicalTrials.gov: NCT02563002; NCT02060188).27

In a phase III trial called KEYNOTE177, which focused on first-line mCRC patients with MSI-H, pembrolizumab monotherapy was compared to standard therapy (NIH-ClinicalTrials.gov: NCT02563002). A total of 852 screened patients were enrolled, with 307 (36% of those screened) randomized to receive either chemotherapy or pembrolizumab (153 and 154 patients, respectively). Following disease progression, 60% of the patients switched from chemotherapy to anti-PD-1 therapy (56 to pembrolizumab, and 37 discontinued treatment). The median OS with pembrolizumab was not reached at the time of analysis, while it was 36.7 months (with a range of 27.6 to not reached) with chemotherapy. Although pembrolizumab did not demonstrate superiority over chemotherapy in overall survival because the statistical significance threshold was not met (prespecified error of 0.025), the median PFS for pembrolizumab was 16 months (with a range of 5 to 38 months) compared to 8 months (with a range of 6 to 10 months) for chemotherapy. As a result, pembrolizumab as a monotherapy for MSI-H tumors is becoming the standard first-line treatment for mCRC.28

In the CheckMate142 trial, the combination of nivolumab and low-dose ipilimumab was evaluated for efficacy and safety as a first-line therapy for patients with MSI-H mCRC.29 After a median follow-up of 13.8 months, the ORR and DCR were 60% and 84%, respectively, with a complete response (CR) rate of 7%. At 29 months, the ORR increased to 69%, and the CR rate increased to 13%. Notably, the combination of ipilimumab and nivolumab showed superior efficacy and safety compared to pembrolizumab monotherapy.

Additionally, treatment-naive mCRC patients with dMMR/MSI-H were included in the ongoing, randomized phase III COMMIT trial (Table 1), in which 347 patients were enrolled to receive mFOLFOX6/bevacizumab with or without atezolizumab. The primary endpoint of the trial was PFS, and secondary endpoints included OS, ORR, DCR, and frequency of adverse events (NIH-ClinicalTrials.gov: NCT02997228).

Table 1

Ongoing trials in patients with dMMR or MSI-H CRC

TreatmentClinicaltrials.gov IdentifierPhaseStudy treatment groupsPrimary endpointRecruitment status
First-lineNC102563002IIIPembrolizumab versus standard-of-care chemotherapyPFS, OS, ORRActive, not recruiting
NCT02060188IINivolumab ± ipilimumab or daratumumab or anti-LAG3ORRActive, not recruiting
AdjuvantNC102912559IIIAdjuvant atezolizumab + FOLFOX versus FOLFOX aloneDFSrecruiting
NeoadjuvantNCT03026140IINivolumab + Ipilimumab ± Celecoxibsafetyrecruiting
NCT02948348Ib/IICapecitabine + Radiation + Nivolumab + Surgical therapypCRunknown
NC102921256IIPembrolizumab/veliparib + chemotherapy + radiotherapyNAR scoreActive, not recruiting

CRC, colorectal cancer; DFS, disease-free survival; dMMR, deficient mismatch repair; FOLFOX, fluorouracil, leucovorin, Oxaliplatin; LAG3, lymphocyte-activation gene 3; MSI-H, microsatellite instability-high; NAR, neoadjuvant rectal cancer; ORR, objective response rate; OS, overall survival; pCR, pathological complete response.

Neoadjuvant and adjuvant therapy

Postoperative adjuvant therapy is needed for Stage III CRC patients. The ATOMIC study enrolled 700 stage III dMMR/MSI-H colon cancer patients to evaluate the efficacy of immunotherapy as an adjuvant treatment (NIH-ClinicalTrials.gov: NCT02912559).30

The control arm received only FOLFOX for 6 months, while the experimental arm received FOLFOX plus atezolizumab for 6 months, followed by 6 months of atezolizumab alone. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were OS and adverse event frequency. Treatment of early-stage CRC with neoadjuvant immunotherapy has yielded promising results. In the NICHE trial, a phase II study, 40 colon cancer patients (stage I and III) were included. Among them, 21 had dMMR tumors, and 20 had pMMR tumors (NIH-ClinicalTrials.gov: NCT03026140).31 All 21 patients with dMMR tumors who underwent ipilimumab and nivolumab treatment after successful surgery achieved a pathological response, indicating the primary endpoint of safety and survival. The efficacy of veliparib or pembrolizumab in combination with chemotherapy and radiation therapy (RT) was evaluated in the NRG-GI002 trial among patients with locally advanced rectal cancer (LARC) (NIH-ClinicalTrials.gov: NCT02921256). The primary endpoint was a reduction in the neoadjuvant rectal cancer score, while the secondary endpoints were sphincter-sparing surgery, pathological CR (pCR), clinical CR (cCR), DFS, toxicity, and OS.32

In another study, patients with locally advanced resectable rectal cancer received capecitabine radiation followed by sequential neoadjuvant immunotherapy. Three of the 5 patients with dMMR/MSI-H tumors achieved successful outcomes, specifically, pathologic complete response and major pathologic response (NIH-ClinicalTrials.gov: NCT02948348).33 These findings suggest that neoadjuvant immunotherapy may replace current CRC treatments for patients with dMMR/MSI-H tumors.

MSS/MSI-L CRC immunotherapy

In contrast to dMMR/MSI-H CRCs, which demonstrate a good response to ICIs, MSS/MSI-L tumors, accounting for approximately 95% of all mCRC, exhibit poor efficacy with ICI treatment due to their low mutational load and limited recruitment of immune cells. To address primary resistance to ICIs, researchers are exploring new approaches and immunomodulatory techniques for MSS/MSI-L CRCs, building on our increasing understanding of the tumor microenvironment in CRCs. Studies have shown that anti-PD-1/PD-L1 and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have synergistic effects.34 In the CCTG CO.26 study, the efficacy and safety of combination ICI therapy were evaluated in patients with advanced refractory CRC. This was a phase II trial that compared a combination of PD-L1 and CTLA-4 inhibitors, tremelimumab, and durvalumab, to best supportive care alone in patients with pMMR-MSS/MSI-L CRCs.35 At a median follow-up of 15 months, the experimental group had a median OS of 6 months, while the best supportive care group had a median OS of 4.1 months. This study was the first to indicate that the combination of anti-CTLA-4 therapy and anti-PD-L1 therapy could improve OS in MSS mCRC patients. Preclinical models have suggested that reducing prostaglandin E2 production could enhance the antitumor efficacy of ICIs.36,37 In the NICHE phase Ib trial conducted in 2014, patients with pMMR tumors received preoperative treatment with ipilimumab and nivolumab, with or without celecoxib, and a pathologic response was observed in 4 out of 15 patients (27% response rate). In MSI-H tumors, CD8+PD-1+ T-cell infiltration was found to be predictive of response. For KRAS/NRAS/BRAF wild-type mCRC, panitumumab, an epidermal growth factor receptor-targeted monoclonal antibody, was utilized. However, resistance to this treatment has been linked to increased expression of CTLA-4 and PD-L1.38 In the LCCC1632 single-arm phase II clinical trial, the safety and efficacy of combining nivolumab, ipilimumab, and panitumumab were evaluated in patients with mCRC (NIH-ClinicalTrials.gov: NCT03442569). Among the 49 evaluable subjects, a median PFS of 5.7 months and a 35% response rate at 12 weeks were observed. The trial recruited participants after reaching the primary endpoint due to favorable safety and efficacy outcomes, indicating that the combination of ICI and anti-epidermal growth factor receptor therapy could be used for treating MSS mCRC.

Combination of ICI and radiation therapy

Preclinical investigations have revealed that RT can trigger immunogenic cell death and release damage-associated molecular patterns. Additionally, it can augment antigen presentation by APCs, activate T lymphocytes, and enhance effects through abscopal effects.39 Damage-associated molecular patterns, characteristic of immunogenic cell death, include immunogenic cell surface markers, inflammatory cytokines, and cancer-related neoantigens that are upregulated on tumor cells. In a single-arm phase II study,40 the combination of pembrolizumab and external radiation produced a response in only one out of 22 patients with MSI-L CRC. However, more promising outcomes were observed when CTLA-4 and PD-1 were inhibited in combination with RT in a phase II clinical trial (NCT03104439). In this trial, the DCR was 29.2% (7/24), and the ORR was 12.5% (3/24).41

Initial findings from the phase I/II VOLTAGE-A trial indicate that a comprehensive approach involving radical surgery, nivolumab, and neoadjuvant chemoradiotherapy could be an effective treatment for MSS patients with LARC.34 Among the patients in the study, one patient (3%) achieved a cCR but opted out of radical surgery, while 11 out of 37 patients (30%) achieved a pCR. Notably, 38% (14/37) of patients experienced a major pathologic response, illustrating the potential of combining ICIs and RT in the treatment of cancer.

ICI and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combination

Inhibition of the MEK pathway, a downstream component of the Ras- mitogen-activated protein kinase system, leads to increased expression of MHC-I and PD-L1 within tumors. This enhances the clonal expansion of T lymphocytes surrounding the tumor and improves the effectiveness of ICIs.42,43 In a phase Ib trial, researchers evaluated a combination approach using the MEK inhibitor cobimetinib and the PD-L1 inhibitor atezolizumab.44,45 Preliminary results from a 2016 trial indicated that out of 23 patients with CRC, 4 (17%) achieved a partial response. Among them, 3 had MSI-L tumors, and 1 had an unknown status. In the 2018 follow-up data, a total of 7 out of 84 mCRC patients, comprising 6 with MSS/MSI-L and 1 with MSI-H, experienced manageable side effects and partial responses.46 Despite the potential for synergy that has been established in earlier trials, a subsequent phase III trial, IMblaze 370, which compared atezolizumab versus atezolizumab alone versus regorafenib in refractory CRC patients with MSI-L, did not confirm the anticipated synergistic effects.47 Nevertheless, several studies have investigated the combination of MEK inhibitors and ICIs (NIH-ClinicalTrials.gov: NCT02060188; NCT03428126; NCT03271047).

ICIs and anti-vascular endothelial growth factor agents

According to preclinical findings, antiangiogenic drugs have the potential to enhance the infiltration of CD8+ T cells into tumors. These drugs can also boost the antitumor activity of CD8+ T cells through various mechanisms, including the upregulation of PD-L1 expression, reduction of immunosuppressive cells such as tumor associated macrophages and Tregs, and improved interaction between APCs and dendritic cells.48–50

Additionally, one patient who received ICI therapy combined with an antiangiogenic agent (atezolizumab plus bevacizumab) achieved an objective response.51,52 Recent studies have also demonstrated remarkable antitumor efficacy with the combination of regorafenib and nivolumab.53 To investigate the safety and efficacy of the combination of nivolumab and regorafenib, 25 mCRC patients (24 with MSS and 1 with dMMR/MSI-H) were enrolled in the REGONIVO phase Ib/II trial. The results were intriguing, with an ORR of 36% and a median PFS of 7.9 months. The 1-year PFS and OS rates in patients with CRC were 41.8% and 68%, respectively. Given these favorable outcomes, larger cohort studies are warranted.53 In another study, the combination of pembrolizumab and lenvatinib was assessed in patients with treatment-naive advanced non-MSI-H/pMMR CRC in the LEAP-005 trial, which was an open-label, randomized, phase II trial.54 At a median follow-up of 10.6 months, the ORR and DCR for the 32 patients were 22% and 47%, respectively. The median PFS and OS were 2 and 3 months, respectively. The duration of the response is still ongoing. Due to the excellent antitumor efficacy and manageable safety profile of these agents, the enrollment in the study was increased to 100 patients.54

Biomarkers for immunotherapy

To improve the effectiveness of immunotherapy, it is crucial to investigate biomarkers that contribute to treatment response. The four main categories of biomarkers for CRC immunotherapy include PD-L1 expression, preexisting immune responses, tumor mutations, and the microbiome. Tumor mutation burden (TMB) quantifies the total number of somatic mutations per coding region of the tumor genome and encompasses all nonsynonymous coding mutations in the tumor exome.55,56 TMB has been shown to be an independent predictor of successful ICI treatment in patients with various malignancies, including CRC.57–59 Immunotherapy is likely to be more effective for tumors with high TMB due to the correlation between strong immunogenicity and elevated TMB. Notably, both MSI-H and MSS tumors can have increased TMB. Preliminary confirmation of immunotherapy efficacy was obtained in patients with elevated TMB in MSS CRC. In the REGONIVO trial, an exploratory analysis of 23 patients with CRC evaluated the TMB. The group with high TMB had a median PFS of 12.5 months, while the low TMB group had a median PFS of 7.9 months, with ORRs of 50% and 35.3%, respectively. Additionally, the CCTG CO26 trial utilized ctDNA analysis of blood samples to assess plasma TMB. In MSS CRC patients treated with PD-L1 and CTLA-4 inhibitors, improved OS was associated with increased plasma TMB, with a threshold of 28 mutations per megabase. A plasma TMB of 28 was suggested as a potential biomarker for identifying patients who could benefit from receiving durvalumab in combination with tremelimumab.

Role of polymerase ɛ (POLE)/DNA polymerase delta 1 (POLD1)

Polymerase ɛ POLE/ DNA polymerase delta 1 (POLD1) play a crucial role in DNA replication.60,61 In the context of CRC, the development of a hypermutation phenotype in DNA is linked to somatic or germline mutations in POLE and POLD1.62,63 These mutations are present in approximately 0.1% of tumors classified as MSS or MSI-L, affecting nearly 7.4% of all CRC patients.64 Notably, POLE-mutant CRCs exhibit distinct characteristics compared to POLE-wild-type CRCs. They are more likely to express effector cytokines, infiltrate CD8+ lymphocytes, express cytotoxic T-cell markers, and have increased levels of PD-L1, PD-1, and CTLA-4.65 POLE has been found to be more immunogenic than other approved biomarkers, such as MMR and MSI, and it is expected that it could be included as an important biomarker (NIH-ClinicalTrials.gov: NCT03435107; NCT03827044; NCT03150706). The presence of tumor-infiltrating lymphocytes, especially cytotoxic CD8+ T cells, has been associated with improved survival in retrospective studies of CRC.66 The density and location of T cells within the tumor may have greater predictive value for CRC patients compared to conventional TNM staging approaches.67 The Immunoscore, a scoring method that assesses the number of CD3+ T cells and CD8+ T cells at the tumor center and infiltrative margins using standardized parameters, was used to evaluate this aspect. Presently, a phase II multicenter trial is underway to evaluate the efficacy of ICIs in combination with chemical and angiogenesis inhibitors as primary therapies for pMMR-MSI-L mCRC patients with high Immunoscores (NIH-ClinicalTrials.gov: NCT04262687). Based on the Immunoscore, tumors are classified as hot, transformed, or cold depending on their immune response. Tumors with T-cell infiltration are referred to as hot tumors, those with inflammation but lacking infiltration are called transformed tumors, and noninflamed tumors are termed cold tumors.68 This classification considers not only the Immunoscore but also the immune signature and tumor microenvironment. Patients with hot tumors tend to respond better to ICIs, suggesting that they might benefit more from immunotherapy.

PD-L1 levels

The most extensively studied biomarker assessed through immunohistochemistry is the coinhibitory receptor ligand PD-L1. However, it has not been definitively established whether the PD-L1 expression level is linked to the effectiveness of ICIs in treating CRC. In the KEYNOTE016 phase II trial, which evaluated pembrolizumab in patients with refractory mCRC, PFS or OS was observed irrespective of the PD-L1 expression level.69 Similarly, in the Checkmate142 phase II trial comparing the efficacy of nivolumab monotherapy versus nivolumab in combination with ipilimumab, no significant correlation was found between PD-L1 expression and the ORR.70

Role of the microbiota

The gut microbiota plays a significant role in influencing the effectiveness of immunotherapy across various types of cancer. The composition of the gut microbiota might serve as a predictor of the efficacy of ICIs. Certain beneficial bacteria, such as Orcenera, Lactobacillus johnsonii, and Muciniphila, have been identified in this context. Moreover, Inosin-A2A receptor signaling was found to enhance the antitumor effects of ICI therapy when influenced by Bifidobacterium pseudolongum and A. mucinifera. A specific mechanism through which the gut microbiota positively interacts with immunotherapy involves T-cell-specific A2A receptor signaling. However, further research is needed to fully comprehend how the gut microbiota regulates the host’s antitumor immune response in the context of immunotherapy.

Future directions

Given the important results obtained in adjuvant, first-line, and second-line immunotherapy for patients with MSI-H CRC, current research efforts are directed toward achieving similar outcomes in patients with MSS CRC, where immunotherapy has given disappointing data. Another challenge is to enhance patient profiling and identify new response drivers to optimize immunotherapy response.

Conclusion

In recent years, immunotherapy has led to significant improvements in the survival of a small subset of CRC patients with the MSI-H phenotype. The U.S. Food and Drug Administration has approved pembrolizumab and nivolumab (with or without ipilimumab) as second-line therapies for mCRC patients with dMMR/MSI-H based on strong evidence from two phase II clinical trials. Furthermore, pembrolizumab was approved as a first-line therapy for mCRC with MSI-H status in 2020, following positive results from the KEYNOTE177 trial. Ongoing and upcoming clinical trials suggest that ICIs may also be beneficial as neoadjuvant therapy for early dMMR/MSI-H CRC. However, the majority of mCRC patients with MSI-L tumors face challenges in overcoming primary immunotherapy resistance. To address this subgroup, various ICI-based strategies have been explored to modulate immune cells and enhance therapeutic efficacy. These strategies include RT, combination therapy with antibodies that inhibit PD-1 or CTLA-4, combination therapy with small molecule tyrosine kinase inhibitors such as MEK inhibitors and ICIs, and the use of antiangiogenic agents. Early-phase clinical trials have shown promising results, but further research is necessary to establish the safety and efficacy of these approaches. As immunotherapy progresses, the transition toward biomarker-based therapies is expected. Selection criteria will be crucial in identifying patients who will benefit the most from these therapies. Although some biomarkers have already been identified, ongoing research aims to discover and validate highly sensitive and specific biomarkers.

With expanding knowledge in this field, new combinations of therapies and biomarkers will guide clinicians toward more personalized and targeted treatment strategies for patients with CRC. This personalized approach holds promise for improving outcomes and enhancing the overall effectiveness of immunotherapy in CRC management.

Finally, the limitations of our review are attributed to the small number of studies available for patients with d-MMR and the small number of studies on patients with p-MMR.

Abbreviations

APC: 

antigen-presenting cell

CR: 

complete response

clinical CR: 

cCR

CRC: 

colorectal cancer

CTLA-4: 

cytotoxic T lymphocyte-associated antigen-4

DCR: 

disease control rate

DFS: 

disease-free survival

dMMR: 

deficient mismatch repair

FOLFOX: 

fluorouracil, leucovorin, oxaliplatin

LAG3: 

lymphocyte-activation gene 3

LARC: 

locally advanced rectal cancer

ICI: 

immune checkpoint inhibitor

mCRC: 

metastatic colorectal cancer

MEK: 

mitogen-activated extracellular signal-regulated kinase

MMR: 

mismatch repair

MSI: 

microsatellite instability

MSI-H: 

MSI-high

MSS: 

microsatellite stability

NAR: 

neoadjuvant rectal cancer

ORR: 

objective response rate

OS: 

overall survival

pCR: 

pathological complete response

PD-1: 

programmed death-1

PD-L1: 

programmed death ligand 1

PFS: 

progression-free survival

pMMR: 

proficient mismatch repair

POLD1: 

DNA polymerase delta 1

POLE: 

polymerase ɛ

RT: 

radiation therapy

Declarations

Acknowledgement

We thank all the authors for their contributions.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

AC and CMP collaborated on the paper’s conception and wrote the paper. VG, AC and CMP reviewed the paper and approved the final version of the article to be published

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-249 View Article PubMed/NCBI
  2. Pinsky PF, Doroudi M. Colorectal Cancer Screening. JAMA 2016;316(16):1715 View Article PubMed/NCBI
  3. Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116(3):544-573 View Article PubMed/NCBI
  4. Sargent D, Sobrero A, Grothey A, O’Connell MJ, Buyse M, Andre T, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2009;27(6):872-877 View Article PubMed/NCBI
  5. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94(7):982-999 View Article PubMed/NCBI
  6. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25(29):4575-4580 View Article PubMed/NCBI
  7. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371(17):1609-1618 View Article PubMed/NCBI
  8. Hornbech K, Ravn J, Steinbrüchel DA. Outcome after pulmonary metastasectomy: analysis of 5 years consecutive surgical resections 2002-2006. J Thorac Oncol 2011;6(10):1733-1740 View Article PubMed/NCBI
  9. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 2015;125(9):3335-3337 View Article PubMed/NCBI
  10. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res 2008;18(1):85-98 View Article PubMed/NCBI
  11. Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 2019;16(6):361-375 View Article PubMed/NCBI
  12. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 2001;158(2):527-535 View Article PubMed/NCBI
  13. Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 1999;154(6):1805-1813 View Article PubMed/NCBI
  14. Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 2001;91(12):2417-2422 PubMed/NCBI
  15. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013;14(10):1014-1022 View Article PubMed/NCBI
  16. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5(1):43-51 View Article PubMed/NCBI
  17. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A national cancer institute workshop on microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58(22):5248-5257 PubMed/NCBI
  18. Battaglin F, Naseem M, Lenz HJ, Salem ME. Microsatellite instability in colorectal cancer: overview of its clinical significance and novel perspectives. Clin Adv Hematol Oncol 2018;16(11):735-745 PubMed/NCBI
  19. Lenz HJ, Ou FS, Venook AP, Hochster HS, Niedzwiecki D, Goldberg RM, et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J Clin Oncol 2019;37(22):1876-1885 View Article PubMed/NCBI
  20. Heinemann V, Kraemer N, Buchner H, Weikersthal LFv, Decker T, Kiani A, et al. Somatic DNA mutations, tumor mutational burden (TMB), and MSI Status: Association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE-3 (AIO KRK-0306). J Clin Oncol 2018;36:3591 View Article
  21. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011;117(20):4623-4632 View Article PubMed/NCBI
  22. Venderbosch S, Nagtegaal ID, Maughan TS, Smith CG, Cheadle JP, Fisher D, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 2014;20(20):5322-5330 View Article PubMed/NCBI
  23. Le DT, Uram JN, Wang H, Bartlett B, Kemberling H, Eyring A, et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J Clin Oncol 2016;34:103 View Article
  24. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18(9):1182-1191 View Article PubMed/NCBI
  25. Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol 2018;36(8):773-779 View Article PubMed/NCBI
  26. Andre T, Lonardi S, Wong M, Lenz H-J, Gelsomino F, Aglietta M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142. J Clin Oncol 2018;36:553 View Article
  27. Damato A, Iachetta F, Antonuzzo L, Nasti G, Bergamo F, Bordonaro R, et al. Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated - NIVACOR trial (GOIRC-03-2018). BMC Cancer 2020;20(1):822 View Article PubMed/NCBI
  28. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 Study. J Clin Oncol 2020;38:LBA4-LBA View Article
  29. Lenz HJJ, van Cutsem E, Limon ML, Wong KY, Hendlisz A, Garcia-Alfonso P, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann Oncol 2018;29(suppl 8):714 View Article
  30. Sinicrope FA, Ou FS, Shi Q, Nixon AB, Mody K, Levasseur A, et al. Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502). J Clin Oncol 2017;35:TPS3630-TPS View Article
  31. Chalabi M, Fanchi L, van den Berg J, Beets G, Lopez-Yurda M, Aalbers A, et al. LBA37_PRNeoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann Oncol 2018;29:731 View Article
  32. Rahma OE, Yothers G, Hong TS, Russell MM, You YN, Parker W, et al. NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)-Pembrolizumab experimental arm (EA) primary results. J Clin Oncol 2021;39:8 View Article
  33. Yuki S, Bando H, Tsukada Y, Inamori K, Komatsu Y, Homma S, et al. Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol 2020;38:4100 View Article
  34. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25(21):9543-9553 View Article PubMed/NCBI
  35. Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry SR, Couture F, et al. Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol 2020;6(6):831-838 View Article PubMed/NCBI
  36. Zelenay S, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N, Acton SE, et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell 2015;162(6):1257-1270 View Article PubMed/NCBI
  37. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26(4):566-576 View Article PubMed/NCBI
  38. Lee MS, Loehrer PJ, Imanirad I, Cohen S, Ciombor KK, Moore DT, et al. Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC). J Clin Oncol 2021;39(3):7 View Article
  39. McLaughlin M, Patin EC, Pedersen M, Wilkins A, Dillon MT, Melcher AA, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 2020;20(4):203-217 View Article PubMed/NCBI
  40. Segal N, Kemeny N, Cercek A, Reidy D, Raasch P, Warren P, et al. Nonrandomized phase II study to assess the efficacy of pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) patients. J Clin Oncol 2016;34:3539 View Article
  41. Parikh AR, Clark JW, Wo JY-L, Yeap BY, Allen JN, Blaszkowsky LS, et al. A phase II study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC). J Clin Oncol 2019;37:3514 View Article
  42. Rosen LS, LoRusso P, Ma WW, Goldman JW, Weise A, Colevas AD, et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs 2016;34(5):604-613 View Article PubMed/NCBI
  43. Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. Immunity 2016;44(3):609-621 View Article PubMed/NCBI
  44. Bendell JC, Kim TW, Goh BC, Wallin J, Oh D-Y, Han S-W, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 2016;34:3502 View Article
  45. Bendell JC, Bang Y-J, Chee CE, Ryan DP, McRee AJ, Chow LQ, et al. A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 2018;36:560 View Article
  46. Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2019;20(6):849-861 View Article PubMed/NCBI
  47. Sclafani F. MEK and PD-L1 inhibition in colorectal cancer: a burning blaze turning into a flash in the pan. Lancet Oncol 2019;20(6):752-753 View Article PubMed/NCBI
  48. Davis PJ, Mousa SA. Anti-Angiogenesis Strategies in Cancer Therapeutics. Boston: Academic Press; 2017, 125-131
  49. Mousa SA, Muralidharan-Chari V, Davis PJ. Anti-Angiogenesis Strategies in Cancer Therapeutics. Boston: Academic Press; 2017, 51-68
  50. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2014;2(7):632-642 View Article PubMed/NCBI
  51. Hochster HS, Bendell JC, Cleary JM, Foster P, Zhang W, He X, et al. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J Clin Oncol 2017;35:673 View Article
  52. Bendell JC, Powderly JD, Lieu CH, Eckhardt SG, Hurwitz H, Hochster HS, et al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 2015;33:704 View Article
  53. Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol 2020;38(18):2053-2061 View Article PubMed/NCBI
  54. Gomez-Roca C, Yanez E, Im S-A, Alvarez EC, Senellart H, Doherty M, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors-Results from the colorectal cancer cohort. J Clin Oncol 2021;39:94 View Article
  55. Yarchoan M, Albacker LA, Hopkins AC, Montesion M, Murugesan K, Vithayathil TT, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 2019;4(6):126908 View Article PubMed/NCBI
  56. Fancello L, Gandini S, Pelicci PG, Mazzarella L. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges. J Immunother Cancer 2019;7(1):183 View Article PubMed/NCBI
  57. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med 2017;377(25):2500-2501 View Article PubMed/NCBI
  58. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018;362(6411):eaar3593 View Article PubMed/NCBI
  59. Panda A, Betigeri A, Subramanian K, Ross JS, Pavlick DC, Ali S, et al. Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors. JCO Precis Oncol 2017 2017;1(1):1-13 View Article PubMed/NCBI
  60. Pursell ZF, Isoz I, Lundström EB, Johansson E, Kunkel TA. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 2007;317(5834):127-130 View Article PubMed/NCBI
  61. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 2016;16(2):71-81 View Article PubMed/NCBI
  62. Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013;45(2):136-144 View Article PubMed/NCBI
  63. Li HD, Cuevas I, Zhang M, Lu C, Alam MM, Fu YX, et al. Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. J Clin Invest 2018;128(9):4179-4191 View Article PubMed/NCBI
  64. Wang F, Zhao Q, Wang YN, Jin Y, He MM, Liu ZX, et al. Evaluation of POLE and POLD1 Mutations as Biomarkers for Immunotherapy Outcomes Across Multiple Cancer Types. JAMA Oncol 2019;5(10):1504-1506 View Article PubMed/NCBI
  65. Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, Epicolon consortium, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol 2016;1(3):207-216 View Article PubMed/NCBI
  66. Huh JW, Lee JH, Kim HR. Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Arch Surg 2012;147(4):366-372 View Article PubMed/NCBI
  67. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391(10135):2128-2139 View Article PubMed/NCBI
  68. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 2019;18(3):197-218 View Article PubMed/NCBI
  69. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372(26):2509-2520 View Article PubMed/NCBI
  70. Overman MJ, Linardi S, Leone F, McDermott RS, Morse MA, Wong KYM, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: update from CheckMate 142. J Clin Oncol 2017;35(4):519 View Article
Copyright © 2024 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Exploratory Research and Hypothesis in Medicine
  • pISSN 2993-5113
  • eISSN 2472-0712

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 1979521
  • Visits today : 2879
Back to Top

Immunotherapy in Colorectal Cancer: A Review

Alfredo Colombo, Vittorio Gebbia, Concetta Maria Porretto
  • Reset Zoom
  • Download TIFF