Immunotherapy in Colorectal Cancer

Colorectal cancer (CRC) ranks as a leading cause of cancer-related deaths worldwide, with many cases diagnosed at a metastatic stage. Despite advancements in traditional treatments like surgery, chemotherapy, and radiation, the prognosis for metastatic CRC (mCRC) remains poor. Recently, immunotherapy has emerged as a promising treatment modality, particularly for patients with certain genetic profiles. This paper reviews recent advancements in immunotherapy for mCRC, focusing on its application, challenges, and future directions.

mCRC patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors have shown remarkable responses to immune checkpoint inhibitors (ICIs). These genetic features are present in approximately 4-5% of all mCRC cases and are characterized by a high mutational burden that enhances immunogenicity.

Clinical trials have validated the efficacy of ICIs for these patients. The KEYNOTE 016 trial demonstrated that pembrolizumab achieved an objective response rate (ORR) of 40% and a disease control rate (DCR) of 89% in dMMR/MSI-H mCRC patients. The CheckMate142 study further supported these findings, reporting an ORR of 55% and a DCR of 80% for MSI-H patients treated with nivolumab, with or without ipilimumab. These results have led to the approval of pembrolizumab, nivolumab, and the combination of nivolumab and ipilimumab as first- and second-line treatments for dMMR/MSI-H mCRC.

In contrast, microsatellite stable (MSS) tumors, which represent the majority of mCRC cases, present significant challenges for immunotherapy. MSS tumors are characterized by a "cold" microenvironment with low mutational burden and minimal immune cell infiltration, making them less responsive to ICIs. This resistance is a major hurdle, as the majority of mCRC patients have MSS tumors.

Efforts to enhance the efficacy of immunotherapy in MSS tumors are focused on altering the tumor microenvironment to make it more immunogenic or "hot." These strategies include:

Combination Therapies: Combining ICIs with other treatment modalities such as chemotherapy, targeted therapies, or radiation therapy. These combinations aim to increase tumor antigen release and enhance immune system activation. For instance, combining anti-angiogenic agents with ICIs has shown potential in modifying the tumor vasculature to improve immune cell infiltration.

Immune Modulators: Developing novel agents that can modulate the tumor microenvironment. These include cytokines, oncolytic viruses, and toll-like receptor agonists, which can stimulate the immune response and promote a pro-inflammatory microenvironment.

Biomarkers for Immunotherapy Response: Identifying and validating biomarkers that predict response to immunotherapy is crucial for personalizing treatment. Biomarkers such as tumor mutational burden, PD-L1 expression, and specific genetic mutations are being explored to better stratify patients and optimize therapeutic outcomes.

Several ongoing clinical trials are investigating new combinations and strategies to improve outcomes for both MSI-H and MSS mCRC patients:

First-Line Immunotherapy: Trials like KEYNOTE177 and CheckMate142 are evaluating the efficacy of pembrolizumab and nivolumab, respectively, as first-line treatments for MSI-H mCRC. Early results suggest that these agents can provide durable responses and improve overall survival compared to traditional chemotherapy.

Neoadjuvant and Adjuvant Immunotherapy: Trials such as NICHE and ATOMIC are exploring the use of ICIs in the neoadjuvant (pre-surgical) and adjuvant (post-surgical) settings for early-stage CRC with dMMR/MSI-H. These studies aim to reduce recurrence rates and improve long-term survival.

Combination Strategies for MSS Tumors: The CCTG CO.26 trial is assessing the combination of durvalumab (an anti-PD-L1 antibody) with tremelimumab (an anti-CTLA-4 antibody) in MSS mCRC. Preliminary data indicate potential improvements in overall survival, suggesting that such combinations could overcome the resistance seen in MSS tumors.

Immunotherapy has significantly advanced the treatment landscape for mCRC, particularly for patients with MSI-H/dMMR tumors. However, overcoming the resistance seen in MSS tumors remains a critical challenge. Ongoing research aims to refine these therapies, enhance their efficacy, and expand their applicability to a broader patient population. Future directions include the development of robust biomarkers for predicting treatment response and the optimization of combination strategies to convert "cold" tumors into "hot" ones, making them more susceptible to immunotherapy. The integration of these novel approaches holds promise for improving the prognosis and quality of life for mCRC patients.

Full text:

https://www.xiahepublishing.com/2472-0712/ERHM-2023-00008

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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