Colorectal cancer remains a significant public health challenge. Traditional treatments involve surgery, chemotherapy, and radiation, but immunotherapy has introduced a new approach. Immunotherapy is a systemic treatment that uses certain drugs to help a person’s own immune system recognize and destroy cancer cells. The success of this treatment in colon cancer, however, depends heavily on specific molecular characteristics within the tumor.
Immunotherapy and Key Biomarker Selection
Immunotherapy is not a standard first-line treatment for all types of colon cancer; its use is highly selective and guided by specific molecular markers. The most important characteristic dictating eligibility is the status of the tumor’s DNA repair machinery, specifically the mismatch repair (MMR) system. Tumors are categorized as either deficient mismatch repair (dMMR) or proficient mismatch repair (pMMR). The dMMR status corresponds with a high level of a genetic abnormality called Microsatellite Instability-High (MSI-H).
The MMR system is normally responsible for correcting errors that occur when DNA is copied. When this system is deficient, an extremely high number of genetic errors accumulate throughout the tumor’s DNA. This accumulation of mutations leads to the production of abnormal proteins called neoantigens, which are foreign to the immune system. This makes the tumor highly visible, which is why dMMR/MSI-H tumors respond favorably to immune checkpoint inhibitors.
Defining Efficacy: How Success is Measured
Oncologists rely on several precise metrics to gauge the efficacy of cancer treatment in clinical trials. The most direct measure of a treatment’s effectiveness in shrinking tumors is the Objective Response Rate (ORR). ORR is the percentage of patients whose cancer significantly shrinks or completely disappears after treatment.
Another common measure is Progression-Free Survival (PFS), which tracks the length of time a patient lives without their disease worsening or growing. The most meaningful and long-term measure is Overall Survival (OS). OS measures the average length of time patients remain alive after starting a particular treatment, providing the clearest evidence of a treatment’s value in extending life.
Success Rates Based on Tumor Status
The numerical success rate of immunotherapy for colon cancer is starkly divided based on the tumor’s molecular status. In patients with metastatic dMMR/MSI-H colon cancer, immunotherapy provides a durable clinical benefit, with success rates significantly higher than traditional chemotherapy. Single-agent immune checkpoint inhibitors, such as those targeting the PD-1 protein, typically achieve an Objective Response Rate (ORR) of approximately 30% to 40%. The 1-year Overall Survival (OS) rate for patients receiving PD-1 monotherapy was reported to be around 76%.
Combining two different types of immune checkpoint inhibitors, such as an anti-PD-1 agent with an anti-CTLA-4 agent, further improves these outcomes. This combination therapy has shown an even higher Objective Response Rate, reaching approximately 55% in clinical trials. The 1-year OS rate with this dual-immunotherapy approach increases to about 85%. This high level of success has positioned immunotherapy as a preferred first-line treatment option for this specific subgroup.
However, the majority of metastatic colon cancer cases (roughly 95%) are categorized as microsatellite stable (MSS) or proficient mismatch repair (pMMR). The success rate of single-agent immunotherapy in this large group is extremely limited, often resulting in an Objective Response Rate of less than 5%. These MSS tumors are considered “cold” because they have a low mutation burden and few tumor-infiltrating immune cells, making them largely invisible to the immune system. Single-agent immune checkpoint inhibitors are therefore not a recommended treatment for the vast majority of patients with MSS colon cancer.
Factors Influencing Response and Future Strategies
Although immunotherapy achieves remarkable success in dMMR/MSI-H tumors, not all patients in this group respond, pointing to mechanisms of intrinsic or acquired resistance. Some tumors may develop secondary genetic changes, such as mutations in genes like JAK1 or B2M, which allow cancer cells to evade detection even when the immune system is activated. Understanding these specific genetic factors is an area of ongoing research aimed at improving outcomes for the 45% of dMMR patients who do not achieve a response with combination therapy.
For the majority of patients with MSS colon cancer, current research focuses on strategies to convert these immunologically “cold” tumors into “hot” ones that can respond to immunotherapy. One promising approach involves using combination therapies to enhance the tumor microenvironment’s susceptibility to immune attack. Clinical trials are investigating the pairing of immune checkpoint inhibitors with conventional treatments like chemotherapy, radiation, or targeted agents. These combinations are designed to cause localized tumor damage, which can release neoantigens and attract immune cells, potentially expanding the benefit of immunotherapy to the MSS population.