Colorectal cancer, affecting the colon or rectum, ranks as the third most common cancer globally, accounting for approximately 10% of all cancer cases. It is also the second leading cause of cancer-related deaths worldwide. While traditional treatments like surgery, chemotherapy, and radiation directly target cancer cells, immunotherapy offers a different approach by harnessing the body’s own defense mechanisms. This treatment stimulates the patient’s immune system to recognize and eliminate cancer cells.
Understanding Colorectal Cancer Immunotherapy
Immunotherapy for colorectal cancer works by strengthening or restoring the immune system’s natural ability to identify and fight cancer cells. Normally, the immune system protects the body from foreign invaders like viruses and bacteria. However, cancer cells can sometimes evade detection by the immune system, allowing tumors to grow and spread. Traditional cancer treatments, such as chemotherapy and radiation, primarily focus on directly destroying cancer cells.
In contrast, immunotherapy aims to overcome the ways cancer cells hide from the immune system. It helps the body’s immune cells, particularly T-cells, to recognize cancer as a threat. These substances work with the immune system to destroy cancer cells and inhibit their spread to other parts of the body.
Key Immunotherapy Approaches for Colorectal Cancer
Immune checkpoint inhibitors represent the most established and widely used form of immunotherapy for colorectal cancer. These drugs function by targeting specific proteins, called checkpoints, on immune cells and cancer cells that act as “on” or “off” switches for immune responses. Cancer cells can exploit these checkpoints to suppress the immune system and avoid being attacked. By blocking these inhibitory checkpoints, immune checkpoint inhibitors essentially “release the brakes” on the immune system, allowing T-cells to become active and target cancer cells.
Two main types of immune checkpoint inhibitors are used in colorectal cancer: PD-1 inhibitors and CTLA-4 inhibitors. PD-1 inhibitors, such as pembrolizumab and nivolumab, target the PD-1 protein on T-cells. When blocked, this protein can no longer prevent T-cells from attacking cancer cells. Similarly, CTLA-4 inhibitors, like ipilimumab, block the CTLA-4 protein on T-cells, which also helps to boost the immune response against cancer. Combination therapies, often involving both PD-1 and CTLA-4 inhibitors, have shown promising results, sometimes surpassing the effectiveness of single-agent treatments.
While checkpoint inhibitors are the primary immunotherapy approach, other methods are being explored in clinical trials. Oncolytic viruses are one such emerging strategy, where viruses are modified to selectively infect and destroy cancer cells while also stimulating an immune response against the tumor. Cancer vaccines are another area of research, aiming to train the immune system to recognize specific cancer-related proteins and mount a targeted attack. These emerging therapies may offer additional avenues for treatment, particularly for tumors that do not respond to checkpoint inhibitors.
Who Benefits from Immunotherapy?
Not all colorectal cancer patients are suitable candidates for immunotherapy, as its effectiveness is closely tied to specific biological characteristics of the tumor. The presence of certain biomarkers, particularly Microsatellite Instability-High (MSI-H) and Deficient Mismatch Repair (dMMR), is a strong indicator of potential responsiveness to immunotherapy. These biomarkers highlight genetic alterations within the cancer cells that make them more recognizable to the immune system.
Mismatch repair (MMR) genes are responsible for correcting errors that naturally occur in DNA during cell division. When these MMR genes are deficient (dMMR), the cell’s ability to repair DNA mistakes is impaired. This leads to an accumulation of errors, especially in repetitive DNA sequences called microsatellites. When these microsatellites become highly unstable due to unrepaired errors, the tumor is classified as Microsatellite Instability-High (MSI-H).
Tumors with MSI-H or dMMR status tend to have a higher number of genetic mutations, which results in the production of many abnormal proteins. These abnormal proteins act as flags that make the cancer cells more visible and distinct to the immune system’s T-cells. Consequently, the immune system is more likely to launch an effective attack when stimulated by immunotherapy drugs. Testing for MSI-H and dMMR status is therefore a fundamental step in determining if a colorectal cancer patient is likely to benefit from immune checkpoint inhibitors.
What to Expect from Immunotherapy Treatment
Immunotherapy for colorectal cancer can lead to significant and lasting benefits for those who respond to the treatment. Patients with MSI-H/dMMR metastatic colorectal cancer receiving combination immunotherapy, for example, have shown progression-free survival rates of 71% at 12 months. This indicates many patients experience a halt in disease progression. While immunotherapy does not work for every patient, those who do respond can experience durable responses, sometimes leading to prolonged remission.
The side effects of immunotherapy, known as immune-related adverse events (irAEs), differ from those seen with chemotherapy or radiation. These side effects arise because immunotherapy activates the immune system, which can sometimes lead to it attacking healthy tissues. Common irAEs can affect various organ systems, including fatigue, skin rashes, gastrointestinal issues like diarrhea or colitis, endocrine problems such as thyroid dysfunction, and inflammation of organs like the liver or lungs.
The onset and severity of irAEs can vary, with some appearing within weeks of treatment initiation and others developing months later. For instance, skin rashes often appear early. It is important for patients to report any new or worsening symptoms to their healthcare team promptly, as early recognition and management can often lead to their resolution and allow treatment to continue. While serious irAEs are less common, they can be potentially life-threatening if not addressed quickly.