Targeted and Immunotherapy Treatments for Colorectal Cancer

March 20, 2024

In recent years, significant advancements in medical research have revolutionized the landscape of cancer treatment, particularly for colorectal cancer (CRC). Traditional treatments like chemotherapy and surgery have long been the mainstays, but the emergence of targeted therapies and immunotherapy has opened new avenues for more effective and precise interventions. These advancements offer exciting possibilities for improved patient outcomes, particularly for those with advanced or metastatic disease. In this blog post, we’ll delve into the innovative realm of targeted and immunotherapy treatments for colorectal cancer, exploring their mechanisms, benefits, and current status in clinical practice.

Understanding Colorectal Cancer

Before we delve into the intricacies of targeted and immunotherapy treatments, let’s first understand colorectal cancer (CRC). It is one of the most common cancers worldwide, with significant morbidity and mortality rates. Colorectal cancer develops in the colon or rectum, typically beginning as benign polyps that can gradually transform into cancerous tumors. There are well established screening and diagnosis guidelines and practices which involve fecal and blood tests, colonoscopy, proctoscopy, and biopsy. Cancer cells from biopsy samples may undergo further molecular testing typically for mutation of the KRAS, NRAS, BRAF, MSI, and MMR genes. Identification of gene and protein changes may assist with supporting targeted and immunotherapy options.  

Targeted Therapy

Targeted therapy involves the use of drugs or substances that specifically target cancer cells while sparing normal cells, thereby minimizing adverse effects. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, targeted therapy aims to disrupt specific molecular pathways that drive cancer growth and progression. In CRC, these therapies can involve targeting:

• Epidermal growth factor receptor (EGFR): Drugs such as cetuximab and panitumumab inhibit EGFR, thereby impeding cancer cell proliferation and survival. These targeted agents are particularly effective in patients with certain genetic mutations, such as KRAS and NRAS, which render traditional chemotherapy less effective.

• HER2 overexpression: For HER2-positive CRC, drugs like trastuzumab can block HER2 signaling pathways, hindering cancer cell growth and proliferation.
• RAS and BRAF mutations: While uncommon, specific mutations in these genes can be targeted with drugs like adagrasib and sotorasib, offering promise for this subset of patients.
• NTRK gene fusions: A small percentage of CRCs harbor NTRK gene rearrangements. Larotrectinib and entrectinib capitalize on this by targeting the resulting abnormal TRK proteins.
• Vascular endothelial growth factor (VEGF) pathway:. Bevacizumab and aflibercept are anti-angiogenic agents that block VEGF, thereby inhibiting the formation of new blood vessels that nourish tumors. By depriving tumors of their blood supply, these drugs can slow cancer progression and improve patient outcomes.

Immunotherapy

Immunotherapy harnesses the power of the immune system to recognize and eliminate cancer cells. Unlike traditional treatments that directly target tumors, immunotherapy works by enhancing the body’s natural immune response against cancer. In colorectal cancer, two main categories of immune checkpoint inhibitors have emerged as a promising approach to treatment.

• PD-1/PD-L1 blockade: Pembrolizumab and nivolumab are examples of immune checkpoint inhibitors that target the PD-1/PD-L1 pathway, a mechanism by which tumors evade immune detection. These drugs are most effective in tumors with microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), indicating a high mutational burden and increased recognition by the immune system.
• CTLA-4 blockade: Ipilimumab works by blocking CTLA-4, another immune checkpoint that suppresses T cell activity. While not used alone for CRC, it can be combined with PD-1 inhibitors to enhance the overall immune response.

Combination Therapies

In recent years, researchers have explored the potential synergies of combining targeted therapy with immunotherapy in colorectal cancer treatment. By simultaneously targeting multiple pathways involved in cancer growth and immune evasion, combination therapies have the potential to enhance efficacy and overcome resistance mechanisms.

Clinical Outlook

While targeted and immunotherapy treatments have shown promise in colorectal cancer, several challenges remain. Research is ongoing to:

• Develop additional targeted therapies for specific mutations and signaling pathways.
• Refine patient selection based on comprehensive tumor profiling for optimal treatment allocation.
• Explore combination strategies involving targeted therapies, immunotherapies, and traditional chemotherapy for potentially synergistic effects.
• Investigate the potential of CAR T-cell therapy, a personalized approach where a patient’s own T cells are engineered to recognize and attack cancer cells.

Moreover, the cost and accessibility of these novel therapies pose significant barriers to widespread adoption.

Targeted and immunotherapy treatments represent a paradigm shift in the management of colorectal cancer, offering new hope for patients and clinicians alike. By precisely targeting cancer cells or boosting the body’s immune response, these therapies hold the potential to improve outcomes and prolong survival. As research continues to advance, the future of colorectal cancer treatment looks increasingly promising, with targeted and immunotherapy playing pivotal roles in personalized and precision medicine approaches.