Targeted Therapy and Immunotherapy in Colorectal Cancer: Current Landscape and Future Directions - Dr Amit Javed

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide, and advancements in targeted therapy and immunotherapy have significantly transformed its treatment landscape.

These approaches have shifted the paradigm from one-size-fits-all chemotherapy to more personalized and effective treatment strategies. This article explores the current state of targeted therapies and immunotherapies in CRC and delves into the future directions shaping their development.

Role of Targeted Therapy in CRC

Targeted therapies in CRC are designed to interfere with specific molecular pathways involved in tumour growth, progression, and survival. These therapies are primarily used in advanced or metastatic colorectal cancer (mCRC) settings and are tailored based on the molecular profile of the tumour.

EGFR Inhibitors

Epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab and panitumumab, are widely used in mCRC patients with wild-type RAS genes (KRAS and NRAS).

These monoclonal antibodies inhibit the EGFR pathway, which drives tumour growth and proliferation. However, patients with RAS mutations are resistant to EGFR inhibitors, highlighting the importance of biomarker testing in guiding therapy.

Anti-VEGF Therapies

Angiogenesis, the formation of new blood vessels, is crucial for tumor growth. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, inhibits angiogenesis, thereby starving the tumor of nutrients and oxygen. This therapy is often combined with chemotherapy to enhance efficacy. Other agents targeting VEGF, such as aflibercept and ramucirumab, are also used in mCRC.

BRAF and HER2 Targeting

Approximately 8–12% of mCRC patients harbor BRAF mutations, most commonly the V600E mutation, which is associated with poor prognosis. The combination of BRAF inhibitors (e.g., encorafenib) with EGFR inhibitors has shown promise in improving outcomes for these patients. Additionally, HER2 amplification is observed in 3–5% of CRC cases. HER2-targeted therapies, such as trastuzumab and pertuzumab, are being explored in this subset of patients.

Rise of Immunotherapy in CRC

Immunotherapy, which harnesses the body’s immune system to fight cancer, has revolutionized treatment for various cancers, including CRC. However, its efficacy in CRC is closely linked to the tumour's genetic and immunological characteristics.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have shown remarkable success in CRC patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). These tumours exhibit a high mutational burden, producing neoantigens that make them highly immunogenic. By blocking checkpoints like PD-1 or CTLA-4, these therapies reinvigorate T-cell activity against the tumour.

While immune checkpoint inhibitors have transformed care for MSI-H/dMMR CRC patients, their efficacy in microsatellite-stable (MSS) CRC, which represents the majority of cases, remains limited. Combination strategies with chemotherapy, radiation, or targeted therapies are being investigated to overcome this challenge.

Tumour-Directed Vaccines and CAR-T Therapy

Emerging immunotherapy approaches include tumour-directed vaccines and chimeric antigen receptor (CAR) T-cell therapies. Tumour vaccines aim to elicit immune responses against specific tumour antigens, while CAR-T therapies involve engineering T-cells to recognize and attack tumour-specific markers.

Although still in early stages for CRC, these approaches hold promise for personalized immunotherapy.

Challenges and Future Directions

Despite significant advancements, both targeted therapies and immunotherapies face challenges. Resistance to targeted therapies often develops over time due to genetic alterations or alternative pathway activation. Similarly, immunotherapy has limited efficacy in MSS CRC, underscoring the need for novel approaches.

Future research is focusing on combination therapies to enhance efficacy and overcome resistance. For instance, combining checkpoint inhibitors with VEGF-targeting agents or oncolytic viruses is being studied to improve responses in MSS CRC.

Additionally, efforts to identify new biomarkers, such as tumour mutational burden and gut microbiome composition, are critical to expanding the scope of precision medicine.

The use of next-generation sequencing (NGS) and liquid biopsies is also driving innovation, enabling real-time monitoring of tumour evolution and guiding adaptive treatment strategies.

Advances in artificial intelligence and machine learning are expected to further refine predictive models for therapy selection and response assessment.

Targeted therapy and immunotherapy have redefined colorectal cancer treatment, offering improved outcomes for many patients. However, significant gaps remain, particularly in addressing MSS CRC and overcoming resistance.

Ongoing research into combination strategies, novel biomarkers, and emerging technologies will be instrumental in expanding the impact of these therapies. By continuing to innovate and refine these approaches, the future of colorectal cancer care looks increasingly promising.