New targets in immunotherapy

New immunotherapies go beyond CTLA-4 and PD(L)1 and show promising results for treating various types of cancer, including colorectal cancer.

Lessons learnt from the first generation of checkpoint inhibitors

The first generation of checkpoint inhibitors (ICIs) such as CTLA-4 and PD(L)1 blockades have revolutionised the understanding and treatment of various malignant tumours. Drugs such as nivolumab and pembrolizumab have demonstrated efficacy against melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and microsatellite instable (MSI-H) tumours. The success of these therapies is also reflected in the large number of FDA approvals for PD1 or PD-L1 inhibitors.

Colorectal cancer: practical changes

A notable example is PD-1 blockade with dostarlimab in mismatch repair-deficient rectal cancer. Clinical trials have shown that patients achieved complete remission, even without chemoradiotherapy or surgery. In addition, there was no progression or recurrence of the disease. These results mark a significant advance in treatment. At the same time, it is important to consider the toxicity of such treatments and to develop prognostic markers for toxicity.

Toxicity and immunotherapy

While anti-PD-1 therapies show better overall response rates and a better toxicity profile, toxicity remains a challenge. PD-L1 is only selectively expressed in healthy human tissue, mainly in the placenta, tonsils and a small proportion of macrophage-like cells in the lung and liver. Despite the success of PD(L)1 ICIs, many patients remain refractory. 60-70% of patients do not respond to single agents, which reinforces the need for alternative approaches. The mechanisms of resistance in ICI treatment of colorectal cancer also need to be further investigated.

To strengthen the immune response, tumour-specific T cells can be expanded and the tumour microenvironment specifically influenced. Initial immunotherapies with IL-2 showed promising results, but were highly toxic. New data suggest that antibody-targeted IL-2 variants, which preferentially stimulate immune cells in tumours, are less toxic.

One example is the combination of CEA-TCB and atezolizumab, in which patients with heavily pretreated MSS metastatic colorectal cancer (mCRC) have shown promising antitumour activity. Such combinations could improve clinical activity and increase safety.

Conclusion: Immunotherapy in transition

Immunotherapy has significantly changed the treatment of colorectal cancer, especially in patients with MSI-H or dMMR tumours. Challenges remain for MSS or pMMR tumours, which are often resistant to ICIs. Exploration of new therapeutic targets beyond immune checkpoint blockade, including targeted therapies and genetically engineered immunotherapies, offers the prospect of overcoming resistance mechanisms.