Targeting IL-1α in metastatic colon cancer: a clinical feasibility study showing promising results in a phase 1 trial.

Introduction
Colorectal cancer (CRC) is one of the most common cancers in Europe and a leading cause of death worldwide(1). For advanced stages, current treatments mainly rely on a combination of chemotherapy and targeted therapies, such as monoclonal antibodies(2). However, when these treatments fail, options become limited. Recently, a combination of two drugs, trifluridine/tipiracil and bevacizumab, has proven effective as a third-line therapy(3).
A key discovery is that chronic inflammation plays a major role in cancer development and progression, including CRC(4). One inflammatory protein, IL-1α, produced by cancer cells, is particularly involved(5,6). It increases tumor aggressiveness and weakens the immune system's ability to fight cancer(7–9). Neutralizing this protein could slow tumor growth and enhance the effectiveness of treatments.
In this context, a new monoclonal antibody, XB2001, was developed to specifically target IL-1α. Preliminary studies have shown that a similar antibody, bermekimab, improved symptoms in patients with metastatic CRC. This study tested the combination of XB2001 with a standard treatment (trifluridine/tipiracil and bevacizumab) to evaluate its safety and effectiveness. The results could pave the way for a promising new therapeutic option for advanced CRC patients.
This study tested the new drug XB2001, combined with existing treatments, in patients with advanced colorectal cancer.
Here’s a summary of the key findings:
- Patient Profile
- 17 patients participated, aged between 49 and 81, with most having advanced-stage disease and significant prior treatment history.
- About 76% had genetic mutations commonly associated with colorectal cancer, and over half had tumors on the left side or liver metastases.
- Safety
- XB2001 was generally well tolerated, with no serious side effects directly caused by the drug.
- Most side effects were mild (e.g., nausea, anemia), and serious side effects were rare (17.6% of patients).
- The highest tested dose (1000 mg every 2 weeks) was deemed safe for further studies.
- Effectiveness
- The treatment stabilized or shrank tumors in 76% of patients.
- 4 patients had partial tumor shrinkage, 9 had stable disease, and 4 had disease progression.
- The average progression-free survival (time without cancer worsening) was 9.4 months.
- Patients treated with higher doses of XB2001 often stayed on treatment longer, with some still benefiting up to 16 months.
- Biological Effects
- XB2001 successfully reduced levels of inflammation-related proteins, particularly IL-6, which is tied to cancer progression.
- Decreased IL-6 levels were linked to better disease control and longer progression-free survival.
- The treatment also showed signs of activating the immune system, though its exact role remains under investigation.
- Immune Response
- Tumor samples revealed that higher levels of immune activity (like CD8 T cells and PD-L1 expression) before treatment predicted better responses.
- This suggests the immune system's state may influence how well patients respond to XB2001.
Conclusion
XB2001, combined with standard therapy, shows promise in treating advanced colorectal cancer. It was well-tolerated, effectively reduced inflammation, and controlled disease progression in most patients. A randomized phase 2 clinical trial comparing the current standard treatment (trifluridine/tipiracil + bevacizumab) to this combination is currently enrolling patients and it will allow us to determine whether the combination is beneficial for patients and to identify potential biomarkers of response to the treatment.
References
- Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 71, 209–249 (2021).
- Cervantes, A. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Ann. Oncol. 34, 10–32 (2023).
- Prager, G. W. et al. Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N. Engl. J. Med. 388, 1657–1667 (2023).
- Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, Inflammation, and Cancer. Cell 140, 883–899 (2010).
- Lurje, G. et al. Polymorphisms in interleukin 1 beta and interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer. Pharmacogenet. Genomics 19, 95 (2009).
- Apte, R. N. et al. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev. 25, 387–408 (2006).
- Voronov, E. et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc. Natl. Acad. Sci. 100, 2645–2650 (2003).
- Hurtado, C. G., Wan, F., Housseau, F. & Sears, C. L. Roles for Interleukin 17 and Adaptive Immunity in Pathogenesis of Colorectal Cancer. Gastroenterology 155, 1706–1715 (2018).
- Liu, C. et al. Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer. J. Immunother. Cancer 9, e001895 (2021).
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