BRAF V600E and immune checkpoint inhibitors

​BRAF and MEK inhibitors in melanoma treatment 

BRAF, a member of the RAF family of protein kinases, is found to be mutated in approximately 8% of all cancers and most commonly mutated in melanoma. Approximately 45% of melanoma patients have a BRAF V600 mutation resulting in a constitutively active mitogen-activated protein kinase (MAPK) pathway (Amaral et al. 2017). One of the most well studied of these BRAF mutations is BRAF V600E (Valine to glutamate switch) , capable of elevating the activity of the MAPK pathway in vivo causing proliferation and tumor growth (Chapman et al. 2011).

New insights into the abundance and function of the BRAF V600E mutation have resulted in novel treatments that improve life expectancy for those suffering from metastatic melanoma (Malissen et al. 2018). Some of the most common treatments for patients carrying the V600E mutation are small molecule BRAF and MEK inhibitors (Chen et al. 2017). Combinations of these two treatments have proven to be extremely effective (Gonzalez et al. 2012).

Immune checkpoint therapy: a new player for BRAF/MEK combination treatments

There are still a significant number of cases in which the tumors treated with BRAF and MEK inhibitors show resistance, especially for the most aggressive types of melanoma (Amaral et al. 2017b and 2017c). The need for improvements to this type of therapy has led to the investigation of combining immunotherapy with BRAF/MEK inhibition (Liu et al. 2015). Anti-PD1 and anti-CTLA4 antibodies have been successfully used in cancer therapeutics to boost anti-tumor immunity, making these strong candidates to improve the longevity of BRAF/MEK combination therapy.

The CTLA-4 inhibitor ipilimumab is currently approved for use as a melanoma treatment with promising response rates (Hodi et al. 2010). Even more advantageous is the use of multiple immunotherapies to take advantage of different immune response mechanisms. The combination of ipilimumab with the PD-1 inhibitor nivolumab has had favorable results in clinical trials for the treatment of advanced melanoma (Wolchok et al. 2013). Recent studies have attempted different combinations of BRAF inhibitors with immunotherapy; however, there is still much progress to be made to find the optimal treatment timings and combinations (Aya et al. 2016 and Johnson et al. 2017). 

Progress your BRAF/immune checkpoint research with our gold-standard IHC optimized antibodies 

Our range of recombinant monoclonal Spring (SP) clone antibodies are IHC-optimized and considered the gold-standard for pathology. Our clone VE1 monoclonal antibody for BRAF V600E is designed using a synthetic peptide containing the V600E mutation, which specifically detects the mutated and constitutively active BRAF protein. The antibody is cited in over 80 papers from top journals including Nature Genetics and Nature Neuroscience. 

See the BRAF V600E antibody​

If you want to combine your BRAF research with immune checkpoint targets, we have SP clone antibodies for the most well-studied immune modulators, including CTLA-4 and a recombinant monoclonal PD-1 antibody. Also, take a look at our recombinant monoclonal SP clone antibody against PD-L1 that is cited in over 60 papers from excellent journals including Nature. 

References

1. Amaral, T., Meraz-Torres, F., & Garbe, C. (2017). Immunotherapy in managing metastatic melanoma: which treatment when? Expert Opinion on Biological Therapy, 17(12), 1523–1538.

2. Amaral, T., Sinnberg, T., Meier, F., Krepler, C., Levesque, M., Niessner, H., & Garbe, C. (2017b). The mitogen-activated protein kinase pathway in melanoma part I e Activation and primary resistance mechanisms to BRAF inhibition. European Journal of Cancer, 49, 1–8.

3. Amaral, T., Sinnberg, T., Meier, F., Krepler, C., Levesque, M., Niessner, H., & Garbe, C. (2017c). ScienceDirect MAPK pathway in melanoma part II d secondary and adaptive resistance mechanisms to BRAF inhibition. European Journal of Cancer, 73, 93–101.

4. Aya, F., Gaba, L., Victoria, I., & Tosca, M. (2016). Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma. Clinical and Translational Oncology. 19, 119–124.

5. Chapman, P., Hauschild, A., Robert, C., Haanen, J.… BRIM-3 Study Group (2011). Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. NEJM. 364: 2507-2516.

6. Chen, P., Chen, F., & Zhou, B. (2017). Therapeutic efficacy and safety of combined BRAF and MEK inhibition in patients with malignant melanoma: a meta-analysis. Onco Targets Ther. 10: 5391–5403.

7. Gonzalez, R., Kefford, R. F., Ph, D., Sosman, J., Hamid, O., Schuchter, L., … Ph, D. (2012). Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. NEJM. 367: 1694-1703.

8. Hodi. S., O’Day, S., McDermott., Weber, R., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Ph, D., Schadendorf, D., … Ph, D. (2010). Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. NEJM. 363: 711–723.

9. Johnson, D. B., Pectasides, E., Feld, E., Ye, F., Zhao, S., Johnpulle, R., … Sullivan, R. J. (2017). Sequencing Treatment in BRAF V600 Mutant Melanoma : Anti-PD-1 Before and After BRAF Inhibition. J Immunother. 40(1), 31–35.

10. Liu, L., Mayes, P. A., Eastman, S., Shi, H., Yadavilli, S., … Hoos, A. (2015). The BRAF and MEK Inhibitors Dabrafenib and Trametinib : Effects on Immune Function and in Combination with Immunomodulatory Antibodies. Clin Cancer Res (10), 1639–1652.

11. Malissen, N., & Grob, J. J. (2018). Metastatic Melanoma: Recent Therapeutic Progress and Future Perspectives. Drugs. (12): 1197-1209.

12. Wolchok, J., Kluger, H., Callahan, M., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Reed, K., Burke, M. M., Caldwell, A., … Sznol, M. (2013). Nivolumab plus Ipilimumab in Advanced Melanoma. NEJM. 369:122-133.