A new study from Harvard University and the Massachusetts General Hospital may have uncovered a biomarker indicating a strong response among cutaneous melanoma patients treated with talimogene laherparapvec or T-VEC. The gene is the telomerase reverse transcriptase (TERT) gene, and the promoter region is mutated in responders.
The finding is exciting because with more research verifying the result, future clinical trials could include the mutational status of TERT as a prognostic marker for T-VEC patient selection. This would help identify patients most likely to respond to T-VEC and allow predicted non- responders to try another therapy instead.
The study analyzed sixty-nine patients who received T-VEC. Twenty-one (30.4%) of these patients had a complete regression of all melanomas with T-VEC and did not require additional therapy. That means the patients showed a total reversal of melanoma and its symptoms. Twenty-eight patients (40.6%) had no response, and twenty patients (29.0%) showed a partial response.
With such remarkable results among a small percentage of the patients, the team wanted to find a genetic biomarker to differentiate the responders from the non-responders. The group tested the melanoma lesions from all the patients for mutations in order to look for a biomarker.
Although most patients had mutations in genes commonly seen in cutaneous melanoma, like BRAF, NRAS, and CDKN2A, the only significant mutation among patients who had any response to T-VEC was found in TERT. All of the mutations were located specifically in the gene’s promoter region DNA, which is the area that controls whether the gene is made or not. The TERT mutations in the promoter region were most commonly single nucleotide variants (n=35), copy number gains (n=2), and insertions or deletions (n=3). Among the single nucleotide variants, there was a specific hotspot among C228T or C250T variants, which are usually mutually exclusive. No other gene mutations were statistically significant among responders. Interestingly, the C228T variant occurred more often and is a known activating TERT promoter mutation observed among recurrences and poor outcomes in various types of cancers. One study observed that tumors with C228T had 16-times more TERT mRNA than normal. Activation of TERT is associated with the hallmarks of cancer because it allows cells to achieve immortality by acquiring the ability to maintain telomere length.
Now, it will be up to scientists to determine why tumor cells with TERT mutations in the promoter region can generate a robust immune response with T-VEC. Understanding how and why these cells are more likely to develop a positive response against cancer could uncover cellular mechanisms that should be targeted for future drug development.
Other factors, in addition to TERT mutations, were present in those who had a clinical response to T-VEC. These factors included patients having Stage III disease, an absence of macroscopic nodal disease, and no metastasis to the central nervous system.
The summary is based on the article by Sierra-Davidson K, et al., “Genetic Factors Associated with Clinical Response in Melanoma Patients Treated with Talimogene Laherparapvec: A Single- Institution Retrospective Analysis.” It was published in the Annals of Surgical Oncology online on October 18, 2024.
Other studies with findings mentioned in this article include:
- Hanahan D and Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
- Kumar N and Sethi K. Telomerase and hallmarks of cancer: An intricate interplay governing cancer cell evolution. Cancer Lett. 2023:578:216459. doi: 10.1016/j.canlet.2023.216459.
- Marczyk VR, Maia AL and Goemann IM. Distinct transcriptional and prognostic impacts of TERT promoter mutations C228T and C250T in papillary thyroid carcinoma. 2024:31(9):e240058. doi.org/10.1530/ERC-24-0058
