Melanoma, here is precision immuno-oncology: new predictive biomarkers

Precious information can come from the tumor microenvironment that allows us to know in advance which melanoma patients can or cannot benefit from immunotherapy treatments . Pushing 'precision immuno-oncology' a step further are two studies presented by Paolo Ascierto, president of the Melanoma Foundation and director of the Melanoma Oncology, Oncologic Immunotherapy and Innovative Therapies Unit of the Pascale Institute in Naples, at the annual meeting of the American Society of Clinical Oncology (Asco), currently underway in Chicago. Both studies were conducted as part of the Secombit clinical study, designed to evaluate the efficacy of different therapeutic sequences in patients with metastatic Braf-mutated melanoma, a type of melanoma characterized by a genetic mutation that pushes tumor cells to grow.

“The study tests different sequences of Braf inhibitor drugs, which ‘turn off’ the hyperactivated gene, and immunotherapeutics, that is, drugs that remove the ‘brake’ that prevents immune cells from attacking the tumor,” explains Ascierto. “These combinations have revolutionized the treatment of melanoma with Braf mutation, offering high response rates and prolonged clinical benefits even in patients with metastases. However, not everyone responds to these combinations and we are learning to understand why.”

In the first study, the researchers focused on the so-called spatial biology, a method that aims to examine the localization and interactions of different types of cells in the tumor microenvironment. “Through advanced analyses conducted on 42 pre-treatment biopsies, we identified 15 types of cells, including 10 different populations of immune cells, as well as 10 markers of cellular status,” says Ascierto. “We thus studied 1,941 spatial characteristics, from which we selected the main ones associated with a better response to treatments, therefore with greater survival and greater prolonged clinical benefit.”

In particular, from this complex map the researchers demonstrated that when tumor cells interact with the microenvironment, following specific spatial coordinates, worse response rates to combined treatment are recorded. While when there is a greater interaction between tumor cells and specific cells of the immune system, also in this case within precise coordinates, the response to treatments is better. "Our work underscores the importance of spatial biology in the personalization of treatments - comments Ascierto -. This approach offers a promising path for the advancement of personalized medicine, particularly in melanoma, and for the improvement of clinical outcomes in both immunotherapy and targeted treatment".

In the second study, researchers focused on a well-known biomarker of hematological tumors: thymidine kinase 1 (TK1). This is an enzyme that plays a fundamental role in the synthesis and repair of DNA, whose increased concentration in the blood can indicate increased cellular proliferation activity, as occurs in tumors. "In this new study, the first conducted on TK1 in metastatic melanoma, we analyzed 81 patients: 40 with high levels of TK and 41 with low levels of the same enzyme," explains Ascierto. "The results showed a marked difference in prognosis between the two groups." In detail: the median 5-year survival was lower in patients with high levels of TK: 19 months, while in patients with low levels of TK it had not yet been reached.

“Surprisingly, the difference in survival between the TK-high and TK-low groups was not statistically significant (47% versus 44) among patients who received a ‘sandwich approach’, that is, treated first with Braf inhibitors, then with immunotherapy and immediately after with Braf inhibitors,” explains Ascierto. “It is clear that this therapeutic strategy works independently of TK levels.”

As for overall survival at 5 years, the researchers found a marked difference between patients with high and low TK: 20% versus 60% in the group of patients who started the targeted therapy first. The difference was equally marked (38% high TK vs 78) among patients who were administered immunotherapeutics first and then Braf inhibitors. The difference between patients with high and low serum TK levels was present, but less clear-cut in those who were treated with the sandwich approach (46% versus 75%). “We have entered the era of precision immuno-oncology,” concludes Ascierto. “The results of the studies confirm that treatments can be selected based on the characteristics not only of the tumor, but of the microenvironment and the immune system. This means being able to immediately give patients the most effective therapy, avoiding unnecessary treatments with heavy side effects.”