Immunotherapy has been a game changer in the fight against cancer. Just over a decade ago, this innovative therapeutic approach, which is based on the stimulation of the immune system itself to better destroy the tumor, entered oncology like a cyclone and began to change the prognosis of previously devastating diseases. These drugs have achieved unusual survival in unthinkable scenarios. and they continue to do so. But they are not infallible weapons: there are tumors where they cannot penetrate and patients who escape the umbrella of these new treatments.
Immune checkpoint inhibitors are a type of immunotherapy that prevents the tumor from slowing down the immune system, to prevent it from killing it. They have already saved thousands of lives, but they have a double sided: they only work in 25% or 30% of patients. The scientific community has dedicated itself to studying why these revolutionary treatments fail and has found that factors such as the tumor’s surroundings or the impact of previous treatments on the body have an impact. Now, new research published Nature went a step further and identified a formula to interrupt cancer resistance to these immunotherapies.
The international study, directed by the Spanish Ignacio Melero, co-director of Immunology and Immunotherapy at the Top and at the University of Navarra Clinic he focused on GDF-15, a cytokine produced in many types of tumors to escape the immune system. This substance works as a kind of repellent for the body’s defense army, preventing it from penetrating cancerous tissue. In a Phase I-IIA clinical trial (intended to test the safety and clinical activity of the therapy), researchers treated a handful of patients with tumors resistant to one type of immunotherapy (anti-PD and anti-PD checkpoint 1 inhibitors). -PDL). 1) and was given a drug that neutralizes the effect of GDF-15. “In patients previously refractory to immunotherapy,the treatment manages to save between 15% and 25% and they benefit from immunotherapy again,” summarizes the immunologist. Research has shown that when this substance produced by the tumor is blocked, the cells of the immune system are once again able to recognize and attack the cancer.
Melero says the inspiration came from the placenta. From the knowledge they have of how the cytokine GDF-15 works in that context. «It is a factor that is produced in abundance in the placenta and which probably works as a repellent, preventing the introduction of immune cells by the mother that could reject the fetus. And we thought that if it was a good mechanism for allogeneic placentation,it could be a great target in tumors that have hijacked that mechanism to escape the immune system. The strategy was to neutralize it with a monoclonal antibody”, explains the immunologist. And it worked: Although the number of patients who responded was modest, combining this GDF-15 blocker with immunotherapy achieved deep, long-lasting responses, with tumors shrinking in size or even disappearing.
In the scientific article published this Wednesday in the magazine Nature researchers describe the first results of this new way of addressing cancer resistance to immunotherapy. First, in a phase I study to study the safety and appropriate dosing of the therapeutic strategy, and then, in another phase II-A study to profile patients who could benefit the most (people with non-small-cell lung cancer cells, urothelial tumors, colorectal tumors, melanoma and hepatocarcinoma) and delve into the clinical activity of this medical approach. All patients studied had very advanced cancers and had relapsed or failed to respond to treatment with checkpoint inhibitors. In total, nearly 200 patients have been or are being treated (the phase II-A study is still ongoing) with different d
The researchers point out in the article that the drugs were well tolerated and that this combination of treatments achieved clinical benefits in some patients, including a decrease in tumor size.The response rate in the lung cancer cohort was 14.8% (four of 27 patients) and in the urothelial cancer cohort it was 18.5% (five of 27 patients). in the group with hepatocellular carcinoma, still under study, the provisional response is 20%. In melanoma and colorectal cancer, however, researchers have observed no antitumor activity with this treatment regimen. “In the biopsies of the patients we saw that the activated cells of the immune system entered the tumor and we observed that four patients to whom we administered increased doses had tumor regressions,” explains Melero. Moreover, in certain specific cases, the response was very long-lasting for such advanced disease contexts, keeping the tumor at bay even a year after treatment.
In the absence of larger clinical studies confirming these data, Melero moves between optimism and caution: “We hope this is as transformative as it seems. We need to compare this with longer series of patients and available treatments. but the signs we have now are unprecedented. “We are in uncharted territory.”
A key therapeutic target
The immunologist assumes that the cytokine GDF-15 is just one of many resistance pathways generated by cancer, but claims that it is a key target in the tumor’s attempts to escape the immune system. “GDF-15 is not the only resistance pathway, but it is the first that functions as a repellent against the entry of immune cells into the tumor. We certainly know that there are multiple targets, such as TGFβ [otra proteína que también pueden absorber las células cancerosas para burlar al sistema inmune]but we were unable to inhibit this pathway in patients. When we tried it, serious side effects appeared,” explains the scientist.
The cytokine GDF-15 is under the spotlight of the scientific community for several reasons. In addition to its role in cancer as an immune system repellent, it has also been found to be a mediator of cancer cachexia, a progressive deterioration syndrome that causes loss of muscle and fat. an article published in the magazine New England Journal of Medicine confirmed that another drug also developed to block GDF-15 is effective in treating cachexia and patients who gain weight.In fact, in Melero’s study it was also reported that the subpopulation of patients with high levels of GDF-15 showed an increase in body weight after blocking this cytokine.
César Rodríguez,president of the Spanish Society of Medical Oncology,believes that the research published in Nature “It responds to a problem encountered in clinical practice.” “What happens with immunotherapy is that in many tumors they are very active strategies, but in some scenarios we see a loss of that response due to the tumor’s resistance mechanisms. And we find patients who respond for a while and then not. What this study shows is that a modest, but not negligible, number of patients responds again to treatment and these responses are long-lasting, they are not a mirage,” says the oncologist, who was not involved in this research.
Rodríguez warns that the data must be interpreted “with caution” and recalls, as Melero underlined, that further research and refinement of the selection of patients who will benefit most from this therapeutic strategy are necessary, but he also admits that the first results are losing ground on hope in patients who have tired standard treatments.
even the oncologist Ernest nadal, member of the board of directors of the Spanish Lung Cancer Research Group, maintains that the results of Melero’s study are “preliminary, but captivating data”: “The target is a cytokine involved in a profile more immunosuppressive.” reversing that immunosuppressive environment is very interesting. “What we’re trying to do is change the profile of the tumor and make it more immunogenic.” Nadal, who is also director of the Thoracic Tumors Program at the Catalan Institute of Oncology (ICO) and did not participate in
this study, points out that the percentage of patients who respond is small, “but the responses are profound.” Furthermore, he adds, it is an “attractive combination because the toxicity is low,” which is very vital in the context of patients with advanced disease who have already followed many lines of treatment. “This cytokine may be very relevant and become a key to transformative change in treatment. The next step is to take it to earlier stages,” agrees the oncologist.
How does GDF-15 contribute to tumor immune evasion?
Time.news Interview: Breaking New Ground in cancer Immunotherapy
Editor: Welcome to Time.news! Today, we’re diving deep into one of the most exciting frontiers in oncology—immunotherapy.Joining us is Dr. Ignacio Melero, a leading expert in immunology and immunotherapy from the University of Navarra clinic. Dr. Melero, thank you for being here.
dr. Melero: Thank you for having me! It’s a pleasure to discuss this vital topic.
Editor: immunotherapy has revolutionized cancer treatment over the past decade, yet there are still important challenges. Can you explain to our readers what makes these treatments so groundbreaking?
Dr. Melero: Absolutely! Immunotherapy, notably immune checkpoint inhibitors, empowers the body’s immune system to target and eliminate cancer cells. This approach has led to remarkable survival rates in cancers previously deemed untreatable. Though,it’s essential to acknowledge that these treatments work effectively in onyl 25-30% of patients,which highlights the need for further research.
Editor: That’s a profound statistic. Your recent research focuses on a cytokine called GDF-15. How does this align with your goal of improving immunotherapy responses?
Dr. Melero: GDF-15 acts as a sort of camouflage for tumors, preventing immune cells from effectively attacking cancerous tissues. By neutralizing GDF-15 with a monoclonal antibody, we’ve discovered that we can reopen the pathways for our immune cells to recognise and target the tumor onc more.
Editor: That’s fascinating! Can you tell us more about the inspiration behind targeting GDF-15, particularly its connection to pregnancy?
Dr. Melero: Certainly! GDF-15 is produced abundantly in the placenta and plays a crucial role in preventing the mother’s immune system from attacking the developing fetus. We hypothesized that tumors might hijack this mechanism to evade immune detection. Thus, targeting GDF-15 could turn the tide in the fight against cancer.
Editor: The clinical trial results you’ve shared are quite promising! you mentioned that around 15-25% of previously refractory patients showed a positive response. What does that mean for the future of cancer treatment?
dr.Melero: It’s a meaningful step forward. While the response rate may seem modest, the key lies in the durability and depth of those responses. Some patients experienced remarkable reductions in tumor size or even complete disappearance of tumors, which is extraordinary given the advanced nature of their diseases.
Editor: That sounds like hopeful news! However, you’ve also stated there are still many unanswered questions. How do you balance optimism with caution, especially in research?
Dr. Melero: Scientific curiosity drives us, but discernment is paramount. While our early results are unprecedented, we must conduct larger studies to confirm these findings. The journey of translating research from the lab to the clinic is fraught with challenges, and we’re in uncharted territory.
Editor: Wise words indeed. As we wrap up, Dr. Melero, what do you envision as the next steps for research in immunotherapy and targeting mechanisms like GDF-15?
Dr. Melero: Moving forward, we aim to refine our understanding of which patient populations will benefit the most from this therapy. We’ll be conducting larger clinical trials to further explore the synergy of combining GDF-15 neutralization with existing immunotherapies. Our ultimate goal is to broaden the efficacy of these treatments and save more lives.
Editor: Thank you so much for your insights today, Dr. Melero. Your work is paving the way for a brighter future in cancer treatment.
Dr. Melero: Thank you! It’s crucial to keep pushing the boundaries of research for the sake of patients and the future of oncology.
Editor: And thank you to our readers for joining us! Stay tuned for more updates on groundbreaking medical research right here at Time.news.