Immunotherapy has revolutionized the fight against cancer, winning unthinkable battles and rescuing almost hopeless people from a disastrous fate. In just over a decade, these drugs, which stimulate the immune system itself to annihilate malignant cells, have changed the prognosis of many tumors, but their impact is still uneven: they do not reach everywhere. There are patients who show very long-lasting responses; others for whom it works for a while, but then relapse again; and some whose tumor cells always manage to escape the attack of these drugs. Scientists believe, however, that immunotherapy has not yet exploited its full potential and have begun to test different combinations with other treatments to enhance its effect.
In that race to get the most out of the elite of oncological therapies, two independent investigations published this Thursday in the journal Science have proven that combining a type of immunotherapy—checkpoint inhibitors—with a targeted drug (JAK inhibitors) improves the response in patients with lung cancer and Hodgkin lymphoma resistant to other treatments. Jerry Zak, a researcher in the Department of Immunology and Microbiology at the Scripps Research Institute in California and author of the study on Hodgkin lymphoma, assures that the trials are small and still in early stages, but the results are promising: “Immunotherapy has not reached its full potential at all. In this case, we believe that JAK inhibitors remodel the immune system to make it more responsive to checkpoint inhibitors. In other cases, combination therapies could overcome key resistance pathways hijacked by tumor cells to evade the immune system,” he explains.
Checkpoint inhibitors are drugs that lift the molecular brakes that prevent the immune system from attacking malignant cells. Without those obstacles created by the tumor, the lymphocytes can now recognize its presence and annihilate it without mercy. But, sometimes, it happens that the immune cells that make up the body’s army are exhausted from fighting a malignant agent. They can’t take it anymore. And in those cases, it doesn’t matter if immunotherapy lifts the brakes because the lymphocytes are so exhausted that the immune response will be deficient.
The researchers of both articles thought that if they managed to modulate the immune system, reactivating those exhausted cells, it could help make checkpoint inhibitors more effective. And they began to look for molecules that could reverse this lymphocyte exhaustion. “Unexpectedly,” Zak says by email, in 2019 they discovered that JAK inhibitors rescued some immune cells from exhaustion. “It was unexpected because JAK inhibitors, which are clinically approved primarily for autoimmune inflammatory disorders such as arthritis, are considered immunosuppressive and therefore are expected to hinder rather than enhance antitumor immunotherapy. “We thought that this contradiction was conceptually interesting and potentially novel, so we designed more experiments to obtain JAK inhibitors in the context of cancer immunotherapy,” says the scientist.
It turns out that the JAK protein is closely related to the production of interferon and the entire inflammatory response that occurs when there is an attack on the body (be it a wound, a blow or a tumor). In the event of an injury, the body produces chemical substances, such as cytokines, that produce an immune response to try to heal that damaged part. But in cancer, specifically, a kind of paradox occurs: exposure to cytokines, such as interferon, can help the immune system fight malignant cells, but prolonged exposure can also generate the opposite effect and cause immunosuppression that allow tumor proliferation.
The balance of this dual inflammation response is very complicated and, according to the authors of the lung cancer study, “makes it difficult to take advantage of the benefits of cytokine activation during cancer immunotherapy, while avoiding harmful consequences.” On this basis, scientists postulated that if the sometimes opposing functions of this cytokine activation could be correctly modulated, the effectiveness of immunotherapy could be improved and the development of resistance mitigated.
Better control of the tumor
And that’s where JAK inhibitors came into play, which are capable of reactivating and proliferating lymphocytes that will help the immune response. “In several experimental models, combining JAK inhibition with checkpoint inhibition led to more effective tumor control and longer survival. Mechanistically, we believe that the synergy is explained by the fact that JAK inhibition inhibits myeloid suppressor cells, a notorious mechanism of immune suppression in cancer,” explains Zak.
In the Hodgkin lymphoma trial, researchers enrolled 19 patients who had a blood tumor that was resistant to other treatments, including checkpoint inhibitor monotherapy. All of them were administered ruxolitinib, a JAK inhibitor, in combination with nivolumab, an immunotherapy already approved for different tumors in other clinical settings. And they found that 87% of the patients were still alive at two years, a survival much greater than that recorded among those who received immunotherapy alone—only 24% survived after two years. “In this patient population, these response rates are remarkable and exceeded our expectations,” Zak said.
Blanca Sánchez, hematologist at Hospital del Mar, points out that this research is “very important.” “When checkpoint inhibitors fail, the situation is dramatic and the prognosis is very poor. This finding gives us hope. It is very important because it can open treatment avenues for patients who have a poor prognosis,” says the specialist, who has not participated in the research.
“Combination therapies could overcome key resistance pathways hijacked by tumor cells to evade the immune system.”
Jerry Zak, researcher in the Department of Immunology and Microbiology at the Scripps Research Institute in California
The study in lung cancer, with a therapeutic approach similar to that of Hodgkin’s lymphoma, also yields favorable results. In a phase II trial, researchers enrolled 21 patients with a metastatic non-small cell lung tumor and gave them itacitinib, which also targets the JAK pathway, in combination with the immunotherapy pembrolizumab, which is another point inhibitor. of control. The median progression-free survival was almost two years, compared to the 10 months observed in other studies in which immunotherapy alone was administered.
Andy Minn, professor of Radiology Oncology at the University of Pennsylvania and author of the work on lung cancer, argues that adding JAK inhibitors to immunotherapies can improve immune functions that involve multiple different immune cells and multiple different cytokine signaling pathways. . The scientist highlights the robustness of the conclusions along the same lines from the two complementary studies: “I think this suggests the many ways in which JAK inhibitors can improve anti-PD1 [un tipo de inhibidores de puntos de control] and the many clinical scenarios in which they could potentially be beneficial.”
“It is a very interesting strategy, it is not just another thing. Immunotherapy is one of the basic pillars of cancer, but there are patients who develop resistance. The strategy of incorporating drugs that restore immunity that may be exhausted is interesting,” says Mariano Provencio, spokesperson for the Spanish Society of Medical Oncology (SEOM). The oncologist, a specialist in lung cancer, assures that, although the studies are “preliminary, they complement each other and give consistency” to this therapeutic strategy. “The most important thing is to recognize that the plasticity of the immune response means that, with these drugs, lymphocytes that are exhausted and exhausted are restored. So, with a drug you lift the brakes [que pone el tumor al sistema inmune] and with another you make the exhausted immune cells active again,” says Provencio.
Experts also celebrate that JAK inhibitors are marketed drugs and are well known to specialists in other clinical contexts. “This facilitates the development of the drug and makes everything happen faster because we already know the toxicity and what precautions we have to take,” says the SEOM spokesperson. Sánchez agrees: “It gives us a lot of calm because we are already used to handling this drug.”
Multiple tumor strategy
Experts see it as feasible for this combined strategy to be successful beyond lung cancer or Hodgkin lymphoma. Zak notes that in their preclinical models “multiple cancer types were controlled more effectively with the combination therapy than with each therapy alone.” And he adds that the fact that his colleagues have used a different JAK inhibitor and a different immunotherapy in lung cancer encourages his hypothesis that “JAK inhibition targets a broad immune suppression mechanism shared by many types of tumors.” different”. “If this hypothesis is true, patients with various types of cancer, including lung cancer, lymphoma, colorectal cancer, and kidney cancer, could benefit from this therapy. Rather than targeting specific mutations unique to a tumor, this therapy remodels the immune system to counteract some of the cytokine-mediated disruptions in an antitumor immune response. “This is a general phenomenon and, in theory, could be applicable to many types of tumors.”
The combination of drugs to exploit the potential of immunotherapy has only just begun. “Despite the introduction of immunotherapy, we still have the limitation that some patients do not respond or progress over time. The combination of drugs is what is being done massively now with chemotherapy, radiotherapy and targeted therapies,” says Edurne Arriola, oncologist at Hospital del Mar.
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