Every year, new findings from cancer research are presented at the congress of the European Society for Medical Oncology (ESMO). But what John Haanen from the Dutch Cancer Institute presented at the five-day congress in Paris in September also made some experienced experts sit up and take notice.
The doctor from Amsterdam presented a study on a procedure that is no longer new, but on which only small studies have been carried out so far. And he presented very promising data on patients with malignant melanoma, in whom standard immunotherapy had previously failed. The result surprises him and gives him hope, says Stefan Eichmüller from the German Cancer Research Center (DKFZ) in Heidelberg, who was not involved in the study.
Why is? In recent years, a fourth treatment pillar has been established in cancer medicine. In addition to surgery, chemotherapy and radiation, immunotherapy has developed into an essential part of the oncological treatment spectrum within a few years.
But immunotherapy is less uniform than the name might suggest. It includes a wide variety of procedures, all of which have one thing in common: They are intended to induce the immune system to attack a tumor. They are supposed to do this in very different ways.
The checkpoint blockade is currently the most common. It aims – through various pathways – to release molecular brakes that prevent the immune system from attacking tumor cells. Studies have also been examining mRNA vaccinations for years: They are intended to ensure that the body produces tumor proteins and thus “programs” the immune system to attack these structures.
Finally, the standard against certain leukemias and lymphomas is CAR T-cell therapy: T-cells of the immune system are genetically modified in the laboratory before they are given back to the patient by infusion. The approach now presented by Haanen in Paris was described in the USA almost 25 years ago. In 1998, cancer researcher Steven Aaron Rosenberg of the National Cancer Institute introduced a procedure in the Journal of Immunotherapy that he called TIL – tumor-infiltrating lymphocytes.
The principle sounds simple: Doctors isolate T cells of the immune system from removed tumor tissue. “These T cells are actually there to reject the tumor, but for some reason they don’t do it,” explains Eichmüller. The isolated cells are then multiplied in the laboratory. They are then infused into the patient’s bloodstream – billions of them.
In contrast to CAR-T-cell therapy, however, the T-cells remain unchanged here – they are simply multiplied immensely. “The idea behind it is that there are T cells underneath that specifically target the tumor,” explains Eichmüller. “It’s a bit like the motto: a lot helps a lot.” These T-cells are not only supposed to detect and eliminate any metastases in the body in the bloodstream, but also any individual tumor cells that may still be circulating.
In recent years, a number of smaller studies have demonstrated that the procedure can help in principle – in different tumor variants, for example in the lungs, ovaries or cervix. In these smaller phase 1 studies, it was always about testing the safety of the procedure.
At the congress in Paris, Haanen presented by far the largest study of the process. In the phase 3 study, doctors in the Netherlands and Denmark treated a total of 168 patients with advanced melanoma, i.e. black skin cancer. At this stage, the disease has an extremely poor prognosis. Immunotherapy – checkpoint therapy with so-called PD1 inhibitors – had previously failed in almost 90 percent of the participants.
Half of the patients, drawn at random, were treated with the antibody ipilimumab, another common checkpoint therapy. The other 84 participants received the TIL treatment. Almost half of the patients responded to this therapy (49 percent); with the antibody it was only about one in five (21 percent). In addition, the cancer progressed much later than after administration of the antibody, and the survival rate was also significantly higher. Haanen emphasizes that all signs of cancer have disappeared for every fifth participant, at least for the time being.
“It went better than I would have expected,” says Eichmüller, pointing out that PD-1 inhibitors had previously failed in these participants. “The comparator therapy did not work badly, but TIL performed significantly better. Most medical professionals are pleasantly surprised.”
“TIL is an extraordinary therapy,” agrees tumor immunologist George Coukos from the University Hospital in Lausanne. “These results clearly show that it is effective and feasible on a large scale.” The procedure can be used against a wide range of tumors, including lung, cervix and head and neck.
A year ago, a research team led by Stanley Riddell from the Fred Hutchinson Cancer Research Center in Seattle reported in “Nature Medicine” that TIL can help against lung cancer in patients in whom other immunotherapies had been unsuccessful. In this study, the therapy worked in seven of the 14 patients; in two of these, the cancer disappeared for at least 1.5 years. This should encourage further studies, the researchers emphasized in their own commentary in “Nature Medicine”.
The TIL procedure may be particularly suitable for those patients in whom other immunotherapies have failed. “We believe that resistance to anti-PD-1 therapy is mainly due to the microenvironment of the tumor,” says Haanen. “So if we take these cells out of their natural environment, reactivate them in the lab, grow them in very large numbers, and give them back to the patient, we can overcome some of the escape mechanisms.”
In his study, however, all TIL patients had severe side effects; in the comparison group treated with the antibody it was only 57 percent. However, Haanen attributes the high rate less to the administered T-cells than to the two accompanying therapies of TIL: On the one hand, a mild chemotherapy should make room for the newcomers before the increased T-cells are returned.
Above all, however, the side effects result from the administration of interleukin-2 (IL-2). This substance is supposed to additionally activate the immune system and is associated with severe side effects, especially in high doses. These usually subside quickly once the drug is reduced or stopped. “The side effects are accepted if TIL therapy is to be successful,” explains Eichmüller. Haanen says: “The side effects are easily manageable and most have disappeared by the time patients leave the hospital after TIL therapy.”
A detailed publication of the study in a specialist journal has not yet been published. The journal “Annals of Oncology” has so far only published an abstract with rough data on the procedure and results for the lecture in Paris. When asked about this, Haanen replies that he hopes to be able to publish the entire paper in a leading specialist journal as soon as possible.
Another aspect of the study is noteworthy: the phase 3 study intended for approval is being conducted exclusively by researchers, not by the pharmaceutical industry as is usually the case. Haanen emphasizes that the aim is to obtain approval from the European Medicines Agency (EMA) and thus be independent of commercial considerations.
Eichmüller finds this procedure “very unusual”, but there is an explanation for it: The procedure is no longer new, “it is difficult to make money with it,” he says. “The big companies didn’t jump at it.” Isolating and multiplying the T cells is not easy though – clean rooms are required, for example, and the multiplication of the cells takes several weeks.
If the procedure were to be approved in the future, it would have the advantage that it could also be offered to patients outside of studies, says Eichmüller. The health insurance companies might even reimburse the costs. “In any case, the medical need is high,” emphasizes the immunologist. “TIL is a new option in the army of all the other cancer therapies out there now.”
