Swiss cancer research could ‘boost’ immunotherapy

A production operator works with an isolator in the cell production laboratory for immunotherapy of the oncology department of the Center for Experimental Therapies in Cancer Research of the University Hospital of Vaud, CHUV, on Thursday, Jan. 10, 2019 at the Biopole in Epalinges. Keystone / Laurent Gillieron

Immunotherapy is touted as the future of cancer treatment, and Swiss research groups are uncovering ways to make it more effective. But they face a slow process in delivering their discoveries to patients.

Medical miracles can happen: In the last decade, many terminal cancer patients who had undergone experimental immunotherapy had their tumours disappear or go into remission. Immunotherapy offers, in short, help to “self-help”. Instead of attacking cancer cells directly, as is the case with chemotherapy or radiation, immunotherapy aims to stimulate and strengthen the patient’s immune system so that it recognises the cancer cells, destroys them or at least prevents their growth.

Various experiments and clinical trials have shown thatExternal link cancer immunotherapy can prolong patients’ lives as their immune system learns to detect and attack cancer cells if they ever come back. This so-called “immunological memory” helps them stay cancer-free for longer. In addition, the therapy causes fewer side effects because it does not target all cells in the body, but only the immune system.

But immunotherapies still fail in around two-thirds of cancer patientsExternal link and can only act on certain types of tumours. Many patients don’t respond to immunotherapy at all, and if they do, the effects are temporary. Researchers are still puzzling over the reasons. But in Switzerland, a research group might have found a clue.

Cancer killers in a continuous marathon

One explanation is that T-cells – a subtype of white blood cells that play a key role in recognising and attacking cancer cells – become too tired. They lose their ability to halt a tumour’s progression while infiltrating it and battling with cancer cells. This phenomenon is known in science as “T-cell exhaustion” and presents one of the major hurdles to cancer immunotherapy. The problem of metabolic dysfunction means that the T-cells are depleted much faster than they can be regenerated, so they cannot be turned back into effective cancer fighters, explains Li Tang, an associate professor of immuno-engineering at the Swiss Federal Institute of Technology Lausanne (EPFL).

To revitalise exhausted T cells, researchers from Leman Biotech, an EPFL spin-off, have developed a booster protein that can be used in conjunction with immunotherapy drugs. Li, the co-founder of Leman Biotech, humourously describes the mechanism as “metabolic fitness for T-cells”. Currently, immunotherapies stimulate T-cells through different strategies and speed up their metabolism to attack cancer cells, “just like continuously offering a person Red Bull and caffeine to keep them running faster in a 100-meter sprint, which exhausts them very quickly,” says Li.

His team, on the other hand, is studying how to keep T cells cool and maintain their metabolism in a balanced state, as if they were continuously running a marathon. The protein his team has developed helps with this. Preclinical trials on miceExternal link showed a recovery rate of almost 90% when the newly-developed protein was used in conjunction with the most widely-used forms of cancer immunotherapy known as an adoptive T-cell transfer therapy and immune checkpoint inhibitors (see Infobox).

Most promising types of immunotherapy

Adoptive T-cell transfer therapy – also known as CAR T-cells – boosts the natural ability of a patient’s T-cells to fight cancer: Immune cells are taken from their tumour, and those most active against cancer are selected, grown in large batches, and put back into the patient’s body. 

Immune checkpoint inhibitors, on the other hand, are drugs that allow immune cells to respond more strongly to cancer by blocking immune checkpoints – a normal part of the immune system.

The artificial protein engineered by the EPFL spinoff is the equivalent of a booster to enhance therapeutic efficacy of the both treatments.

From lab to clinic

The immunotherapy-boosting protein is just one recent advancement in redirecting the immune system against cancer. Currently, there are dozens of approved immunotherapies and thousands of ongoing clinical trials being conducted in humans worldwide, according to a recent editorial published in the academic journal Nature CancerExternal link, with most trials focusing on solid tumours. Immuno-oncology has become a $30 billion marketExternal link and continues to grow.

But only 15–60% of patients (ranging from 15 to 30% in most solid tumors to 45–60% in melanoma for example) respond to immune checkpoint inhibitors (ICI), leaving a broad swath of patients who do not derive benefit.

On clinicaltrials.gov, a website that aggregates information on past, ongoing and planned clinical studies from around the world, there are over 800 registered trialsExternal link of CAR T-cell therapy, many of which focus on solid tumours. However, only five CAR T-cell therapies have been approved by the US Food and Drug Administration for certain blood cancers, including leukemia, and 90% of treated patients relapse. No CAR T-cell therapy has yet been approved for solid tumours.

The developmental progress of cancer immunotherapy in Switzerland is similar to progress in the United States, according to Pierre-Yves Dietrich, who heads the oncology department at the University Hospital of Geneva.

He points out that Swiss researchers also consider CAR T-cells and other immune cell types to be the most promising therapeutic strategies against cancer. So far, six CAR T-cell treatments have been authorised by Swissmedic, the national regulatory authority. However, Swissmedic spokesperson Alex Josty is cautious when it comes to the concept and efficacy of immunotherapy, pointing out that the approved CAR T-cell treatments are “intended to increase immunity, but this does not really meet the established definition of oncology immunotherapy”.

Dietrich also stresses that immunotherapy is still in its infancy and recalls that the first chemotherapy drugs, developed in the 1950s, were not as effective as modern drugs. He expects the development of cancer immunotherapy to follow a similar, slow curve, but remains optimistic.

“We should maintain major hopes for the next years with novel compounds and novel strategies,” he says.

Cautious but slow approval process

Swissmedic is witnessing a significant increase in the clinical trial submissions of various immunotherapies, especially trials with tumour-infiltrating lymphocytes (TILs). However, compared to the US or Japan, which have introduced mechanisms to fast-track the review and approval process for CAR T-cell therapies, Swissmedic seems to be more cautious when it comes to bringing such therapies into clinical trials. “Cancer immunotherapy medicines are very complex and high-risk products,” says Josty. During the authorisation process, Swissmedic assesses data from preclinical tests very carefully and comprehensively to establish the benefit and risk for patients who are suffering from underlying disease and may have already received other treatments.

Meanwhile, Leman Biotech has been able to raise enough funds to start clinical trials and has also filed international patents for their newly developed therapy. “We have already spent five years doing preclinical studies in mice to demonstrate feasibility,” Li says. But due to the complex and lengthy approval process, it will probably be several years before the booster protein they have developed enters the human clinical phase. 

Dietrich agrees that the approval processes for cancer immunotherapies are complex in Switzerland, but manageable. “We have never had so many advances in such a short time, and this will continue during the next decade. The balance between patient protection and rapid access to new treatments is delicate,” he says.

Edited by Sabrina Weiss and Veronica DeVore