BOOSTING OUR IMMUNE SYSTEM TO PERSONALIZE CANCER TREATMENT

Immunotherapy only broke through about a decade ago but has already won a Noble Prize. This revolutionary way of treating cancer boosts the patient's immune system to destroy cancer cells. The problem is that, while this could save the life of some patients, others may be resistant to the therapy and suffer from the sideeffects and high costs without reaping the benefits. By investigating the response to immunotherapy on the single-cell level, aided by advanced technology and a large number of patients, researchers at the VIB-KU Leuven Center for Cancer Biology are paving the way for more personalized cancer treatment.

Cancer comprises a multitude of different diseases, and every patient reacts differently to frequently used therapeutic approaches, such as radiation and chemotherapy. In the late 19th and the early 20th century, the first attempts in the Western world were made to infect patients with weakened bacteria or viruses to activate their natural defense mechanism, aka the immune system. The results were not overwhelming, but scientists still believed that triggering the immune system might be a successful strategy to fight cancer and kept engaging in basic research into immunity regulation.

Remarkable scientific progress has been made since then, but that has rarely led to generally applicable cancer treatments. However, a change is on the horizon… "When it works, immunotherapy is truly amazing," says Diether Lambrechts, group leader at the VIBKU Leuven Center for Cancer Biology.

The rise of immunotherapy

In 2018, James P. Allison and Tasuku Honjo jointly received the Nobel Prize in Physiology or Medicine. Allison and Honjo each examined a different protein and found that both work as a "brake" on the immune system. The act of releasing that brake, unleashing our immune cells to attack tumors, is what became known as immune-checkpoint blockade (ICB), the mechanism behind a type of immunotherapy called immune-checkpoint blockage therapy.

Over the past few years, the potential of ICB therapy has been investigated through hundreds of clinical studies in multiple cancer types. In many cases, the clinical trials showed encouraging positive effects. However, the results were also extremely variable and unpredictable, while resistance, relapse, and side-effects were common.

The recent developments in single-cell technology have been a major catalyst in understanding why some people respond positively to ICB and others don't. By using such technology, enabling in-depth studies of individual living cells, VIB is able to analyze samples of the tumor and its microenvironment at single-cell level. That way, detailed single-cell maps of the tumor microenvironment before and during ICB therapy can be compared to investigate which biomarkers – measurable indicators of pathogenic processes, in this case the dynamic interactions between cancer and immune cells in the tumor microenvironment – can predict the outcome of the therapy.

"Immunotherapy is a real gamechanger. For some people, it means the difference between life and death."

Diether Lambrechts VIB-KU Leuven Center for Cancer Biology

Setting up fine-grained single-cell maps

To accelerate progress in this emerging field of cancer treatment, VIB started the Pointillism research track within the Grand Challenges Program in 2018. "Immunotherapy is a real gamechanger," states Diether Lambrechts, who's in charge of the research track. "For some people, it means the difference between life and death, as simple as that. That's why we want to gain as many insights as possible, as soon as possible. Our main goal is to predict which patients will respond to the therapy and which won't, before immunotherapy starts. For those who won't respond, we want to use that information to develop different treatments that can extend their lifespan in a qualitative way."

In the Pointillism project, immunotherapy trials have been selected in four different cancer types, to assemble a comprehensive collection of pre- and on-treatment biopsies from patients. Lambrechts: "Since breast cancer is the most common cancer type we're investigating, that particular trial delivered the first results. In collaboration with the Multidisciplinary Breast Center of UZ Leuven, we used single-cell technology to study the tumor microenvironment of 40 early breast cancer patients treated with immunotherapy. This is the first time such a large cohort of breast cancer patients has been analyzed on the single-cell level."

"The results show clear differences between patients predicted to respond to the therapy, so-called responders, and the nonresponders. The clear but subtle differences wouldn't be noticed with other approaches. Studying the differences between both groups allowed us to define a surrogate marker for response based on specific characteristics of the tumor and its microenvironment. This shows that our fine-grained single-cell maps of the changes in the tumor microenvironment during treatment yield results."

Breaking therapy resistance

Jean-Christophe Marine, group leader at the VIB-KU Leuven Center for Cancer Biology, co-leads the Pointillism project and has been focusing on melanoma, a type of skin cancer. For a long time, it was widely accepted that resistance to melanoma therapies was caused exclusively by genetic alterations – mutations – in the cancer cells. However, recent research suggested that the resistance can also arise via non-genetic mechanisms that change the expression of certain genes without altering their DNA sequence. How and why the genetic or non-genetic route prevails remained unclear, but a recent publication in Cancer Cell has lifted a corner of the veil.

"We showed that resistance to melanoma therapies is not random, but predetermined," professor Marine explains. "The presence of a specific cell type, neural crest stem cells, leads to non-genetic rather than genetic therapy resistance. These stem cells can literally "reprogram" themselves to evade therapeutic pressure. We managed to go a step further and identified the protein that promotes the emergence and survival of these stem cells. By blocking the activity of this protein, we were able to drastically reduce non-genetic drug resistance in patient-derived tumor cells that were implanted in mice."

"These findings have important clinical implications," adds senior postdoctoral fellow Florian Rambow, who was involved in the study. "Not only did we show a viable way to suppress non-genetic resistance to melanoma therapy, but we also demonstrated that the presence of specific cells dictates which resistance mechanism is likely to occur. This will help us to predict the resistance routes in patients and develop personalized therapies."

Diether Lambrechts and Chris Marine VIB-KU Leuven Center for Cancer Biology

A personalized approach to medicine

Professor Lambrechts strongly believes in the future of immunotherapy for treating different cancer types and patients: "Immunotherapy as we know it emerged only 10 years ago but is already being applied to over 30 cancer types. We've been targeting only two molecules until now, and the Grand Challenges Program will help us to target new ones with new therapies. Research into cancer vaccines is another promising immunotherapy-based way to fight cancer.

"We're on our way towards a personalized approach to medicine – and not only for cancer – thanks to incredible technological developments and extensive collaboration between research centers, hospitals and patients. The Pointillism project is an important lever in that respect."

VIB Grand Challenges

This translational research program aims to increase

the societal impact of our science. By teaming up with

experts with complementary expertise outside of VIB, we

can generate new, otherwise untapped avenues to create

added value for society.

Three examples included in this edition of VIBtimes are the

Soy in 1000 Gardens project (p14), the Pointillism project

(p26) and several of our COVID-19 actions (p28).

vib.be/grand-challenges

Flamingo Tx, another flock of potential cures

In 2016, the VIB team of professor Marine, together with researchers from Ghent University and KU Leuven, revealed that

the growth of aggressive skin cancer is highly dependent on the presence of a non-coding RNA gene called SAMMSON. The

results of their research were published in Nature. In 2020, VIB co-founded Flamingo Therapeutics, a spin-off focusing on the

development of innovative therapies based on these insights.

COO Floor Stam: "We're the only company in the world developing this type of cancer treatment in such an advanced stage.

Flamingo Tx is an international organization, but our link with Belgium and VIB is very important because of the know-how

we have here."

flamingotx.com