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HUMAN PHARMA“Kick-starting our
“Kick-starting our
immune system
into the fight
against cancer”
Boehringer Ingelheim is battling cancer on two fronts. Together with partners from all over the world, scientists are not only targeting tumor cells directly, but also attempting to trigger the immune system to fight cancer. Clive Wood, PhD, Head of Discovery Research at Boehringer Ingelheim, explains how specific and powerful T-cells are and how we are giving them a ‘helping hand’.
Clive, you have been working in the field of immuno-oncology for many years. What fascinates you the most about this research field?
Our immune system is one of the most complex and powerful systems in our body. It gives the body the ability to distinguish non-self from self – and do it with exquisite specificity – and then eliminate non-self in order to keep us healthy. Unfortunately, many tumors avoid immune detection by directly inhibiting immune cell activity and the small number of specific mutations in a particular tumor can hinder the ability of the immune system to recognize the tumor as non-self. The immune system is then unable to do its job. As an immunologist, I see an opportunity to change this and ‘kick-start’ the immune system into action to attack these so-called cold tumors.
This approach did not show any significant success for a long time.
For decades, ideas of using the immune system to fight cancer were considered unrealistic by many and its ability to do so unproven. It was forbidden territory in many companies. I experienced some vehement reactions in the industry against such concepts.
What turned the tide?
Some discoveries were made in the late 1990s that led to the approval of antibody therapeutics in 2011 (anti-CTLA4) and 2014 (anti-PD-1) that have opened up this whole new immune targeting front in the fight against cancer. They have brought big benefits to some patients, but sadly still to a limited number. There is no longer any question of whether the immune system can succeed in fighting cancer. The focus is now on how to use it to benefit many more patients.
Turn cold tumors hot
Clinical research has shown that the current wave of checkpoint-centric therapies is beneficial in those patients with immunologically active and highly-mutated so-called hot tumors. But they have limited efficacy in those tumor types that lack these properties, commonly known as cold tumors. The objective for the next wave of therapeutics is to alert the immune system to the presence of these cold tumors, and this is where Boehringer Ingelheim is focusing on.
To lead this battle against cancer, Boehringer Ingelheim is attacking cancer on two fronts.
Correct. We are developing a new generation of drugs that directly target the drivers of cancer cell growth. And we are working to boost the body’s immune response against cancer by blocking the tumor’s immune-inhibitory mechanisms and enhancing the recognition of the tumor as non-self. In both areas, we are building a portfolio of first-in-class innovations. The combination of tumor cell-targeted and immune cell-targeted medicines may hold the greatest benefit for most patients.
You want to turn cold tumors hot.
That is the basic principle. Hot tumors contain T-cells and have ongoing immune activity. Cold tumors lack T-cells and are a suppressive environment for the immune system. We are very focused on patients with cold tumors – and are excited by the concept of T-cell engagers, for example.
What are T-cell engagers?
T-cell engagers support the body’s immune cells in being able to find and destroy cancer. These protein therapeutics are engineered to bind to both T-cells and tumor cells, creating a bridge between them that enables the T-cells to deliver toxins directly to the tumor cells to trigger their destruction. In the absence of the immune system recognizing the tumor as non-self on its own, the T-cell engager is a ‘helping hand’ that guides the T-cell to its target.
T-cells are very specific.
Our body has a repertoire of different T-cell receptor specificities, many billions, in fact. When our body is invaded by a pathogen, a small subset of T-cells with specificities to this invader gets activated and expanded. We need the T-cells of a cancer patient to recognize the tumor cells as ‘invaders’.
Cold tumors may be present in more than half of all cancer patients
Highlight components of a tumor
Highlight components of a tumor
This is where cancer vaccines come into play?
Exactly. Just like using a conventional vaccine to elicit a protective response against a bacterium or virus, we seek to do the same with tumors. With cancer vaccines, we can tell the body which T-cells are needed to ramp-up the necessary response.
Oncolytic viruses are yet another powerful tool to turn cold tumors hot and fight cancer.
Oncolytic viruses have the potential to selectively kill tumor cells, leaving normal cells unharmed. In addition to this direct killing of tumor cells, the oncolytic virus can accelerate the recognition of the tumor cell as non-self. We still have more to learn about how this happens, but fragments of dying cancer cells combined with immune-activating signals in the tumor milieu may enhance immune recognition.
You are starting to combine oncolytic viruses and cancer vaccines. Why are you doing that?
Evidence from many different sources suggests that we can boost the immune response by treating with cancer antigens in different ways. Preclinically, we show that we achieve a stronger response by treating with a cancer vaccine (‘prime’) from AMAL Therapeutics and then later with an oncolytic virus expressing the same antigens (‘boost’). We are testing this now in clinical studies. In addition, we are building other prime-boost candidates. The most recent to enter preclinical development contains six different potential cancer antigens, including one with a specific mutant KRAS.
You just mentioned AMAL Therapeutics, a Swiss biotech company that Boehringer Ingelheim acquired in 2019. It is one of many partnerships in oncology that Boehringer Ingelheim has initiated in the past years. How important are these collaborations to us?
To develop breakthrough medicines for patients, we must work together with the best and brightest across the world. External partnerships are very important to our innovation strategy. A number of recent acquisitions have strengthened our capabilities. These include AMAL Therapeutics in Geneva, Switzerland, and Vira Therapeutics in Innsbruck, Austria, with oncolytic virus technology. In addition, the acquisition of Labor Dr.Merk & Kollegen (today: BI Therapeutics) in Ochsenhausen, Germany, which has amassed considerable expertise in process development, manufacturing, and analytical characterization of viral therapeutics such as oncolytic viruses expands our know-how even further.
What is the next exciting direction in immuno-oncology?
We are learning more about additional types of cells in the microenvironment of the tumor and how these possibly influence the ability of the immune system to reject the tumor. Targeting these other cell types may be important for turning cold tumors hot. An exciting example comes from our recent partnership with Northern Biologics. This is a monoclonal antibody targeting a protein of the tumor stroma that is in preclinical development.
These approaches are as numerous and as diverse as our oncology portfolio. When do you expect Boehringer Ingelheim to offer new treatment options for patients?
Today, we have a very strong early stage oncology development portfolio, with over fourteen Phase I and preclinical development stage immuno-oncology projects. 2024 onwards will be very exciting for potential launches of new medicines for cancer patients.
