Behind the Science

I am a Medical Oncologist; my job involves treating patients with cancer with drug treatments. As part of my role, I also run early phase clinical trials. These research trials are the first stage of testing new cancer drugs.   

As you say, immunotherapy has revolutionized cancer treatment in many types of cancer. However, immunotherapy doesn’t work for all patients. It is therefore important that we work out why immunotherapy does not work in some cases so we can design new drugs, or drug combinations, to combat immunotherapy resistance.  

Immunotherapy relies on the body’s own immune system being able to fight the cancer once the immunotherapy activates the immune system. We know that there are many ways in which the body’s immune system is suppressed so that is cannot be activated, via a so-called “cold” tumour. So, if we can change this inability to become activated and create a “hot” tumour, then we can bring the benefit of immunotherapy to far more patients.   

Myeloid cells are a type of immune cell that circulate in our body’s blood stream. There is evidence that they might work to suppress the immune system (produce a “cold” tumour”). So if the myeloid cells can be persuaded to stimulate the immune system rather than suppress it, this may help immunotherapy work better.

I am a Principal Investigator on the Phase I MATINS trial of bexmarilimab. This means I run the clinical trial in the Drug Development Unit at the Royal Marsden Hospital/Institute of Cancer Research in the UK. I was attracted to run this trial as I was interested in targeting myeloid cells as a potential way to overcome immunotherapy resistance.   

We know from the laboratory tests and the trial of bexmarilimab that it can change myeloid cells to become immune-stimulating rather than immune-suppressing. This is a really important step in developing the drug and I am really looking forward to seeing bexmarilimab move forward in further clinical trials in selected patient groups.   

I think the future for cancer drug research is very exciting. We have many different drugs in development, many of them being immunotherapy. I am particularly interested in ways that we can become better at picking which patients will benefit from certain drugs. If we can do that, then patients can potentially have a better chance of drug response and we also can avoid exposing patients to side effects.   

I’ve been interested in natural sciences from very early on in my youth. By training, I am a biochemist specialized in molecular biology, with a Ph.D. in cancer biology. I did my MSc and Ph.D. studies at University of Tampere, Finland, as well as a few years of postdoc research. Already during my Master’s studies I decided to find a career having something to do with cancer.

During my Ph.D., I studied the role of the altered import of proteins into the nucleus of cancer cells. While doing my postdoc I focused on the immunology of brain tumors as well as setting up some new experimental methodology for the lab.

Before joining Faron I took a leap away from academia and did a stint at a biotech start-up, doing R&D.

I first heard about Faron at a scientific conference I was attending while still working at the university; Dr. Maija Hollmén, now our CSO, and her research group had a poster presentation about bexmarilimab data and the then-just-initiated MATINS trial (Faron’s Phase I/II trial investigating the potential of bexmarilimab, Faron's wholly owned precision immunotherapy asset, in multiple solid tumor indications). I found it fascinating, that a drug with such a novel mode of action and which was fully developed in Finland, was already in clinical trials.

A few months after the conference, the R&D department at Faron was expanding and there was a Research Project Manager position open that matched my background and expertise very well. I didn’t make the cut at that recruitment round, but Faron promised to keep me in mind if there were any further openings. Then about a year after that, I got a call if I was still interested in joining – and here I am 😊.

Here in the Faron R&D team we run and manage research projects that are needed to support the clinical development programs. For example, we participate in the interpretation of biomarker results obtained in our clinical trials.

The research projects can vary from conducting preclinical studies to assay development and formal validation for the purposes of clinical trial biomarker analytics. Recently, my priority has been on the assay development side with multiple projects in that area ongoing simultaneously. I am also working on our possible future companion diagnostic assay for bexmarilimab that could be used in identifying the patients most likely to benefit from the therapy.

I like the problem-solving nature of the role when something does not go as planned in the research projects. Then I can unleash my analytical mind while trying to troubleshoot the issue. Also, the sense of accomplishment when a project is finished, like when an assay is ready to be taken into use to analyze actual patient samples in a clinical trial, is very rewarding.

The greatest challenges relate to the very scientific nature of my work as well: in science, things don’t always go as expected, and this happens usually when there’s no time for things to go wrong!

With a background in academia and basic cancer research, I am really enjoying seeing the results of a scientific finding in a research lab being taken into the clinic and delivering promising results for cancer patients. The path of bexmarilimab thus far is very intriguing and inspirational.

From my point of view, we are a very scientifically oriented company as we have roots firmly in academia. That shows in the company culture as well, as there are regular scientific presentations in our company-wide meetings.

You will most likely find me at the stables with my horse, Weltkaiser, aka Kassu, with whom I train almost every day and participate in equestrian competitions. There is nothing like a good ride to take your mind off all the troubles in the world!

I did my Ph.D. studies on the immunotherapeutic targeting of ErbB4 receptor in breast cancer. My research was very cancer-oriented despite having to be aware of the effector functions antibodies induce to kill cancer cells via complement and antibody-dependent cell cytotoxicity. I remember one fascinating paper by Clynes et al. from Nature Medicine (year 2000) where they showed that mice deficient of activating Fc receptors do not benefit from Herceptin treatment.

In relation to this, while seeking for a postdoctoral position, I read many papers about macrophages. What sparked my interest was the abundance of these cells in the tumor microenvironment (over half of the tumor mass can consist of macrophages) and the versatile nature these cells have in promoting tumor growth. From the initial macrophage (M1)/M2 concept the field has evolved significantly, and we know now that each tumor has its own composition of various macrophage populations. The function of these is yet to be discovered.

Clever-1 is a very large scavenger and adhesion receptor that binds various ligands. Thus, it has several functions that lead to a multitude of context-dependent outcomes. For example, by scavenging and intracellular sorting of unwanted self-components, Clever-1 regulates extracellular matrix composition, intracellular signaling events and secretion of various molecules.

With this in mind, there are several indications where targeting Clever-1 could provide benefit for patients, the most obvious being cancer of course. But there are several other possibilities for application, such as adjuvant therapy to improve vaccinations or even induction of macrophage responses against tuberculosis. This said, one needs to know what epitope to target on Clever-1 to achieve the desired functions. This is not so simple.

I have worked with two very difficult molecules during my career. The first one was ErbB4, as it was not clear whether it was an oncogene or a tumor suppressor, and it only revealed its secrets when cells were stressed or cultured in 3D.

The other one is Clever-1. Due to its multifunctional properties, it has no single robust read-out and instead can affect a broad spectrum of events. This makes it difficult to design robust potency assays for drugs targeting Clever-1.

As a couple of examples of the challenges in working with Clever-1, it is very hard to overexpress such a big molecule in any relevant cell line or primary cells, stable genetic knockdowns have been impossible to make, and the production of recombinant forms of Clever-1 have mostly been unsuccessful due to low yields or misfolding of the protein.

The precise therapeutic control of myeloid malignancies and cancer-related immunosuppression remains a critically unmet challenge that has not been successfully mastered with the current arsenal of drugs. Targeting Clever-1, expressed by both immunosuppressive macrophage populations and myeloid leukemia cells, presents a way to kill two birds with one stone.

In one hand bexmarilimab can activate the adaptive immune system via increased antigen presentation by macrophages, and on the other hand bexmarilimab can sensitize myeloid leukemia cells to standard of care, such as azacitidine and venetoclax.

Faron is a pioneer in macrophage-targeting therapies and has a novel pipeline that originates from academic discoveries. Faron’s clinical development relies heavily on scientific findings, and the academic research runs in parallel with all of Faron’s activities to support decision making. Overall, I think Faron stands out because it follows its own paths and does not rush like a lemming to the crowded IO space where every other company is at the moment with T-cell targeting drugs.

I am very happy on what we have been able to achieve in our understanding of bexmarilimab activity in advanced solid tumors. Using these same approaches, we expect to be able to understand its activity in myelodysplastic syndromes and acute myeloid leukemia soon. Thus, I think the next big challenge is to identify the patients benefitting from bexmarilimab therapy and to develop an enrichment strategy for patient selection.

I think it’s three key changes: These are philosophical, advances in molecular biology and data.

Firstly, the philosophical change around the growing acceptance of precision medicine is very important. Previously, due to lack of data and ability to measure relevant biomarkers, there was limited understanding about drug response and efficacy, which meant that many clinical trials essentially recruited “all-comers.” It was, for example, all breast cancer patients, or all lung cancer patients, or all asthma patients.

What became evident over the last 30 years was that the efficacy of drugs created using this development paradigm was often not good enough for the regulatory authorities or potential customers (payors, patients, doctors). Many of us involved in clinical trials came to believe strongly that you must understand enough about the drug to know who to give it to. It’s not enough to say: “This is for breast cancer,” you have to say: “This is for the subset of patients most likely to respond?” I think that is one of the major philosophical changes.

The second change over the last 20 years, has been dramatic advances in molecular technologies which have led to the ability to do in-depth detailed molecular biology on humans. This is possible today even at a cellular level where individual cells are used in clinical trials to measure what’s going on. The growing ability to detect cancer and other diseases from blood samples is also bringing a revolution in how we identify patients likely to respond to particular therapies.

Thirdly, the ability to manage and analyse very large amounts of data is also a critically important development. As soon as you go anywhere near any sort of omics (i.e. genomics, transcriptomics, proteomics, or metabolomics), you need sophisticated computer analysis and insightful statistics.

Here is a brief example. One of the challenges of developing immune agents is that when you first give them to responding patients, the tumor often gets bigger, (a phenomenon called psuedoprogression). As a result, patients get taken off the study, quite possibly prematurely as in some cases they are responding to the therapy with inflammation of the tumor. We will never know, if we had continued, whether the treatment would have led to tumor shrinkage over time.

However, this is where molecular biology comes to help. There are now published studies that have measured circulating DNA from the tumor showing that, even if the patient gets pseudoprogression, by reducing the amount of circulating DNA in the blood, the patient has a much better prognosis in terms of survival. In other words, they move to stable disease. It’s a good example of how molecular biology is changing how we are developing drugs, in particular oncology drugs.

When I retired from Head of Group Research at Roche over ten years ago, I accepted a limited number of part-time positions around the world, one of which was a position at the University of Helsinki in the then brand-new Finnish Institute for Molecular Medicine. This was, at the time, almost unique in its ability to bring state-of-the-art molecular biology, high level computer technology and automation of drug screening to leukaemia patient samples and then, in some cases, to patients directly.

As part of that, Markku Jalkanen [CEO of Faron Pharmaceuticals], with whom I had previously worked with in Finland in the 1980s, approached me to join the Board of “a really interesting company with really interesting projects about modulating the immune system.” Despite my existing commitments, the Clever-1 project was exactly in my area of interest, so I joined the Board of Faron and, after a few years, moved to become Chairman of its Scientific Advisory Board where I have been focusing on the company’s science and medicine.

The application of precision medicine approaches is today leading to much more efficacious drugs. One of the first examples of this is of course Herceptin (trastuzumab) from Genentech. When we first started advocating for subdivisions of patients into responding groups there was a push back from the pharmaceutical industry and the medical community due to the added complexity of this approach. Unless you are a specialist, it’s easier to say, “Oh you have asthma, try this.” That model has broken down dramatically in cancer and it is starting to change in many other disease areas. It has become clear that, for any drug, there will be some patients who respond well, some patients who respond a bit and some patients who don’t respond at all. So, if you can focus the drug only on the patients who have a higher likelihood of responding, obviously the drug efficacy will increase.

Precision medicine in cancer means much better outcomes for cancer patients including long-term remission. For oncologists, treatment guidelines say that if you get pancreatic cancer, for example, we give you this medicine first as a first line therapy, and when that fails then we give you this second line therapy, and then we give you the third line, if there is one. This is the old paradigm of saying that pancreatic cancer is all one thing. This approach has evolved in breast cancer and lung cancer and, to some extent, colorectal cancer. However, it’s mostly still, “You have this type of cancer and therefore this is what we give you first,” even though the data tell you that often the majority of patients won’t respond to the first guideline recommended treatment. In fact, you are giving more than 50 per cent of patients what could essentially be the wrong drug.

There is good emerging evidence from population studies of cancer patients treated with drugs predicted by molecular diagnostics, that indicates which drugs are more likely to work versus which ones are less likely to work. The second evolution that’s emerging is the importance of using drugs in combination. For infectious diseases like HIV this is already very clear and cancer is, in a number of ways, like an infectious disease.

Unfortunately, the current requirements for testing and approval of cancer drugs do not support the testing of multiple combinations. Indeed, the number of possible combinations you can test in clinical studies is very limited because the number of drugs out there is so large. This is leading to a new paradigm – the collection of real-world patient response data associated with very detailed molecular markers and patient medical history, so we can evolve the rules of which drugs, which drug combinations and which order of drugs work for which molecular profile and patient type.

Where the number of treatable patients is very low, then the answer is obviously yes – as you can see for rare diseases. Where the number of potential treatable patients is large, then today we need a very large, preferably blinded, clinical study.

Large scale clinical trials will of course include patients who respond and patients who don’t respond. It’s the understanding of the mechanistic reason behind the non-responding patients that allows you to refine patient selection for the next study, or even for registration, a group of patients for whom the drug is most efficacious. In this sense you are using individual patient responses as you will have an in-depth analysis of their molecular pathology and their previous medical records.

The immune system is very complicated and, in addition, it often functions differently in different organs. Cancers modify the degree of local and often systemic immunosuppression and so create a number of completely different kinds of environments. The most obvious difference is that there are hot tumors, that are full of lymphocytes and other immune cells and hormones, and there are cold tumors, where the cancer has successfully signalled to the immune system that there is “nothing happening here."

Importantly, what we are starting to see in Faron’s bexmarilimab studies, is that when you can limit systemically the ability of the cancer to hide from the immune system, the immune system can now find other metastatic tumors and kill them. Most of us probably get cancer cells every day but they are usually eliminated as the immune system recognises them immediately and wipes them out. It’s only with age, or other immune impairing disabilities, that our immune system loses this ability.

In contrast to the many companies developing copies of existing immune therapies, Faron is unique in developing a very powerful and brand-new agent that modulates the immune system in a completely different way from existing immunotherapy drugs. There are apparently at least 33 antibodies targeting the PD-1 mechanism being tested in 2000 clinical trials and the futility of this huge investment was recently discussed in an excellent article by two leading FDA regulators in the New England Journal of Medicine. It is clear that what patients and society really need is investment in new, novel, immune therapy agents such as bexmarilimab.

Interestingly, the concept of bexmarilimab comes from understanding immune suppression in pregnancy. An embryo prevents the mother from rejecting it by using large amounts of the Clever-1 ligand. Faron has been very smart in saying, “If nature can do that to create new human beings, then why don’t we turn it around and use it backwards to allow cancers to be seen?” It’s important to remember that cancers can use any mechanism that the body uses anywhere to do whatever they need to survive. This is clearly a key mechanism that is seen by the distribution of expression of the Clever ligand – you can see its use by many cancers.

A key focus for Faron is to look at molecular markers to better understand which patients are responding to treatment and which aren’t. Determining drug efficacy in clinical studies is challenging as they are often run, for regulatory reasons, in very sick patients. This is a big challenge for immune agents because they require an effective immune system and very sick patients, who have undergone multiple therapies without success, essentially have their immune systems deeply compromised. Therefore, the likelihood of efficacy in this patient population is much smaller with immune oncology agents.

Bexmarilimab has a favorable safety profile, and there is a strong argument for using it in combination with other agents in earlier lines of therapy. So, I would say the next key step for Faron is to focus on the efficacy of bexmarilimab in its current studies and then its earlier use in patients and also on high level, powerful molecular patient data.

I think it’s two things. It’s more molecular diagnostics in the context of responding patients and nonresponding patients to understand to whom we should give these agents. The second thing, which is probably even more important for the patients, is which combinations of drugs and for which patient these are most likely to be efficacious.

There is some interesting data to show that patients pretreated with one immunotherapy and then treated with another immunotherapy respond much better. So, combination therapy doesn’t always mean giving them together, it can mean giving one before the other in a sequential manner. So, I think there’s a lot to be done there. All of this will be driven by molecular understanding. I believe in the future that understanding will increasingly come from studies on blood using new molecular technologies that follow the evolution of the cancer and predict which combination of medicines are most likely to work for an individual patient.

The use of these agents will require much more widespread use of diagnostics which hospitals, even a major centre, will not be able to do cost effectively. I think there’s a logistical problem which needs to be solved, as in depth molecular diagnostics, clearly, will have a growing critical role in determining the best treatment for each cancer. It is now clear that in time not just cancer, all other diseases too, will require this approach for effect care. There have been some interesting discussions in the UK about setting up one or more major cancer diagnostics centers to which cancer samples would go for analysis and response prediction. The success of Genomics England in genome sequencing of cancer genomes could be a model for this kind of operation.

I strongly believe that in order to get patients to long term remission from cancer, it is essential to engage the patient’s immune system. For this reason new immune oncology agents like bexmarilimab, often in combination, will become essential first-line therapies for many patients going forward.

Growing up I was always interested in research. That’s really why I went to medical school – to become a researcher. I also learned to love treating patients, which made those early years after medical school incredibly rewarding. But, I missed the research so got my Ph.D., established my own research group and undertook a post doc at the Karolinska Institute in Stockholm, Sweden. Then I became restless and wanted adventure! So, my family and I moved to Abu Dhabi in the United Arab Emirates, where I was Head of Oncology at the Cleveland Clinic. That was an incredible time and we stayed longer than we had planned. But again, I missed the science so we returned home and I took my first role in the pharmaceutical industry. That’s where I began designing clinical development programs, which has been my focus ever since, first with Novartis, both in Europe and the US, then with a number of biotechnology companies. All in the field of oncology.

I became interested in tumor biology at medical school. I’ve always loved detective stories and that’s what tumor biology is like. There are lots of mysteries to solve, to understand why tumors behave the way they do. We have made incredible progress with cancer therapy in recent decades. The first wave of immunotherapies were, without doubt, game-changing but we mustn’t forget that more than 80% of cancer patients don’t respond to these treatments. We know why – tumors are so darn smart, using multiple strategies to supress our immune system. For many years now, that’s where my focus has been, investigating how we can control not just the tumor but also the tumor microenvironment (TME) – those non-cancerous cells surrounding the tumor that have been recruited to help its growth and spread. Controlling the microenvironment is critical for effective cancer treatment.

I have been very lucky to have experienced so many different aspects of the oncology field and I wouldn’t say I have a favorite. Being rooted in the science has always been the most important aspect for me and that’s what has really guided my career path. When I came back to Sweden, from the United Arab Emirates in 2011, I was both a doctor and a researcher. I knew I wanted to get back into the science, but I also knew I didn’t want to pursue research full time. For one, it is very difficult to make it as a researcher. Any researcher will tell you that. And it wasn’t important me to just publish papers. As important as that is for scientific progress, I needed to see my research helping patients. Being part of the drug development path, designing the trials of what will hopefully, one day, be medicines making a difference in patients’ lives. That is incredibly important to me.

Research into the immunosuppressive nature of the tumor microenvironment and the potential of targeting tumor-associated macrophages (TAMs) to overcome that immunosuppression is an area I have worked in a lot and one that I believe holds great promise. Researchers have been exploring this field for some time, pursuing different modalities, but their work hasn’t led to any therapies for patients. Faron’s approach excites me. The preliminary efficacy data for bexmarilimab is promising and the immune activation we have seen when it is used as a single agent is significant.

And there is the safety profile too, we have a drug candidate that has been well tolerated in trials, which is important for these patients who are very ill. It’s also important as we look to combining bexmarilimab with other drugs. Additionally, this is a programme with strong scientific validation – the Clever-1 receptor on the macrophage surface that bexmarilimab targets has been evaluated in many publications so the science is robust. This all provides a real reason to believe.

In the short term there are the challenges from this pandemic. Health systems are at breaking point and that presents practical challenges for clinical trial recruitment and treating and assessing patients with the necessary consultations, biopsies and monitoring. I hope, thanks to the success of vaccination programs, that we are moving to a more positive picture, but there is no quick fix. More broadly, there is still so much we don’t know about tumor biology. Back to the detective mystery! A therapy that works for a patient one day can very quickly become ineffective as the tumor develops resistance to that treatment approach. Cancer is a dynamic disease and generally becomes more heterogeneous as the cancer progresses. Sub-populations of cells and variations in their molecular make up, these all provide fuel for the tumor to become resistant to treatment. Another challenge is that we still have very few clinically useful biomarkers. These are vital for identifying the right patients for the right treatment – who is likely to respond, who can gain the most benefit.

We need to bring the promise of immunotherapy to a broader population. The first immunotherapies sparked a research revolution into how our own immune systems can be harnessed to fight cancer and these therapies have become well established. But too many patients are still being left behind because of primary or acquired resistance. It is up to us to change that. There is a lot of promising research, such as the work we’re doing at Faron, looking at new therapeutic approaches and novel combination therapies that could break that resistance and bring longer-lasting positive effects to a greater proportion of patients.

Long! Being based in Boston, US, working alongside the fantastic team in Turku, Finland requires a strict early morning routine. But I have worked all over the world and so time zone challenges have always been part of my life. The benefit this brings is that I really like the mix between Europe and the US. Faron merges this really well, taking the best of the two cultures, and I believe this can only be a positive thing as we work together to develop new therapeutic for patients.