The shift to tumour-agnostic immunotherapies
Up until recently, cancer treatments focused on the pathology of a cancer – the tissue type and the site of the cancer (e.g. skin, breast, colon, sarcoma, etc.,) and how much cancer the patient has (local, regional, metastatic, how many lymph nodes, etc).
Clinicians focusing solely on the pathology would ask, “What type of cancer does the patient have?” and recommend a treatment based on that information. This focus ignores an important fact: the immune system is the most powerful tool we can leverage in the fight against cancer.
Most conventional therapies do not take the patient’s immune system into account; many of those therapies even weaken the patient’s immune system essentially lowering critical defenses the body has to fight the cancer allowing it to thrive. When functioning at its full potential, the immune system fights our battles for us, conducting immune surveillance to prevent cancer from gaining a foothold, preventing the spread of cancer and preventing the growth of residual disease – the cancer left over after traditional chemotherapy. When the immune system is compromised, none of this happens and the cancer develops without any resistance with a predictable result.
One of the paradoxes of cancer therapy of the last 50 years is that the chemotherapy given to eliminate the cancer weakens the immune system. Weakening the immune system helps the cancer thrive and limits the chance for survival. Have we been our own worst enemies in the fight against cancer?
As Bob Dylan said, “Times...they be a changing.” We are changing the way we approach cancer therapy: a shift to tumour-agnostic immunotherapies that boast the patient’s immune response to the tumour.
The goal of modern immunotherapies is to restore a patient’s immune system to its fully functioning state. These therapies focus on treating the immunology, as opposed to the targeting the pathology. Now, clinicians are beginning to ask, “What can we do to help the patient’s immune system fight the cancer?” Therapies that target the immune system will strengthen it to fight the cancer, no matter what type it is.
Put simply, we should stop worrying about the type of cancer the patient has and worry instead about fixing what is broken in their immune system.
This paradigm shift is evident in recent Food and Drug Administration (FDA) approvals, as well as therapies undergoing clinical trials. There are several examples of therapies and drug candidates that focus on fixing various areas of the immune system that are often defective when cancer is developing.
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Among its various approvals, Keytruda (pembrolizumab) was approved by the FDA for the treatment of unresectable or metastatic solid tumours that have been identified as having microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). The approval of pembrolizumab was notable as it was the first and only time that the FDA approved a cancer treatment based on a common biomarker alone, rather than the location in the body where the tumour originated. Previously approved drugs that were tied to specific biomarkers were also for specific tumour types.
Opdivo (nivolumab) is a checkpoint inhibitor that reduces tumour growth by blocking the interaction between biomarkers PD-1, PD-L1 and PD-L2 that would have prevented activated T-cells from attacking a cancer. The drug to date has been approved by the FDA for the treatment of several cancers including melanoma, squamous cell lung cancer, renal cell carcinoma and classical Hodgkin lymphoma.
YERVOY (ipilimumab) stimulates T-cells and activates the immune system by targeting CTLA-4, a protein receptor on the surface of T-cells that downregulates immune responses by functioning as an immune checkpoint inhibitor. The drug received FDA approval for the treatment of melanoma and is undergoing clinical trials for non-small cell lung carcinoma, small cell lung cancer, bladder cancer and prostate cancer.
Although pembrolizumab is currently the only drug with FDA approval as a tumor-agnostic therapy, ipilimumab and nivolumab illustrate the path which cancer treatment is headed: immunotherapies targeting immunological biomarkers.
Immunological biomarkers allow us to determine the quality of the immune system and monitor the success of our therapies, profiling the patient’s immune system to see what is “broken.” Checkpoint inhibitors in particular have received their many approvals using a traditional tumour-by-tumour clinical trial approach (one trial in melanoma, another in lung cancer, etc.).
The shift to tumour-agnostic medication, with a focus on the immunology and not the pathology is one that will take time; however, we can expect to see more approvals of drugs targeting immunological biomarkers.
Using new immune targeted therapies, we are seeing improvements in remission rates; but we have a long way to go. To continually increase remission rates, we must understand and embrace the vital role that the immune system plays in the battle against the cancer.
The immunology should be centerstage in our approach to new cancer therapies. While we are just at the beginning stages of this revolution, it is the future of cancer therapy, giving us the best chance of seeing increased survival rates.
Raymond J. Tesi, M.D., CEO and CMO at INmune Bio, an immunotherapy company developing treatments to reprogram the patient’s innate immune system. Dr Tesi received his M.D. degree from Washington University School of Medicine in 1982 and has been a licensed physician since 1982. Dr Tesi is also a Fellow of the American College of Surgery
The future of pharma: personalised healthcare
Ever since the very first healthcare systems were created, the earliest documented being in ancient Egypt, medical professionals have had a reactionary approach to finding cures for ailments. That is to say that a solution is sought after someone has become sick, using whatever methods were thought to work at the time. Thousands of years later, with advances in genomics and molecular modelling, emphasis is starting to shift towards preventative, personalised healthcare rather than "sick care".
This move is led by data analytics as well as genetic sequencing to inform decision-making, which can ultimately lead to more individualised care. "Identifying the right data will support personalised health outcomes", explains Chris Easton, who is Takeda’s Senior Director and Global Commercial Lead, specialising in personalised health and innovation and applying this to rare blood disorders. "It's about how we can empower patients, interpret data and then apply it."
"The historic pharma model, in a very simplified form, is: a patient has symptoms, gets diagnosed, and gets given drugs for symptoms", Easton says. "Now, with holistic patient care in mind, it's much more about the additional components to care that would make a difference. Yes, drug therapy is one of them, but likewise, it's okay to talk about mental health, as the impact of chronic diseases means often there is a mental health challenge. So what can we do to build a mental health and physical health support package, both of which have data associated with them, that we can use together?"
By way of example, Easton cites the approach taken by elite athletes and astronauts. "Their model is to keep as healthy as possible. If someone on a space mission gets a cold, they're off the mission - it's not affordable to send someone to space that might have a health issue. If you look at footballers and runners, their coaches maintain them at the highest level, and they're using technology and wearables to help monitor their health so that they can make adjustments to stay at peak level for as long as possible."
The aim is to provide a complete, holistic package of care, which Easton acknowledges will pose some challenges to the pharmaceutical sector. "Our model is not necessarily that of a total care package. It's drug therapy or device and technology support therapy. So some things will need to evolve, and that's part of what my role is about."
One way of effecting this change is by collaborating with other organisations, not necessarily limited to healthcare and life sciences. "I'm a big advocate of partnerships and joint ventures. For the pharma sector, these are traditionally through universities and research houses, but I think we need to be willing to look outside the box and look for scalable and transferable technology that is used in everyday life."
"An example is the smartphone you probably have sitting on your desk or the smartwatch you're wearing. These are gathering data all the time. There are probably hundreds of data points that we could use, just from our everyday technology", Easton adds.
While apps like Apple Health, Google Health, and devices like Fitbit collect data, they could be linked to WhatsApp, WeChat or Telegraph to connect to members of a user's care team if a health issue arises. "It's using technology that is already embedded in our lives, that would enable us to share information and photographs. For example, if your knee is swelling and you want to ask a doctor for their opinion, you can send an image, then share the log from your treatment, and it becomes a way of integrating and sharing information."
Shifting towards preventative medicine is one of Takeda's strategic goals for the next few years. An example of how this could work is how people affected by Von Willebrand disease could be supported. This lifelong bleeding disorder prevents blood from clotting and particularly affects girls and women, causing menstrual bleeding to be excessively long and heavy, which has a big impact on their quality of life.
"It's a hereditary disorder, so many women in a family can be affected, but it's hard to diagnose", Easton explains. However, using existing technology that tracks the menstrual cycle via a smartphone perhaps an alert can be issued to let the user know when it's time to start taking replacement therapy for Von Willebrand.
"This means that by the time a period begins, Von Willebrand levels are normalised, and menstrual flow goes down to normal levels. That's actually a massive outcome for someone who has been living with two-week-long periods that bleed through clothing every month. Suddenly for just four or five days, they can use regular tampons and pads. That's a huge improvement to life."
The field of rare blood disorders typically hasn't seen the same amount of attention focused on it - at least in terms of tech innovation - as other chronic illnesses like diabetes. "Rare blood disorders are difficult to show returns on because you've got small patient numbers and often high costs. But if we think about the total patient journey, we could use technology to triage vast numbers of patients and data into more specific diagnosis boxes, so that what is then presented to physicians are smaller groups, of the more likely issues."
Data analysis could, for instance, show that the combination of headaches, nausea and lethargy equates to a specific type of bleeding disorder. "You can start to put these things in categories", Easton says. "And then you're able to do differential diagnosis. But ultimately, what you're trying to do is get a faster, more accurate diagnosis, leading to a specific therapy."
This would be more efficient than administering plasma-based treatments, for example. "A lot of bleeding disorders are caused by a deficiency of something", Easton explains. "There is a lot of combination therapy in blood disorders when you give people plasma-based products because plasma is like the golden chalice of medicine. It has a bit of everything you need. In some cases, when you don't know what the disorder is, this can help patients, but it's not the most precise way of doing it."
"That's one of the ways having very clear diagnostic support linked to advanced direct therapy can help, only treating what you need to. From a payer's perspective, it's very targeted, and there's no wasting money and resources on patients being hospitalised for things that are not necessary."
"If you go back 15-20 years, market access to the pharmaceutical industry was the emerging trend", Easton adds. "We saw all these diagrams of physician decision-making coming down and payer decision-making going up. Now we have another divergence of change, which is the application of technology to support personalised care. This is one of the transformative pieces of pharma right now, and there are a lot of good companies, big and small, being very intelligent about how they're approaching it and investing in those spaces. There's definitely a community building."