According to Cancer Research UK, 50% of people born after 1960 in the UK will be diagnosed with some form of cancer during their lifetime. Of those 50%, only half will survive cancer for 10 or more years. With more than 200 different types of cancer, finding new techniques for prevention, early diagnosis, and treatment can be challenging.
Traditionally, we have turned to chemotherapy and radiotherapy as primary ways of tackling cancer. As anyone who has had a friend or family member go through chemo can tell you, these techniques have huge limitations and come with a host of unwanted side effects, mostly because they don’t just kill cancer cells; they kill healthy cells too. The lack of specificity in these techniques leaves a lot to be desired.
Cancer occurs when a cell (or small group of cells) begins to grow and multiply in an abnormal way. As this abnormal cell spreads to other tissues, it can form what is called a primary tumor, which simply means the location where a cancer started. If that cancer spreads to other parts of the body, we start to see what are called secondary tumors or a metastasis. When a metastasis occurs, the prognosis for patients rapidly diminishes. If detected at an early enough stage, current treatment options are able to more specifically attack the cancer itself, instead of the entire body. But as cancer spreads, options become less specific and often more painful. This is where biotech is stepping in.
Biotech is playing an essential role in changing how we approach cancer, introducing a range of innovative techniques to increase drug specificity including monoclonal antibodies, immuno-oncology, CAR-T, and more. These treatments being developed could hold the key to not only fighting cancer more efficiently and effectively, but possibly even finding a cure one day.
Monoclonal Antibodies (aka mAbs)
Discovered in 1975 in the UK, the first monoclonal antibody used to treat cancer was applied to a patient with non-Hodgkin’s lymphoma in 1983. Since then, clinical studies using mAbs have been underway for nearly every type of cancer.
Monoclonal antibodies work by mimicking the antibodies the human body naturally produces as part of the immune system’s response to germs, vaccines, and other foreign invaders. Produced in a laboratory, these molecules can be carefully engineered to attach to specific defects detected in cancer cells and deliver a variety of responses. Once attached to a cancer cell, mAbs can help make cancer cells more visible to the immune system, block overactive growth signals telling the cancer cells to grow, stop new blood vessels from forming, deliver radiation/chemotherapy to cancer cells (while leaving the surrounding healthy cells undamaged), and more.
While attaching to a single target makes mAbs great for increasing drug specificity, it’s also a shortcoming. Cancer cells are extremely versatile, and often when one path is inhibited, another one quickly generates. To combat this challenge, scientists are now developing multi-target strategies, including bi-specific antibodies (which have one body but can form ligands with two different target sites) and pairs of antibodies that can work together. While there are only two bi-specific antibody therapies currently available, more than 100 are in development.
If the use of mAbs can be perfected, they could be utilize for two important purposes in fighting cancer: (1) blocking the signal pathways that allow the cancer cells to live and grow and (2) triggering the immune system to defend itself against the harmful cells.
This is the whole idea behind immuno-oncology: instead of poisoning the body to get to the cancer cells, immuno-therapies utilize the body’s own immune system (IS), enabling it to recognize a tumor and prime itself for destruction. Not only does this allow the body to combat a cancer using it’s own defenses, but it also teaches the body the appropriate immune response should the same cancer come back, reducing the rate and severity of relapse.
A study published in the European Journal of Cancer detailed a clinical trial at Barcelona’s Vall d’Hebron University Hospital (Spain) in which 25% of patients using the mAbs treatment Herceptin went into complete remission (opposed to the 5% of patients in the control group.) Using the HER2 biomarker (human epidermal growth factor receptor 2) which is over-expressed in around 15-30% of breast cancers, they were able to deliver a highly targeted treatment.
Cell therapy involves the administration of live whole cells (as opposed to molecules or antibodies) or the maturation of a specific cell population in a patient for the treatment of a disease. The most well-known form of cell therapy for cancer is the process of a bone marrow transplant in which a donor supplies healthy blood stem cells from their bone marrow to a patient suffering from a blood cancer.
The key to a successful bone marrow transplant comes from finding a good immunological match between patient and donor, which is why a close relative is often used. The bone marrow cells of the patient are destroyed during chemotherapy or radiation, whereby the donors healthy cells are grafted into the patient to try and replenish the system. After the bone marrow cells from the matched donor are infused, the self-renewing stem cells find their way to the bone marrow and begin to replicate, as well as produce cells that mature into the various types of blood cells.
One of the biggest shortcomings of this therapy lies in finding a donor that is a strong enough immunologically match (especially when the patient doesn’t have a living or willing relatives to provide the donated marrow.) Bone marrow grafts also have a fairly high failure rate, with as many as one third of patients facing the inability to fully repopulate the bone marrow that was destroyed during chemo. The destruction of that host bone marrow can be lethal, particularly in very ill patients. These requirements and risks restrict the utility of bone marrow transplantation to select patients for the time being.
Another strategy developed by the biotech field is gene therapy, in which scientists modify the expression of an individual’s genes or correct abnormal genes by administrating specific DNA or RNA.
There are two main types of vectors for gene-therapies. The first uses viruses and the second uses a range of non-viral micro-particles. When utilized for cancer treatment, these therapies can induce cancer cell death, trigger the immune system, and/or trigger active cytokines. Two examples include Transgene’s phase II candidate for non small-cell lung cancer and Amgen’s ‘T-VEC’ phase III treatment for melanoma.
While the variety of treatments available in gene therapy is currently much more limited than with mAbs, the technology is extremely promising. In part we have seen a lack of growth in this area because of the stigma association with gene editing, especially in regards to viruses. As a result, many regulatory issues and stringent safety requirements slow progress.
One of the biggest areas of development in the area of oncology research is CAR-T, or Chimeric Antigen Receptor T Cell. A mix between cell therapy, gene therapy, and immuno-oncology, CAR-T works by triggering the immune system to recognize tumors and thus activate cancer cell lysis.
CAR-T is a type of engineered T-cell which is modified genetically in vitro to express a CAR (Chimeric Antigen Receptor) which enables it to recognize and attack a specific tumors antigen.
The first proof using CAR-T was achieved by Novartis and the University of Pennsylvania when researchers targeted the cancerous B cells in leukemia. Up to 3 of the 14 patients in the trial went into complete remission, with one remaining cancer-free for over 5 years and counting. Several new trials are underway. Autolus is conducting trials for the treatment of Acute Lymphatic Leukemia involving targeting theCD19 antigen. Kite Pharma is re-directing T-cells by genetically engineering designer T-cell receptors (TCR) able to recognize antigens both inside and outside of the cell. Immunocore and Adaptimmune broke the record for the biggest private biotech fundraising in the EU (at €300M) while conducting their studies with TCR.
The major advantages of CAR-T are:
- The use of patient-specific cells decreases the risk of immunogenicity (host rejection)
- CAR-T treatment targets the tumor alone, resulting in less adverse side affects (compared to treatments like chemo)
- It teaches the immune system to defend itself, reducing risk of relapse
- Trials have already shown the potential of complete remission
The biggest barrier to CAR-T right now is the cost of production. Because manufacturing has yet to be perfected and standardized, it is still relatively expensive compared to other therapies.
One way some companies, like Cellectis, are overcoming this challenging is by developing allogeneic CAR-T cells, which allow one batch to be used for several patients, versus autogenic grafts in which each batch only suits a single patient. Allogeneic cells eliminate the genes responsible for immunological rejection.
As the biotech industry learns to utilize our own immune system in tandem with new technologies, we can begin to more efficiently heal the body, rather than poising an already sick patient indiscriminately in order to target a few out of control cells. This may sound futuristic or even overly optimistic to many, but we have already seen these and many other therapies mature in huge ways over the last decade.
Biotech drugs have already proven their potential to target cancer cells far more precisely and with less harm done overall than traditional chemotherapy. Before these treatments can become mainstream though, they must be not only perfected from a technical/medical standpoint, but also be made much more cost efficient if insurance companies are going to be willing to pay for them. Luckily, biotech firms are investing in a big way to realize these goals.
Mickael Marsali is a Co-founder and Senior Consultant of Arterial Capital Management. To learn more about his life and career, please visit his main website.