Novel therapies have made it possible to cure metastatic cancers by fighting the disease with cells originating in the patient's own body.
Our bodies are constantly under attack. Viruses and bacteria threaten us from the outside, while mutations occurring inside the body can result in cancer. However, the human body has developed a vigilant defence system.
Balance is the key. If the body's defence system is too feisty, it might turn against its own cells, causing arthritis, diabetes, or other autoimmune diseases. On the other hand, too lax a defence can lead to cancer.
However, autoimmune diseases and cancer are not polar opposites. The picture is more complex. Sometimes cancer can develop alongside autoimmune diseases, or the immune system can maintain a chronic inflammation that suppresses cells which eliminate cancer.
Over the past decade, making use of the defence system of the human body and its white blood cells has become increasingly prevalent in cancer therapies. Of particular interest are T cells, which are able to identify and destroy cancerous cells.
“The immune defensive system is like an orchestra where every player matters. However, due to their ability to identify and kill, T cells are special. They are serial killers with pathogens as the victims,” says Professor Satu Mustjoki, who specialises in leukaemia.
Boosting T cells
At the beginning of 2019, the University of Helsinki launched the Translational Immunology Program under the direction of Mustjoki, comprising ten research groups that include cancer researchers, basic researchers specialising in immunology and autoimmune disease specialists.
“T cells are a central theme in our work. We also have clinicians involved in patient care among us. It’s fascinating to see how the adverse effects of immunotherapy can be compared to symptoms caused by autoimmune diseases,” Mustjoki says.
T cells may be skilled, but cancer knows its way around them. Malignant tumours are able to trick white blood cells by producing a substance whose normal purpose is to ensure that T cells do not attack friendly cells.
“The immune system is effective in defending against pathogens. The rest of the body keeps it in check to prevent it also destroying healthy human tissue. Tumours spread the same suppressor molecules around them,” explains Professor of Oncology Akseli Hemminki, whose group belongs to the research programme.
Fortunately, there are ways to stimulate T cells and make them more effective. They are remodelled to identify cancerous cells and medicated to ignore the suppressing molecules secreted by cancer.
“Most of the therapies currently under development involve the patient’s own T cells. There are a number of promising approaches, many of which can also be combined with each other,” Hemminki says.
Immunotherapies and pharaohs
Immunotherapies have a long history. A papyrus scroll dated all the way to Pharaonic Egypt contains a physician’s description of treating a tumour by making an incision into it and causing an infection.
In the late 19th century, physician William Coley treated cancer patients by infecting them with bacteria. Some benefited from the treatment but others died of the bacterial infection. Subsequently, Coley attempted to extract the beneficial part of the bacteria in question. These compounds known as Coley’s toxins never reached the mainstream of cancer therapies, being overshadowed by chemotherapy and radiotherapy, which were considered more modern forms of treatment.
“For a long time already, immunology has been thought to be relevant to treating cancer. However, investigations have produced disappointing results, as only few patients benefited from the therapies,” Satu Mustjoki explains.
Even today, immunotherapies only help a minority of patients. However, what is special about them is that they have made it possible to cure metastatic cancers that have spread to other parts of the body. This is revolutionary, as the problem with previously developed drugs is that their efficacy diminishes over time, which makes them unable to defeat metastases.
Over time, some patients can also develop resistance to immunotherapies. Even so, treatment outcomes particularly among patients suffering from melanoma are promising. Some patients do not experience symptoms even after several years, and are considered cured.
Throttling up and down
The human immune system is composed of innate and adaptive systems, the latter being founded on identifying and remembering pathogens. The key players in the adaptive immune system are white blood cells – T cells and for example B cells that produce antibodies.
Plenty of research is also being conducted on immunotherapies linked with other components of the immune system. However, the results have not yet seemed as promising as those associated with T cells.
It was observed already a long time ago that the prognosis for cancer patients improves if there are T cells in the tumour. The T-cells may be inactive or exhausted, but they can still be activated. Last year the Nobel Prize in medicine was awarded for determining the basic biology of T cells and the development of related therapies.
By identifying the receptors and complementary antigens of T cells, the researchers succeeded in manufacturing immune checkpoint inhibitors, drugs that attach to T cell receptors and prevent a molecule spread by the cancer cell binding to it and slowing down the immune system.
“T cells have the ability to speed up and slow down their functions. Cancer aims to put down the brake, but that won’t work with the drug bound to the receptor. This is the basis for currently available checkpoint inhibitors,” Mustjoki says.
Hot and cold
Globally, many research groups are also working on putting the pedal to the metal, or accelerating T cells. Mustjoki estimates that within a few years, drugs based on this mechanism may also be introduced to the market.
Several approaches are being taken to enhance T cells. Their ability to identify cancerous cells can be improved, their mobility and activity can be increased, in addition to which they can be helped to dig into cancer tissue and their killing capacity can be intensified.
Oncologists talk about hot and cold tumours. The former already contain T cells, the latter do not. Checkpoint inhibitors can only boost T cells found inside the tumour, making it necessary to first attract them to ‘cold’ tumours. Drugs that alter the surroundings of the tumour, helping white blood cells find their way into the tumour, are among the means employed to make this happen.
T cell therapies are immunotherapies of an entirely different kind where physicians collect the patient’s white blood cells and, after manipulation, restore them to the patient’s body.
In a more traditional form of treatment known as TIL therapy, white blood cells are simply replicated. In the CAR-T therapy, cells are also genetically modified and sent to attack cancerous cells. This works well in the case of leukaemia and lymphoma, as they have a target molecule that can be safely eradicated.
The surface receptor of T cells is modified so that they are able to identify cancer cells, while the surface of leukaemia cells contain a certain molecule to which such genetically modified T cells bind. The molecule does not occur in any vital parts of the body, which is a good thing, as the CAR-T therapy destroys everything where the molecule is found.
No corresponding target molecules that could safely be eliminated in the body have so far been found in solid tumours. Some findings have looked promising in the laboratory, only for the researchers to find out that certain patients have the molecules, for example, in their heart.
In Finland, CAR-T therapies were recently introduced in the treatment of recurrent leukaemia, with three child patients receiving the treatment so far. In clinical trials, the therapy has also been used in two adult lymphoma patients.
Mustjoki’s group is investigating how to further improve the functioning of CAR-T cells, as well as any potential drugs with which the CAR-T therapy could be combined. Promising pharmacological agent groups have already been identified.
Help from viruses?
As for Hemminki’s group, they are utilising oncolytic viruses to activate T cells. The viruses are common cold viruses, or adenoviruses, modified to only divide in the cancer tumour. At the final stage, they break up the tumour, releasing more viruses to the body to look for cancer cells.
“Viruses can also be armed with molecules that summon T cells to the spot and instruct them to destroy the cancer. We have preliminary clinical evidence of viral therapy also working on cold tumours, which have no T cells to begin with,” Hemminki says.
T-Vec is a therapy based on the herpes virus and the first oncolytic virus to be granted a marketing authorisation in the United States and the European Union. It has been used in clinical trials at the Early Phase Trial Unit of the Helsinki University Hospital Comprehensive Cancer Center. Hemminki thinks adenoviruses are even better at stimulating T cells.
Eliminating double agents
Next, Hemminki wants to experiment with combining virotherapy with TIL therapy. His company, TILT Biotherapeutics Ltd is about to initiate a clinical trial on the subject in the autumn.
T cells required for the TIL therapy are collected from the tumour and replicated outside the patient's body. Before conventional TIL treatment, other white blood cells must be eliminated from the patient’s body, necessitating the administration of white blood cell growth factors afterwards.
“Cancerous cells produce substances with which they trick certain white blood cell groups to inhibit the function of cancer-killing cells. They change sides, as it were, working as double agents, which is why they need to be killed,” Hemminki explains.
According to Hemminki, in the treatment of metastatic melanoma, TIL therapies are more efficient and less expensive than checkpoint inhibitors, but they are currently unavailable in Finland. A cellular laboratory is needed, and the only such laboratory in the country is the one operated by the Finnish Red Cross Blood Service. An agreement concluded between the University, the Hospital District of Helsinki and Uusimaa and the Blood Service may make it possible for the laboratory to also provide TIL therapies for Finns in the future.
“I really hope that it happens, and I have been championing TIL therapies,” Hemminki says.
The trial to be conducted in the autumn will still be a collaboration between Hemminki’s group and two sites in France and Denmark.
How to select the patients?
What complicates all forms of treatment is the complexity of tumours. They are not composed of identical cancer cells upon which drugs or T cell could be set.
“Every human being is unique, while the differences between individual tumours are even more numerous. Cancer is differentiated from normal tissue specifically by alterations known as mutations,” Hemminki notes.
The effectiveness of treatments is affected by differences in immune systems, genes and even the gut microbiota. Another aspect related to the success rate of therapies is linked to the mutations of cancer. The more mutations there are in a tumour, the more effective immunological agents are.
The adverse effects of treatments are also individual. Some patients experience almost no adverse effects at all, while others get quite serious ones. Patients have even died as a result of CAR-T therapies. Then again, chemotherapy can also kill.
What Satu Mustjoki is looking for is improved patient selection – finding the individuals with the most to gain from treatment should be easier.
For his part, Hemminki would like to see drug susceptibility testing employed also in the public sector to predict the effective treatment for each tumour. According to him, such tests are already widely used in the United States, while in Finland they are only utilised in private hospitals.
“Immunotherapies are revolutionary for patients, family members and physicians. Even though they don’t help everyone, the possibility of getting better infuses other patients as well with hope,” Hemminki notes.
Kim Vettenranta, a professor of cell therapy and transfusion medicine, was also interviewed for this article.
The Helsinki University Hospital Comprehensive Cancer Center investigates the function of brand new drugs and those close to completion. In the Early Phase Trial Unit, five to seven trials are conducted every year where pharmaceutical agents are for the first time trialled on humans, while a little under 30 trials following this phase are completed annually. According to Katriina Peltola, head of department, roughly half are related to immunotherapies.
Peltola is the principal investigator of a phase I clinical trial investigating a combination of two checkpoint inhibitors, one of which is a PD-1 inhibitor already in wide use. The other compound is now being trialled in humans for the first time.
Initially, the trial was targeted at eight types of cancer. For further investigation, bladder cancer, melanoma and lung cancer have been selected as targets.
Many of the drugs being trialled already have a marketing authorisation for another cancer type. Often, clinical trials are focused on several drug combinations, such as checkpoint inhibitors combined with chemotherapy or radiotherapy.
“You might think that chemotherapeutic agents which kill white blood cells and checkpoint inhibitors that activate them shouldn’t be administered at the same time. However, in the case of, for example, lung and breast cancer, the combination works,” Peltola says.
“Chemotherapy exposes cancer cells to the immune system, bringing more T cells to the field.”
Peltola assesses therapies on the basis of their adverse effects and benefits. Even though immunotherapies are often gentler than chemotherapy, they may cause permanent adverse effects in the function of the thyroid gland and adrenal gland. Sometimes, very serious life-threatening adverse effects may develop.
Another difficulty with immunotherapies is that, for the time being, no one knows the best way of administering them. There is no certainty on whether patients need boost doses and how often they should be administered.
Even if drugs and therapies based on immunology provided no cure, they can offer a great number of patients a good quality of life for the remainder of their lifespan,” Peltola stresses.
“Thanks to the therapies, many patients continue to live for a couple of years travelling, attending book club meetings and afternoon dances. It’s great to see people getting visibly better.”