T-Cell Therapy: Here’s How the Latest Cancer ‘Breakthrough’ Actually Works

For many years, there were only three possible types of cancer treatment: surgery, chemotherapy, and radiotherapy. In the last decade, drugs that target specific molecular changes on the surface of cancer cells have been developed, such as the drug Herceptin used for breast cancer treatment.

Now there is the promise of a fifth type of cancer treatment: immunotherapy. Instead of drugs, radiation or the surgeon's scalpel, this treatment uses the power of the patient's own immune system to kill cancer cells.

The possibilities of immunotherapy have led to cancer cures hitting the headlines again; scientists have had "extraordinary" success using modified T-cell therapy to treat blood cancers in early clinical trials. Although the research is still unpublished, The Guardian has reported some of the findings announced at the 2016 Annual Meeting of the American Association for the Advancement of Science (AAAS).

In one study, 94 percent of patients with acute lymphoblastic leukaemia (a disease where patients overproduce immature white blood cells) were cured, and patients with other blood malignancies had response rates of over 80 percent. This is a remarkable feat considering that these were patients that had failed other drug treatments and only had months to live.

But what exactly is T-cell therapy, and why is it such a game changer? To answer this, we have to go back to some basics.

The Immune System

The immune system is a collection of molecules, cells and tissues that protect the body from pathogens in the environment. The immune system has two broad categories of defence: innate and acquired immunity.

The innate immune system consists of cells and proteins that are always present and ready to eliminate pathogens. This part of our immune system includes physical barriers (such as our skin) and cells called phagocytes that destroy pathogens by "eating" them.

The adaptive immune system comes into play when pathogens evade or overcome our innate immune system. The components of this immune system are able to adapt to a specific pathogen, destroy it, and remember how to do so if it ever returns (which is why vaccinations work so well).

Despite the presence of both innate and adaptive immune systems, cancers are still able to develop and thrive. This is due to their uncanny ability to evade the body's defences, either by suppressing the immune system or by altering it's ability to recognise cancer cells as a threat.

What are T-cells?

T-cells are a type of lymphocyte (a category of white blood cell) that are an important part of the adaptive immune system. The "T" stands for thymus, a small organ located between the lungs and behind the sternum where these cells mature. There are two main types of T-cells: cytotoxic and helper.

The role of cytotoxic (or "killer") T-cells is to directly attack and destroy cells infected by viruses and sometimes by bacteria. Cytotoxic T-cells can also destroy cancerous cells that haven't evaded the body's immune system. Helper T-cells on the other hand are needed to recognise pathogens and activate both cytotoxic T-cells and B-cells, another type of lymphocyte that produces antibodies.

T-cells can be differentiated from other lymphocytes like B-cells because they contain proteins called T-cell receptors (TCRs) on their cell surface. TCRs are necessary for the activation of T-cells in response to specific proteins (or antigens) on the surface of a pathogen.

What is T-Cell Therapy?

Put simply, T-cell therapy involves using genetically modified T-cells as cancer treatment. The therapy is made by first removing a patient's T-cells from their body. Then, the cells are modified so that they target the patient's immune-system evading cancer. This is done by either altering TCRs so that they then bind to molecules on the surface of the cancer cells or by introducing completely new cancer-targeting receptors onto the T-cells (called chimeric antigen receptors or CARs). Finally, the modified T-cells are allowed to multiply before being infused back into the patient. Once the T-cells are back in the body, the can seek out and attack the patient's cancer directly.

Advantages of this therapy include being able to harness the patient's own immune system and the ability of T-cells to multiply to great numbers. Another advantage of this therapy is that it is able to persist in the body for a person's entire life, meaning that cancer recurrence may be prevented. Indeed, The Guardian article refers to another study that has tracked the presence of "memory" T-cells (T-cells that remember how to fight the cancer cells) for two to 14 years after they had been introduced into cancer patients.

The recent clinical trials reported on by The Guardian used T-cells with CARs that target CD19, a molecule found on the surface of all B-cells. The reason this therapy has been so successful at treating acute lymphoblastic leukaemia is because most cases of this disease are caused by the overproduction of immature B cells. While using this therapy means that all B cells (both good and bad) are targeted and depleted, the resulting condition known as "B-cell aplasia" is a manageable disorder (patients can be infused with antibodies the B cells normally make).

Side Effects and Disadvantages

Despite the early promise of T-cell therapy, it is not without its drawbacks. Possibly the most serious of all the potential side effects is cytokine release syndrome—or CRS—which in the clinical trial described in The Guardian affected 20 patients. Two even died from it.

Finding the balance between activating T-cells enough so they kill cancer, but not too much so they don't cause CRS, has proved difficult. A 2014 study by Maude et al published in The Cancer Journal however has shown that the drug Tocilizumab may be effective at reversing CRS without completely inhibiting the T-cells.

Future Developments

There is still much to be done before T-cell therapy is available for widespread use. Alongside the technical, regulatory and financial challenges that plague most research groups, further clinical trials must be done and the patients monitored for greater periods of time to see how long they remain in remission. Further monitoring will also allow any unforeseen effects of using modified T-cells in the body to be detected.

There is also hope that T-cell therapy will eventually be able to be used against other cancer types, including solid tumours. This would involve identifying target molecules expressed on these cancer cells and designing receptors that safely target these, a time consuming and potentially difficult task.

Having said that it doesn't pay to be too pessimistic, as the rate of new discoveries and treatments are consistently surpassing forecasts.

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