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As one of the most fascinating research areas in biology, cancer immunotherapy, is a promising novel treatment against this widespread disease. In this article, I will outline how the different types of immunotherapy work, current breakthroughs and try to convince you that this might be the future of oncology.

Imagine this: a patient has returned home from a long 3 hour session of IV chemotherapy infusion. Upon arrival, the patient feels nauseated, weak and tired, can’t tolerate sitting nor standing, and knows that these symptoms are only going to get worse over time. This is the reality with which many cancer-fighting patients are faced each day. Now, picture an ideal cellular therapy in which T cells are extracted from the person’s own immune system, then they are modified to target the tumor specifically, and then are reinserted into the patient. Almost miraculously, the cancer has receded considerably in two months.

Surprisingly, the first successful account of cancer immunotherapy happened in 1893. This means that the question, «What if we could use the body’s own immune system to fight off a tumor?», is not a new one. However, the methods that we have at our disposal have increased over the last few years. For instance, it was not until 1989, almost 100 years after the beginning, that chimeric antigen receptor (CAR) T-cell therapy was first conceptualised. From that moment on, there have been multiple research projects aimed at perfecting the technique.

Unfortunately, this has not become the normal way of treating cancer yet, but thanks to the hard work of scientists in this field, we seem to be getting closer to an almost pain-free and successful way of approaching tumors.

Types of immunotherapy

Before delving in to how this therapy works, I must clarify that immunotherapy is an umbrella term that encapsulates not only CAR T-cell treatments, which is what I will discuss in depth, but also other modifications of innate immune components. The following list illustrates the numerous avenues scientists have found to enhance the body’s immune system.

Checkpoint inhibitors

These molecules act as inhibitors of T cells’ control mechanisms. If T cells tried to kill everything in their way, they would be harmful to our own cells (this is what happens in AIDS for example). Therefore, there is a mechanism to regulate this that involves expression of certain molecules from our cells and recognition by the T cells through one of their receptors. The checkpoint inhibitors block these receptors, letting the T cells «run wild».

Monoclonal antibodies

You may have heard of these in relation to treating COVID-19 and, indeed, they are effective not only against cancer cells but other types of viruses and bacteria as well. These are the famous proteins that bind to the antigens (foreign markers) of pathogens and indicate their presence to the immune system. Before this can happen though, the B cells need to recognise which antibodies bind to the particular antigens present. This process of is known as clonal selection and can lengthen the time of response. Because we know what the spike protein for SARS-CoV-2 looks like, we can inject it into organisms (typically mice) which will produce several antibodies against it. Then the B cell expressing the antibody with the highest affinity is selected and can be cultured (by hybridizing it to myeloma cells that) to have multiple antibodies, as depicted in the diagram below.

What about cancer cells? Just like we had discussed for checkpoint inhibitors, our cells all have markers that identify them as endogenous material. Cancer cells sometimes have additional markers signalling «Hey, I’m a defective cell» which can be more effectively targeted through the culture of monoclonal antibodies.

Chimeric antigen receptor (CAR) T-cell therapy

Last but not least, the epitome of personalised medicine and perhaps future of oncology. This therapy relies on modifying the patients own T cells to combat the tumor. In a way, its effects are a combination of the two previous techniques, since it makes these immune cells more effective.

In the next section, I will explain how the cells are reengineered, how they are given back to the patient and what their actions are in the body.

How immunotherapy works

You may have wondered while reading it, what does chimeric antigen receptor mean? It is a special receptor that is engineered into the T-cells. As you probably guessed, this receptor will be specifically designed to bind the cellular markers of the cancer cells. Each cancer is different, so if a patient receives immunotherapy for leukemia, the genes of the CAR that will be inserted into the T-cells will be different than for a patient who receives immunotherapy for breast cancer.

Cell extraction

The process of cell extraction is quite straightforward and similar to dialysis. Two IVs are given to the patient: one to extract blood and another to return the blood without the white blood cells. The T-cells are a kind of lymphocyte, which in turn are leukocytes (white blood cells), so they are filtered out to be used later.

Once the T-cells reach the lab, the gene for the CAR is inserted into their DNA using genetic modification techniques. It is important here to acknowledge the sophistication of this treatment. Instead of directly inserting brand new cells with that gene, the patient’s cells are used, since they will not be rejected by the body. Then, there are multiplied in vitro and once there are enough, they are administered back to the patient.

Cell reinsertion

The most common adverse effect is generating too much immune response: a cytokine storm. This leads to inflammation and can be life threatening. So, while these therapies are still being tweaked, the patient normally remains in the hospital several weeks under observation after the 15 minute infusion with the CAR T-cells.

Once they are in the body, these modified cells reach the tumor and bind to the antigens on its surface. As they are T cells, they signal B cells and T cytotoxic cells to mount all their defence tactics against the tumor and eliminate it.

Recent breakthroughs in immunotherapy

In October of 2021, there was an article published by the MIT News, alerting of a new promising combination of treatments, including CAR T-cell, that could improve the effectiveness of fighting cancer.

Normally, therapies are already administered in conjunction with several others to improve the chances of survival of the individual (so long as there are no contraindications). Nevertheless, this precise triple-threat had not been tested until Prof. Michael Yaffe and Prof. Darrell Irvine tried it in their study. The trick is chemotherapy, tumor injury and immunotherapy.

In addition to the personalized T-cells we have seen through this article, it seems that damaging tumor cells using chemotherapy outside the body and then reinserting them also boosts the immune system. Sounds amazing, right? If we can take advantage of chemotherapy without the negative side-effects that bother most cancer patients and still implement immunotherapy to ensure the tumor is minimised, we would certainly be closer to solving this problem. Indeed, «in mouse studies, the researchers found that this treatment could completely eliminate tumors in nearly half of the mice.»

Let’s hope that these studies yield positive results if they are to be tried in humans too in the near future.

Conclusion

This idea of immunotherapy has the benefit that it makes a lot of sense even without knowing anything about biology. Sometimes, it is the simplicity and elegance of these concepts that turn out to be so groundbreaking and beneficial in the field of science.

By improving our own immune system, either directly through CAR T-cells or indirectly through checkpoint inhibitors and monoclonal antibodies, we can help combat one of the worst genetic diseases for humans- cancer. Nevertheless, they also work well against other illnesses, including COVID-19.

We now know much more than we did about this subject a decade ago, thanks to investigators such as Michael Yaffe and Darrell Irvine. We are slowly gaining an understanding of how to minimize the side effects, while improving the efficacy and efficiency of these therapeutics to eventually substitute more invasive ways of treating cancer.

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Lilly Pubillones
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Trinity College Hartford
Biochemistry

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