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by Kimberly Hagel
figures by Alexandra Was

We, as humans, tend to idealize that which is bigger, better, faster, and stronger. It is in our nature to strive towards the best. To improve. To win. Indeed, the penetrance of this mentality reaches to our very core, even to the individual cells of which we are composed. A prime example of this: cancer.

Today, cancer is the second leading cause of death worldwide, with 1.6 million new cases expected to occur in 2017 in the United States alone. Cancer, while terribly destructive to the human body as a whole, is nothing more than a collection of previously normal cells that have begun to grow and divide uncontrollably. They become everything so many of us strive towards — bigger, better, faster, stronger. They outcompete the cells around them, and when they ultimately win, the cancer patient unavoidably loses.

This presents a daunting task. How are we to fight a disease that is effectively caused by ultra-strong and ultra-competitive versions of our own cells? Luckily for us, evolution has favored the development of cells whose sole purpose is to protect us from disease. This army of protective cells makes up our immune system. In the last few decades, the field of cancer biology has become irrevocably intertwined with that of immunotherapy, or using the cells of the immune system to fight disease. This technology offers a unique and exciting chance to pit living cell against living cell, and hopefully to fight fire with fire.

The basics of cancer

To many, the word cancer evokes the image of an ominous, amorphous thing that relentlessly attacks the body, breaking it down without our volition and without remorse. While this characterization is not far from the truth, it is important to remember that a cancer cell is nothing more than a normal cell that has acquired changes, or mutations, to its genes. These genetic changes occur randomly and often represent mistakes made by our cells during their normal growth and division cycles. Alternatively, these mutations can arise from environmental insults, such as cigarette smoke and UV light from the sun’s rays.

Sometimes, these genetic changes have no effect at all, and other times they are so deleterious that they simply kill the mutated cell. Problems arise, though, when these genetic changes give the cell new abilities, such as the ability to grow and multiply without limits. Evolutionarily speaking, these advantageous changes make the cancer cell king, allowing it to grow and divide in the unabated fashion that all too often leads to the formation of tumors. But what if these changes could also mark cancer cells for destruction? For this, scientists have turned to the immune system.

Figure 1: Cancer can arise when a normal cell undergoes genetic changes, or mutations, that confer survival benefits. These benefits may include increased growth rate, enhanced ability to divide, and avoidance of cell death. Cancer-causing mutations can derive from many sources, including internal cellular errors and environmental stressors like tobacco smoke, UV light, and pollution.
Figure 1: Cancer can arise when a normal cell undergoes genetic changes, or mutations, that confer survival benefits. These benefits may include increased growth rate, enhanced ability to divide, and avoidance of cell death. Cancer-causing mutations can derive from many sources, including internal cellular errors and environmental stressors like tobacco smoke, UV light, and pollution.

The immune system can recognize cancer

Normally, the job of our immune cells is to eliminate foreign substances in the body, be those viruses, bacteria, or some other unwelcome invaders. The immune system does this by recognizing molecules that are specifically made by disease-causing organisms but not by our own cells. These molecules, known as antigens, are displayed on the surface of invaders, as well as on the surface of any of our own cells that have succumb to infection by the invaders. These surface antigens effectively mark cells as foreign, dangerous, and in need of elimination. Upon antigen recognition, our immune cells destroy the unwelcome invaders, and because our own cells do not bear these foreign tags, they are generally spared from immune-mediated attack. Incredibly, though, cancer can be an exception to this rule. Despite the fact that cancer cells originate from our own cells, the immune system appears to nonetheless recognize them as foreign, dangerous entities.

Figure 2: Immune cells carry specialized protein receptors on their surface that can specifically recognize foreign tags, called antigens, displayed on the surface of many invaders. These antigens can be displayed by organisms like bacteria, as well as by our own cells that have undergone a viral infection. Importantly, immune cell receptors do not recognize or bind to the normal surface proteins displayed by our healthy cells. This inability of immune receptors to bind the proteins of normal, healthy cells is critical for preventing autoimmune diseases.
Figure 2: Immune cells carry specialized protein receptors on their surface that can specifically recognize foreign tags, called antigens, displayed on the surface of many invaders. These antigens can be displayed by organisms like bacteria, as well as by our own cells that have undergone a viral infection. Importantly, immune cell receptors do not recognize or bind to the normal surface proteins displayed by our healthy cells. This inability of immune receptors to bind the proteins of normal, healthy cells is critical for preventing autoimmune diseases.

By definition, cancer cells are mutated versions of normal cells. While these mutations may benefit the cell by allowing it to grow without limits and to become immortal, they can also have unanticipated side effects. Specifically, the very mutations that make a cancer cell a cancer cell can also lead to the production of mutated molecules that differ from those made by normal cells. These mutated molecules can effectively act as foreign antigen tags that cancer cells display on their surface, just as bacteria do. Excitingly, this means that some cancer cells actually can be recognized and killed by the immune cells in our own bodies. This fact opens the door to a wide variety of therapeutic options aimed at helping the immune system do its job.

CAR T-cells are engineered to fight cancer

While there are many different immunotherapies, one particularly promising option is to engineer immune cells that specifically recognize the “foreign” antigens on cancer cells. This strategy, called chimeric antigen receptor (CAR) T-cell therapy, can supplement and invigorate the body’s natural anti-tumor responses, and it can also increase the abundance of immune cells that specifically target cancer cells. CAR T-cell therapy involves a particular type of immune cell called T cells that are collected from a patient’s own body. Once the T-cells have been taken from a patient, scientists insert a special protein into their surface that makes them particularly potent killers of cancer cells. This surface protein, called a CAR, has a lock-and-key relationship with the foreign tags on cancer cells, thus enabling the CAR T-cells to recognize and kill the cancer cells. Once made, the CAR T-cells are infused back into the patient’s blood and allowed to do their job.

Figure 3: Although genetic changes are important for driving cancer cell growth and survival, these changes can also result in the production of altered or mutated surface proteins on cancer cells. These proteins can then act as foreign antigens that induce immune cells to attack cancer cells. CAR T-cell therapy aims to enhance this natural anti-cancer immunity by creating T-cells whose surface receptors have been specifically designed to recognize the mutated cancer antigens.
Figure 3: Although genetic changes are important for driving cancer cell growth and survival, these changes can also result in the production of altered or mutated surface proteins on cancer cells. These proteins can then act as foreign antigens that induce immune cells to attack cancer cells. CAR T-cell therapy aims to enhance this natural anti-cancer immunity by creating T-cells whose surface receptors have been specifically designed to recognize the mutated cancer antigens.

CAR T-cell therapy has shown spectacular success in combatting certain types of cancer, such as leukemia. For example, trials for leukemia patients have reported complete remission rates between 70 and 90%, even for some patients who had advanced, relapsed disease. These preliminary results caused an explosion in the field of cancer immunology, with scientists around the world scrambling to study this exciting new treatment. In the last seven years alone, the number of CAR T-cell clinical trials jumped from only three worldwide to over one hundred! Even so, it is important to note that this therapy is still very much in the trial phase. It is not perfect, and there are still many aspects that need improvement.

New approaches to CAR T-cell Therapy

Despite the incredibly promising nature of CAR T-cell therapy, one major issue is that each treatment is patient-specific. This is because the current way to make CAR T-cells involves taking the T-cells from a patient’s own body, engineering them into CAR T-cells, and putting them back into the same patient. This process is both costly and time-intensive, but it has traditionally been favored because using an individual’s own T-cells reduces the risk of CAR T-cell rejection that can accompany the use of donor cells from a different individual. Another problem with this approach is that not all patients have enough T cells to use for this therapy. For instance, young children often do not have sufficient numbers of T-cells, nor do patients who have undergone aggressive chemotherapies, as these treatments often weaken and damage the immune system.

The ideal solution to these problems would be to create a universal, off-the-shelf CAR T-cell designed to attack certain cancers. The mass production of these cells would increase the speed of therapy, reduce costs, and provide an option for patients who do not have enough T-cells of their own. Why, then, are off-the-shelf CAR T-cells not widely used? The main issue again involves the natural function of the immune system: to attack cells that it recognizes as foreign. Because the off-the-shelf CAR T-cells do not come from the patient, they often carry foreign antigens that tag them for destruction by the patient’s immune system, just as an invading bacterial cell or virus would. Thankfully, though, there may be a creative solution to this issue.

Recently, scientists have developed a strategy to modify CAR T-cells and remove some of the antigens that identify them as foreign invaders. This strategy was recently used in the UK to treat two infants with relapsed leukemia. Neither of these children, ages 11 and 16 months, had sufficient T-cells in their own bodies to use for CAR T-cell production, so scientists used the T-cells from healthy donors to make the CAR T-cells. Before treating the children with these donor cells, scientists first used gene-editing technology to remove foreign antigens from the surface of the CAR T-cells. Amazingly, both of these infants went into complete remission, and neither rejected the CAR T-cells. Although this is just a preliminary trial with two patients, it presents a new and incredibly exciting strategy for making CAR T-cell therapy accessible to the patients who desperately need it.

This strategy of antigen removal is just one example of an innovative solution to the issues of CAR T-cell therapy. It is important to note that many other issues still exist with the CAR T-cell therapeutic option, including toxicities and limited applicability to many cancer types. However, the hope is that continued research in this area will make CAR-T cell therapy a standard and widespread treatment option for cancer patients worldwide.

Kimberly Hagel is a first year graduate student in the Biological and Biomedical Sciences PhD program at Harvard Medical School.

For more information:

See reviews of CAR T-cell therapy by The Leukemia and Lymphoma Society and the National Cancer Institute

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