Where the Wild Things Are: CAR T-Cell Therapy

 

A rambunctious child, Max, who has been ignoring house rules and arguing with his mother is appropriately wearing his favorite wolf suit when his mother calls him a, “wild thing!”, and is sent to his room without supper to learn his lesson.

Alone in his bedroom and filled with rage, Max imagines the walls of his bedroom disintegrating and becoming a vast ocean. He quickly makes a sailing boat and after a year in the ocean, Max finally lands on an unknown jungle filled with beasts known as the ‘Wild Things’.

Max’s desire for adventure, danger, and a deep longing for friendship(s) even if that means it must be with the ‘Wild Things’, it comes with no surprise that when Max meets these large creatures ashore, he is un-phased by their frightening features of sharp claws, large fangs, and great striking eyes.

Subsequently, our protagonist, Max is unanimously declared the wildest creature of them all and is made king. Max’s first decree as King is to, “Let the rumpus begin!” Here the adventure truly begins as Max and the ‘Wild Things’ start dancing in the moonlight, hanging from trees of the land, and run riot.

However, it is difficult to miss the significance of ‘supper’ and the ‘Wild Thing’s’ appetites which is weaved into these adventures that Maurice Sendak maintains throughout the tale. And it is when Max smells his supper that he decides to give up being King. Max realizes how much he misses his mother, her love, and home.

This touching masterpiece and a forever classic children’s book by Maurice Sendak that ‘Where the Wild Things Are’ that reiterates the importance of ‘time outs’ for children. ‘Time outs’ are necessary for in a childhood so that children can learn to deal with anger management, to channel the negative energy (such as rage) into creative outlets, and ultimately face their true self’s.

Max’s story and adventures reminds us (adults, especially) how wonderful a child’s imagination can be and the power it has. Imagination can catapult anyone to greatness and even according to Albert Einstein is a true mark of intelligence. This story- specifically- teaches audiences and readers alike that imagination lets a child know that he or she can become anything they want to be and go anywhere they want to in life.

INTRODUCTION:

As of August 2017, the Food and Drug Administration (FDA) officially approved CAR T-cell therapy as a treatment option for Acute Lympho-Blastic Leukemia (ALL) which is the most common form of cancer to affect children diagnosed with cancer. This treatment option will very soon also be available for adults with advanced lymphomas.

Researchers, however, caution that CAR T-cells and other types of ACT are not developed enough to ensure the safety and effective outcomes in patients with solid tumor growths such as breast and colorectal cancer. Different types of ACT are still in development.

Cancer treatment consists of 3 pillars (surgery, chemotherapy, and radiation therapy) but, the combination of targeted therapy and specific medications has begun to replace these pillars in the past 20 years. This approach works by applying target cancer cells found in the body by detecting cells that have molecular changes that are common in cancer cells.

Adoptive Cell Transfer (ACT) collects and uses patients’ own immune cells to treat cancer. This quickly emerging immuno-therapy tactic includes many varying other types of ‘ACT’ (i.e. “ACT: TILs, TCRs, and CARs”). Immuno-therapies are known to recruit and strengthen patients’ immune system to attack tumors located in the body and in the past few years has been considered as the ‘5^th pillar’ of cancer treatment.

CAR T-cell therapy has been restricted to small clinical trials which focused primarily on patients with advanced blood cancer. These treatments have earned the vast attention and recognition of researchers and general public alike because of its remarkable responses from both child and adult patient volunteers for whom all other treatments stopped working.

BACKGROUND INFORMATION:

Chief of the Surgery Branch in NCI’s Center for Cancer Research (CCR), Steven Rosenberg M.D., PH.D., is the immunotherapy pioneer whose lab results were the first to report successful cancer treatment with CAR T-cells. It was only due to recent drastic developments in CAR T-cells and other ACT approaches that have aided researchers to their breakthrough(s) in better understanding these therapies. They also can better translate this new knowledge into improving ways to develop and test therapy options.

T-cells make up the backbone of CAR T-cell therapy which are known as the pillars of the immune system and that their key role is in orchestrating the body’s immune response and killing cells infected by pathogens. 

CAR T Cell Therapy Is a Type of Cancer Immuno-therapy that works with your immune system by using your T cells (or fighter cells). It was created by adding a new receptor to the human body’s T-cells which are part of the immune system. This receptor is known as a ‘Chimeric Antigen Receptor’ or ‘CAR’. Once the body’s T-cell has added CAR it is now officially a CAR T-cell. 

T cells are crucial to the human immune system as they release cytokines. Cytokines are chemical messengers that help stimulate and direct the immune response. With CRS there is a rapid and massive release of cytokines into the bloodstream that leads to dangerously high fevers and precipitous drops in blood pressure.

Researchers explained that the presence of CRS is an on-target effect of CAR T-cell therapy which at the same time demonstrates the activity of T-cells working in the body. Like all cancer therapies, CAR T-cell therapy can have troubling and fatal side effects. The most frequent side effect is cytokine-release syndrome (CRS). The greater the severity of a patients’ disease before receiving CAR T-cells, the greater the risk of experiencing severe CRS.

Many patients whether they are children or adults, can use standard supportive therapies including steroids to manage CRS. With the recent gain of knowledge and experience on CAR T-cell therapy, researchers are also learning how to apply this information to manage the more serious cases of CRS.

Research team at CHOP noticed something unique in patients experiencing severe CRS many years ago. The observation was that they all had particularly high levels of IL-60, which is a cytokine secreted by T-cells and macrophages (which causes inflammation and is the body’s immune response). 

With this information, CHOP was able to perform therapies that treated inflammatory conditions meanwhile approving drugs such as tocilizumab (Actemra) that blocks IL-6 activity. This approach was successful in rapidly resolving difficulties most patients reported on experiencing. Since then, tocilizumab has become a standard therapy for managing severe CRS.

Another possible side effect of CAR T-cell Therapy of an ‘off-target effect’ is a ‘B-cell aplasia’ which causes large amounts of B-cells to die off. On the surface of normally functioning B-cells, CD19 are expressed on their surface(s) and function to produce antibodies to kill off foreign pathogens.

Normally functioning B-cells within the body can die from infused CAR T-cells too. To compensate for all this cell death, patients must undergo a process known as ‘immunoglobulin therapy’ which provides patients with the critical antibodies to fight off infections.

Even more recently, researchers discovered a fatal side effect which swells the brain or creates a ‘cerebral edema’ that revealed itself in some of the volunteer patients who were part of the larger trials. These larger studies were created in the hopes of creating potential support from the FDA of CAR T-cell therapies for patients with advanced leukemia.

It has been reported that a company even stopped any developments referring to CAR T-cell therapy when patients from their clinical trials died. The cause of death was due to treatment-induced cerebral edema. Many other trails concerning CAR T-cell therapies have observed no cerebral edema complications or deaths. 

Other side effects (aka: ‘neuro-toxicities’) are misperception, seizure-like activity which have been seen in most CAR T-cell therapy trials. Almost all cases that reported such side effects lasted for a short period of time and were reversible. It is speculated that these ‘neuro-toxins’ may be related to CRS.

These special receptors allow the T cells to recognize and attach to an antigen (a specific protein) on the tumor cells. The CAR T cell therapies are the furthest along in development target an antigen found on B cells called CD19 yet. Once the collected T cells have been engineered to express the antigen-specific CAR, they are “expanded” in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a “lympho-depleting” chemotherapy regimen). If all goes as planned, the engineered cells further multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

The CAR on the cell’s surface is composed of fragment-like synthetic antibodies. The areas used affect how well receptors can recognize or bind to the antigen of tumor cell(s). Although there are important differences between the discussed therapies, similarities do exist as well.

Receptors depend on stimulation signals from inside the cell to do their job. Each CAR T cell has signaling and “co-stimulatory” domains inside the cell that signal the cell from the surface receptor. This is how different domains used in trials or in possible future treatment options can affect a cell’s overall effectiveness and function. 

With time, advances in the intra-cellular engineering of CAR T cells will improve artificially engineered T-cells’ ability to produce an even larger quantity of T-cells. However, this will only occur after its infusion into the patient (known as the ‘expansion’ part of the procedure) and subsequent longer survival period in the body’s circulatory system (known as ‘persistence’).

The initial development of CAR T-cell therapies has focused largely on ALL. Over 80% of children with ALL can be found in their B-cells, this being a predominant type of ALL, can be cured with intensive chemotherapy. Those who experience relapse despite being treated with chemotherapy or receiving a stem cell transplant, their treatment options are depleted to approximately none (leading cause of death in childhood cancer).

In the body, CAR T-cells function to find their counterpart pair(s) on cells so that they are successful in attacking the existing tumor(s). Since the majority of CAR T-cell therapies must use patients or hosts own cells to create cancer-fighting cells, each therapy is made specific for each patient. 

Although CAR T cell therapies have shown promise in treating some forms of cancer, the side effects vary from mild to moderate. Some patients have reported to experience sever, life-threatening reactions. Please note, that all treatments have side effects that vary from case to case and at times even be unpredictable.

Typically, cancer treatment includes therapy where blood is first drawn from the cancer patient, T-cells from the blood sample are separated, a disarmed virus is then used for T-cells to begin producing their genetically engineered receptors located on their surfaces. These receptors are known as ‘Chimeric Antigen Receptors’ or ‘CARs’. These receptors do not exist naturally and are only created when needed (aka: they are “synthetic molecules”). 

Dr. Carl June M.D. from the University of Pennsylvania Abramson Cancer Center, led a series of CAR T-cell clinical trials to explain this ‘synthetic molecule(s)’ phenomenon that is most commonly seen in leukemia patients.

RESEARCH:

In an earlier trial that used CD19-targeted CAR T-cells, patients’ signs of cancer all disappeared (a complete response). Out of the 30 total patients, 27 of them experienced this complete recovery with no continuing signs of recurrence long after treatment was over.

These breakthroughs gave researchers to possibility and the foundation needed for larger trailExit Disclaimer of CD19 targeted CAR T-cell therapy. Many of the patients who participated in the trial, had complete and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017. 

Pediatric Oncology Branch (or ‘POB’ for shot), has led similar studies of which the results in trials where CD19-trageted CAR T-cells. Terry Fry, M.D., who has been the lead investigator on several POB trials of CAR T cells, believes in an optimistic future from the progress made with CAR T-cell therapy in children with ALL.

CD19-targeted CAR T cells were initially tested in adults. But, it was the agency’s decision to approve the new therapy for children and adolescents with ALL before adults that left many in the scientific world stunned as this is an ‘unheard of’ action. Nevertheless, this has been a true turning point moment for ALL patients. 

There is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. In a small NCI-led trial of CAR T cells, primarily in patients with advanced diffuse large B-cell lymphoma, more than half had complete responses to the treatment. 

The data provides a true glimpse of the potential that this approach will have in patients with aggressive or advanced lymphomas (as well as those who in the medical field typically are considered ‘virtually untreatable’). 

The trial’s lead investigator, James Kochenderfer, M.D., of the NCI Experimental Transplantation and Immunology Branch. Since then, larger trialExit Disclaimer studies were conducted with the primary focus on developing ACT-based therapies which have officially proven and confirmed earlier results. These observations are expected to help support FDA’s approval of Kite Pharmaceuticals (who are working with NCI to make these discoveries)’ product for specific patients with lymphoma.

The results in lymphoma to date have been incredibly successful and CAR T cells are almost certain to become a frequently-used therapy for several types of lymphoma. The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential. Cohorts of patients who would have been considered terminal and are now in a stable condition, durable, and are progressing in meaningful remissions are leading quality life of up to 5 years.

CONCLUSION:

CAR T cell research is ongoing with the majority focused on blood cancers and solid tumors. Five years ago, only a couple of trails existed compared to today’s 180 plus. Most of today’s trials have used CD19-targeted CAR T cells, but this too is quickly changing. Ever since the biopharmaceutical industry has become personally invested in the research, the number of clinical trials testing CAR T-cells have increased dramatically as a result.

Some patients with ALL do not respond to the CD19-targeted therapy and those who experience a complete response 1/3 of these cases had their disease return within a year. Many of these disease recurrences have been linked to ALL cells’ no longer expressing CD19, a phenomenon known as antigen loss.

Researchers in NCI’s POB are testing CAR T cells that target the CD22 protein, which is also often overexpressed by ALL cells. The first trial of CD22-targeted CAR T-cells Exit Disclaimer of which most patients treated had complete remissions even those whose cancer progressed after initially having a complete response to CD19-targeted therapy. 

Compared to cases with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon. There is a lot of improvement to look forward to considering the durability of remissions. 

A possible way to improve durability or at least stall antigen loss (if not prevent it completely), is to simultaneously attack multiple antigens at once. There are NCI researchers that are currently developing T-cells to target both CD19 and CD22. CHOP researchers are also testing a CAR T cell that targets both CD19 and CD123, another antigen commonly found on leukemia cells. The hope is to trial test this new approach before the end of 2017.

A possible way to improve durability or at least stall antigen loss (if not prevent it completely), is to simultaneously attack multiple antigens at once. There are NCI researchers that are currently developing T-cells to target both CD19 and CD22. CHOP researchers are also testing a CAR T cell that targets both CD19 and CD123, another antigen commonly found on leukemia cells. The hope is to trial test this new approach before the end of 2017.

Early animal studies suggested that dual targeting can indeed prevent antigen loss. Antigen targets for CAR T-cell therapy have been identified in other blood cancers including multiple myeloma. Dr. Kochenderfer and his colleagues at NCI who are working with Kite have developed CAR T cells that target the BCMA protein (a protein found on almost all myeloma cells). Since earlier results from BCMA-targeted CAR T-cell trials showed positive, Kite is moving forward with further testing of these cells but in a larger trail.

There is some skepticism that CAR T cells will have the same success in solid tumors. Finding suitable antigens to target on solid tumors has been a major challenge for researchers and may even prove to be too difficult in most cases. Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful. 

The overwhelming majority of tumor antigens located inside tumor cells are out of reach for CARs and can only bind to antigens on the cell surface. Results already seen in melanoma cases leads scientists and researchers alike to strongly believe that other versions of ACT may be better for treating solid tumors.

This is why researchers are trying to treat such cases with CAR T-cells. Currently trials are being conducted to target the protein mesothelin which is overexpressed on tumor cells in some of the deadliest cancers known to man (pancreatic and lung cancers). The protein EGFRyIII is present in almost all tumor cells in advanced brain cancer patients’ glioblastoma. Unfortunately, early reports from these trials have not reported the same success that has been seen with blood cancers.

When dealing with solid tumors and targeting the antigens, researchers have been using the approach used with CD19 which some researchers like Dr. Brentjens believes will not work in all cases. Dr. Brentjens also brings attention to another key obstacle when dealing with solid tumors which is that the components of the microenvironment surrounding them conspire to dull the immune response.

Therefore, success against solid tumors may need a “super T cell” instead. This ‘super T-cell’ will have to be engineered to overcome immune-suppressing environment(s) of many advanced solid tumors. Teams of researchers from Memorial Sloan Kettering are currently working on a CAR T-cell with the properties mentioned above.

CAR T cells have gained most of the public’s attention concerning cellular therapies involved with ACT approach. Other types of CAR T-cell treatments should be mentioned that have shown promise from their small clinical trials, including in patients with solid tumors. One such approach includes using the immune cells that can go inside the environment and around the tumor. This is known as tumor-infiltrating lymphocytes (TILs).

Researchers at NCI were the first to use TILs to successfully treat patients with advanced cancer. The very first cancers to be tested were skin cancers (aka: melanoma’s), cervical, and other(s).   It wasn’t until recently that NCI researchers developed an innovative tool for identifying TILs to recognize cancer cells and the mutations specific to that cancer. Many cases led to tumor regressions in individuals with advanced colorectal-Exit Disclaimer and liver cancer. 

Another approach involves engineering patients’ T-cells to express specific T-cell receptors (TCRs). Parts of these synthetic antibodies are used by CARs to recognize specific antigens on the surface of these cells and ONLY on the surface. TCRs are naturally occurring receptors that recognize antigens located inside tumor cells.

Small pieces of these antigens are shuttled to the cell surface and “presented” to the immune system as part of a collection of proteins called the MHC complex. In conclusion, TCR T-cells have been tested in individuals varying from a range of solid tumors. The results have showed much promise in melanoma and sarcoma patients.

Other forms of CAR T cells with differing configurations are currently being tested. One type of CAR T-cell therapy that is currently being developed is using the immune cells of healthy donors instead of the patients themselves. The idea behind this approach is to create a ‘so-called off-the-shelf CAR T-cell therapies’ to be immediately available for use and avoids the time-consuming process of manufacturing each therapy to tailor every patient.

A French company known as ‘Cellectis’, has already launched its own off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with acute myeloid leukemia. The trails are in their first phase but it’s produce made using a gene-editing technology named ‘TALEN’ which has already been used in Europe in addition to 2 infants with ALL (who had already tried all other treatment options). Both infants responded positively to treatment.

Numerous other approaches are under investigation. Researchers have countless other approaches that they are investigating. Some teams of researchers are using nanotechnology to create CAR T cells inside the human body, developing CAR T cells with “off switches” as a means of preventing or limiting side effects like CRS, and using the gene-editing technology CRISPR/Cas9 to engineer T-cells more precisely.

There is still much progress to be done when considering the current state/status of existing CAR T-cell therapies. When considering cases that are high risk based on clinical factors and the potential behind CAR T-cells as a treatment option for children with ALL, these patients were given roughly 2 and ½ years before their disease reappearing after their initial chemotherapy.

However, if early indicators implied that these individuals who are high-risk did not respond optimally to chemotherapy, this treatment would be stopped by his or her physician, and the necessary steps would be taken to begin CAR T-cell therapy. In cases where high-risk patients respond well to treatment would be spared another 2 years of chemotherapy.

Links:

[A] https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

[B] https://www.explorecarttherapy.com/about-CAR-T-therapy?gclid=EAIaIQobChMIs-zG4aqI2AIVHFYNCh1bMQ1cEAAYASAAEgJZl_D_BwE

[C] https://www.britannica.com/topic/Where-the-Wild-Things-Are-by-Sendak 

(For more on this topic also visit: National Cancer; “CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers was originally published by the National Cancer Institute.”) 

Quotes By: https://www.bustle.com/articles/9487-where-the-wild-things-are-turns-50-6-quotes-that-will-make-you-cry-even-out

Screenshots By: http://www.fanpop.com/clubs/where-the-wild-things-are/screencaps (screencaps modified/edited by me)