Immunotherapy is a type of cancer treatment that makes use of a patient’s own immune system to target and destroy cancer cells, with the aim of eliminating cancer from the body. There are several different types of immunotherapies. Cytokine-based immunotherapies harness the power of cytokines, which are soluble proteins that stimulate and direct immune cells, to potentiate an immune response against tumors. A rapidly growing field of cancer immunotherapy is that of therapeutic cancer vaccines. These vaccines are designed to train immune cells to detect, target, and eliminate cancer cells. So far, the technique of adoptive cell transfer (ACT) has been demonstrated to be the most effective cancer immunotherapy approach1. This form of treatment involves isolating cancer-targeting immune cells and expanding their numbers in the lab or endowing immune cells with the ability to recognize and kill cancer cells before transferring the modified immune cells back into the patient’s body. One of the most promising ACT approaches that has attracted the greatest attention, is chimeric antigen receptor (CAR) T cell therapy.
As its name implies, the backbone of CAR-T cell therapy is the T cell. T cells are a type of white blood cell that orchestrate and regulate immune responses. The T cell subtype known as CD8+ has the ability to directly kill pathogenic cells. T cells carry out their functions via a set of specialized proteins that are present on their cell surfaces, and which together form the T cell receptor (TCR). This receptor allows T cells to receive signals from their external environment and to then relay these signals to the cell to initiate appropriate cellular changes. Each T cell harbors a unique TCR that can recognize and differentiate between specific marker molecules known as antigens that are displayed on the surface of healthy host cells, pathogens, and tumors. A useful analogy is to think of the relationship between the TCR and an antigen as that of a lock and key. Just as a particular lock can only be opened using the right key, only a unique TCR can recognize and latch onto a particular antigen. Upon recognition of a foreign antigen, T cells become activated, launching a massive proliferation and releasing chemical messengers such as cytokines which act on the T cells to further stimulate them (Figure 1). This also helps to recruit other helper or killer immune cells such as B cells and NK cells to the site, which eventually results in the elimination of the infected cell, pathogen, or tumor.
Figure 1 TCR activation upon binding a specific foreign antigen presented on surface of a pathogen, cancer cell, or infected cell (Created with BioRender; adapted from Miltenyi Biotec, n.d.2)
For cancer regression to occur, the patient must have a repertoire of T cells that can recognize antigens expressed (displayed) by the tumor. There is also the need for an appropriate magnitude of antigen-specific T cells to clear the tumor. Unfortunately, in cancer patients, these two requirements are often not met.
CAR-T cell therapy has shown promise for overcoming these challenges. CARs mimic and combine many facets of TCR activation into a single protein. Typically, CARs have an extracellular domain that consists of synthetic antibodies that are designed to specifically recognize and bind to a tumor antigen. This extracellular domain is connected to the transmembrane protein that anchors the CAR to the cell via a spacer region. The transmembrane protein also connects the extracellular domain to another intracellular protein complex (Figure 2). The intracellular unit attempts to recapitulate the set of stimulatory events that normally happens within a T cell when the TCR binds a foreign antigen. In order to enhance the survival of CAR-T cells and cytotoxic potency, CAR designs have become far more complex than the described three-fragment structure, which is now known as first-generation CARs. Most of the changes that have been introduced into the new generation CARs have been made within the intracellular domain. This is due to the importance of the intracellular signalling events that occur during T cell activation. Second-generation and third-generation CARs combine the activation domain with one or two costimulatory domains, respectively (Figure 2). This additional domain provides a secondary signal to the T cell when it encounters a tumor antigen, reenforcing the activatory signal that is delivered by the activation domain. Fourth-generation CAR-T cells or TRUCKs (T-cells redirected for universal cytokine-mediated killing) are based on second-generation constructs, but have an additional engineered gene that allows the T cell to secrete specific cytokines such as IL-12, IL-18 or IL-15 only upon CAR engagement of their target (Figure 2). This local delivery of cytokines can interfere with the immunosuppressive environment of the tumor, thereby increasing the anti-tumor function of both the CAR-T cells and resident immune cells. Some of these third and fourth generation CARs are currently being tested in the following clinical trials: NCT04007978, NCT03676504, NCT01853631, NCT03814447, NCT04429438, NCT04429438, NCT04430530.
Figure 2 Interaction between a CAR-T cell and a tumor cell and the different generations of CARs (Adapted from Brentjens & Curran, 20123; created with BioRender)
Production and treatment process
The typical CAR-T cell manufacturing and treatment process can be divided into six main steps that are shown in Figure 3.
1) In a process called leukapheresis, a sample of the patient’s own T cells is collected and separated from the other components of the blood. Previous cancer treatments can affect the health of the patient’s T cells. This often means that the patient will have to pause their current treatments ahead of blood collection, to ensure that the T cells collected are as healthy as possible. Determining how long to pause the treatment for is often a challenge, as the doctor has to ensure that the cancer will not become too active or begin to cause severe symptoms when the treatment is stopped.
2) In the laboratory, the isolated T cells are genetically engineered (most commonly by infecting T cells with a disarmed virus) in order to produce a specific receptor called a chimeric antigen receptor (CAR) on their surface. As explained by Dr. June (M.D., University of Pennsylvania Abramson Cancer Center) in a CAR-T cell presentation4, CARs are “synthetic molecules, they don’t exist naturally”.
3) Following genetic engineering, CAR-T cells are cultured in the laboratory. This allows the cells to be produced in large quantities (hundreds of millions). This process can take several weeks, during which it is possible for the patient to restart their regular cancer treatment.
4) Once the CAR-T cells have been prepared, patients may receive a short course of chemotherapy ahead of receiving CAR-T treatment. The chemotherapy is normally given over a period of 2-3 days and the purpose of this is to reduce the number of immune cells in their body in a process called lymphodepletion. This creates space in the patient’s immune system, giving CAR-T cells a better chance to survive and proliferate.
5) Soon after chemotherapy, the patient is given an infusion of the CAR-T cells intravenously, in a process that is similar to receiving a blood transfusion. This is a one-off infusion.
6) The risk period for side-effects in patients that have received CAR-T cell therapy is two to three months and therefore, patients are monitored closely during this time.
Figure 35 Schematic showing how CAR-T cells are produced
If CAR-T therapy is successful, CAR-T cells multiply and go on to activate other immune cells. They can kill tumour cells harboring specific antigens (that CAR-T cells have been programmed to identify) directly, or through these activated immune cells. As CAR-T cells multiply when they are introduced into the patient, CAR-T cells have been referred to as ‘a living drug’.
Which types of cancer is CAR-T cell currently approved for?
The first US Food and Drug Administration (FDA)-approved CAR-T cell therapy was the orphan drug, Kymriah, which was developed by Novartis. Kymriah is used to treat B-cell precursor acute lymphoblastic leukemia (ALL) in pediatric and young adult patients and relapsed diffuse large B cell lymphoma (DLBCL) in adults. The approval of this drug was based on the data collected in the Phase II JULIET clinical trial which involved 115 adult patients with DLBCL. The patients that were recruited in this trial had a poor prognosis and limited remaining treatment options. In patients evaluated for efficacy, 32% had no detectable cancer following treatment while in 18% of patients, a significant decrease in tumor size was observed6. Only two months after Kymriah was approved, Yescarta, an orphan drug developed by Gilead, became the second FDA-approved CAR-T cell therapy in the world. Yescarta is a treatment for follicular lymphoma or large B cell lymphoma (LBCL). Yescarta’s clinical Phase II ZUMA-1 trial showed that 54% of the enrolled patients showed no signs of cancer following treatment7. Recently, the four-year follow-up data from the ZUMA-1 trial was released. The data demonstrate that the four-year overall survival rate was 44%8. With nearly half of patients still alive after a single infusion of the CAR-T cell, this therapy is showing important implications for the treatment of patients that have previously exhausted all viable treatment options.
Recently, three more therapies, Tecartus (Gilead), Breyanzi (Bristol Myers Squibb), and Abecma (Bristol Myers Squibb), have been approved for treatment of leukemias, lymphomas, and myeloma, respectively9, 10, 11. These therapies were found to be promising for cancers which either did not respond to, or returned after initial treatment (first-line therapy) and also for cancers which retuned after subsequent previous treatment(s) (second/third/fourth-line therapy). Unfortunately, currently, there is no approved CAR-T therapy available for solid tumors such as breast cancer, as the therapeutic efficacy of the treatment is significantly reduced due to immunosuppressive strategies used by cancer cells that allow them to avoid being targeted by CAR-T cells12.
Advantages of CAR T cell therapy
- CAR-T cell therapy appears to provide long-lasting protection in many patients8. Even after the initial cancer becomes undetectable, CAR-T cells can persist in the circulation for a prolonged period. Two of the first three patients treated with CAR-T therapy against leukemia had low, but stable levels of the engineered T cells in their circulation eight years following their CAR-T treatment13. This means that the cells are still circulating and can eliminate any new cancer cells that might emerge due to a relapse. In contrast, conventional cornerstones of cancer treatment such as surgery can leave behind residual cancer cells that may have already broken away from the primary cancer site, but which were too few to be detected. While surgeons clearly do their best to remove all of the cancer, at times it may be possible that some cancer cells are left behind at the primary site of cancer. With regards to chemotherapy, this is only effective at killing cells during and shortly after the period of administration. Chemotherapy causes a wide range of side-effects, among which are a weakened immune system and fatigue. The side-effects can be long-term, lingering for many years. Repeated cycles of chemotherapy are needed to ensure that the majority of the cancer cells have been eliminated. In the event of a relapse, it is necessary for the patient to resume chemotherapy or to be given an alternative treatment regimen. Scott MacIntyre, a patient who was diagnosed with DLBCL, described CAR-T as “our ‘hail Mary’ pass”. His cancer kept returning and at the point when it spread to his lungs, he had already exhausted all of his treatment options, including a few rounds of chemotherapy, a stem cell transplant and even two clinical trials. However, a few weeks after he was given CAR-T cell therapy, his bone marrow biopsy showed no detectable cancer. Dr. Sonali Smith, one of his oncologists at UChicago, calls him a “walking miracle”. That was in 2016, and it has now been six years since Scott has been in remission. Scott MacIntyre provides support to other CAR-T cell therapy patients and their families on his private Facebook group 14.
- CAR-T cells are designed based on a detailed analysis of the antigens that are over-expressed on the surface of cancer cells and which are expressed at a low level on the surface of healthy cells. An important advantage of CAR-T cell therapy is that it gives the reprogrammed T cells the ability to discriminate between cancer cells and healthy cells. This specificity avoids damage to healthy tissues, which is often seen with more conventional cancer treatment methods such as radiotherapy and chemotherapy.
- CAR-T cell therapy treatments can usually be completed in a shorter time compared to other treatment regimens such as stem cell transplants and chemotherapy. CAR-T therapy normally involves the administration of a one-time infusion followed by two months of patient monitoring. Although stem cell transplants, which are used to treat high-risk blood cancers, are normally a one-time event, the medical procedure involved is complicated, requiring a pre-conditioning regimen (a procedure that may include chemotherapy and radiotherapy which makes room for the received healthy blood stem cells in the body, allowing them to grow) and long-term care post-transplant. Chemotherapy regimens also require several months to complete with multiple cycles of treatment and recovery.
Risks of CAR T cell therapy
While CAR-T cell therapy can be a safer alternative to chemotherapy, it also has several side effects that range from mild to moderate and can even be fatal under certain circumstances. One of the most serious potential side-effects is cytokine release syndrome (CRS), which is also referred as a cytokine storm (Figure 4). As described earlier, activated T cells secrete cytokines that act as messengers to further stimulate and direct the immune response. In the case of CRS, many inflammatory cytokines are released within a short period of time by hyperactively proliferating CAR-T cells and/or other immune cells, in response to the cytokines released by the infused CAR-T cells (the CAR-T treatment). The clinical symptoms of CRS can range from mild flu to dangerously high fevers and hypotension that may require the admission of the patient to an intensive care unit15,16. Ironically, the absence of CRS raises the concern that the CAR-T cell therapy may not have been successful. In most cases, CRS can be managed using drugs that block the activity of specific cytokines17. Severe cases of CRS can be managed with corticosteroids that decrease the production of inflammatory proteins and limit the activity of certain immune cells15,18. Steve Johnson, who underwent CAR-T cell therapy for relapsed leukemia at the University College Hospital in London, expressed that while the treatment was not pleasant due to fevers and temperature spikes that he experienced for two weeks following the infusion of CAR-T cells, he has no doubt that the treatment has saved his life.”19
Figure 4 Figure comparing normal, regulated cytokine production following T cell activation with the cytokine storm that can be generated in rare cases, following infusion and activation of CAR-T cells (Created with BioRender)
Neurotoxicity is the second most common side-effect related to CAR-T cell therapy. Normally, this condition appears within the first few days of treatment infusion and can occur in conjunction with and/or later, independently of CRS20. Early signs of neurotoxicity include language disorders followed by confusion, agitation, tremors, and headache. “These neurotoxicity events usually begin to resolve after a few days for most patients,” said Dr. Olalekan Oluwole, an assistant professor of medicine at Vanderbilt University who has treated several patient undergoing CAR-T therapy. “We have not yet seen any of these events in which the patients experienced long-term effects.”21 However, it is still critical to continue monitoring the patient. Indeed, more serious and potentially fatal clinical outcomes can occur. These can include seizures and cerebral oedema, which happens when fluid builds up around the brain, thereby increasing intracranial pressure20. It is difficult to characterize the incidence and severity of neurotoxicity since these factors are dependent on the CAR-T product used, dose of infused CAR-T cells and disease history such as pre-existing neurological co-morbidities22. Dr. Oluwole told Neurology Today, that in his experience, the serious or more clinically significant events were closer to 30%21. Corticosteroids remain the mainstay pharmacologic therapy for neurotoxicity, whereby higher doses are administered to patients depending on the severity of the neurotoxicity and specific CAR T product used23. For patients with a known risk of neurotoxicity, anti-seizure prophylaxis may be used18.
Another potential side effect is termed an “on-target and off-tumor” effect. It occurs when CAR-T cells, in parallel with depleting cancerous cells, also attack normal cells that express the target antigen albeit at lower levels in comparison to tumor cells. For example, for leukemia and lymphoma, CAR-T cells are designed to recognize the CD19 antigen, which is found on the surface of both normal and cancerous B cells. B cells are immune cells that are responsible for producing antibodies and are therefore crucial in fighting infections. As CAR-T cells can persist in the circulation for several years, on-target off-tumor effects may cause a profound and prolonged healthy B cell deficit, leaving patients more vulnerable to acute and long-term infections17,24,25. However, this can be managed by frequent administration of IgG replacement therapy, which provides the patient with the necessary antibodies26,27.
While CAR-T still appears to be worth the risks for patients who do not respond to any other available treatments, it unfortunately does not work as a miracle cure for everyone. Graham and Mahmoud, aged 53 and 18 respectively, had both already undergone numerous cancer treatments, but their cancer relapsed when they stopped responding to the treatments. With a very limited number of treatment options remaining, they decided to participate in a CAR-T cell clinical trial at the University College London Hospital. Afflicted by a vicious form of cancer, Graham had to undergo three rounds of CAR-T cell therapy while Mahmoud’s treatment worked initially, but was subsequently ineffective. Soon after, sadly, Graham and Mahmoud both died despite receiving the therapy. Mahmoud’s and Graham’s stories are heart-breaking, but are not without gleams of hope. As rapid progress is made in the field of CAR-T therapy, Dr. Martin Pule, the leader of the CAR-T programme at UCL, stays positive and affirms that the treatment could work. He paid tribute to patients like Graham and Mahmoud as “invaluable contributors”, without whom the CAR-T cell therapy simply could not progress. A BBC documentary called War in the Blood, which was aired in 2019, showed the evolution of CAR-T therapy, starting from the research being conducted by scientists working on developing and improving the therapy, to the clinical team then trialling these therapies in patients, and presenting the patients that participated in these trials. The documentary can be accessed at: https://www.bbc.co.uk/programmes/m0006nzt ) 28, 29.
Accessibility of CAR-T cell therapy
Despite the growing CAR-T cell market, there are significant barriers to therapy access. The cost of CAR-T cell therapy is one of the biggest challenges, not only for patients, but for payers and providers as well. The largest component of the cost is the acquisition of the treatment which ranges from $373,000 to $475,000, depending on the CAR-T product used and its indication30. However, the cost of the therapy goes beyond acquisition expenses. For example, hospital services and the use of other associated drugs significantly increase the cost of CAR-T cell therapies, especially for patients who experience more severe side-effects31 (Table 1). Despite the staggering cost, cost-effectiveness analyses by the Institute for Clinical and Economic Review suggest that CAR-T cell therapy could have significant value, in terms of greater health gains, at their current price32.
Table 130 Average direct costs associated with CAR-T cell therapy for an individual patient in academic and non-academic healthcare settings
Travel burden, in terms of distance, time, and cost, is another significant barrier to CAR-T cell therapy access33. Logistical complexity and safety requirements mean that CAR-T cell therapy needs to be delivered at specialized centers that have the required infrastructure. Currently, CAR-T cell therapy is administered at a limited number of cancer centers that tend to be located in large cities31,34. This means that patients are often required to travel long distances. Furthermore, patients need to remain within a two-hour radius of the medical center for at least four weeks following the CAR-T cell infusion30 and therefore patients need to find accommodation in close proximity to the treatment site during the monitoring period, which further increases the total costs to be borne by the patient and their family.
However, there are promising signs of providers verifying and training qualified treatment centres as well as setting up new infrastructure to enable geographically equitable access to CAR-T cell therapy. For instance, in 2020, Addenbrooke (England) became the first regional centre to offer the CAR-T cell therapy to relapsed BCL and ALL patients. Steve Johnson, a patient who had to make frequent trips to London for a CAR-T clinical trial, said that “I was lucky – for me the trial came at the right time. Having the option to explore and provide revolutionary treatments at places like Addenbrooke’s and the soon to be built Cambridge Cancer Research Hospital, is vital if we are going to rewrite the story of this devastating illness.”19
In a similar vein, more countries are redoubling efforts to commercially approve the CAR-T treatment. Last year, in April, Singapore made history in Southeast Asia by becoming the first country to commercially approve CAR-T cell therapy for DLBCL and ALL in this region35. “This approval is a defining moment for many patients in Singapore and the region who are in need of new treatment options,” says Kevin Zou, Head of Oncology, Asia Pacific and Country President of Novartis Singapore36. Currently, the treatment is available at Singapore General Hospital while the National University Hospital (NUH) is making necessary preparations to become a CAR-T treatment centre for both adult and paediatric patients35.
Yuvan Thakkar’s story precisely highlighted the value and impact that the commercial availability of CAR-T cell therapy holds. Shortly after the CAR-T was approved in the UK, the Great Ormond Street Hospital in London administered the therapy to Yuvan Thakkar, an 11-year-old boy who became the first patient to receive this form of immunotherapy in the UK. This treatment represented his “last hope” as his leukemia had relapsed following two rounds of chemotherapy and a bone marrow transplant. At the time of the treatment, Yuvan’s parents, Sapna and Vinay, had stated that “We are so glad that we at least have this new option now. If he had relapsed a year ago it would have been a different story.”37
Amid the good news, however, it is important to note, that Yuvan’s treatment still required a multi-country collaboration and was not performed independently in the UK. Professor Charles Swanton, Cancer Research UK’s chief clinician, explained that “Yuvan’s cells were processed in both Europe and the US – and needed collaboration across borders to get the T cell infusion back to London so he could be treated.38” This means that processing times for CAR-T, even though shortened by increased numbers in treatment centres, may still be a lengthy process. This has important implications since even modest delays in CAR-T cell therapy can significantly hamper its effectiveness39. A lot of efforts are currently being invested in setting up more manufacturing centres. This year, the Peter MacCallum Cancer Centre in Australia was given the green light to both locally manufacture and deliver the CAR-T product, Kymriah, to patients with relapsed or refractory DLBCL and pediatric patients with relapsed or refractory ALL. “Local manufacturing means patients’ cells can stay here in Australia without the need to ship them overseas, generating greater efficiencies an expectation of quicker timelines to eligible patients to access Kymriah,” said Professor Simon Harrison, director of the Centre of Excellence in Cellular Immunotherapy at the Peter MacCallum Cancer Centre40.
Despite this increased accessibility, many patients still miss out as in some countries such as the UK, patient eligibility is decided by a panel of clinical experts following a referral. Azaylia Cain, who died in April last year at only eight months old was unable to receive treatment in the UK. Her parents decided to fly their daughter to Singapore where CAR-T cell therapy was the only option remaining as she needed to receive the therapy within a matter of weeks. Sadly, her leukemia deteriorated too rapidly and the doctors told the parents that they would not be able to cure Azaylia41. This heart-breaking story highlights the pressing need to develop strategies that minimize treatment delays and address the complications entailed by the referral system, as the uptake rate substantially increases.
What are some of the latest developments in CAR-T cell therapy?
As mentioned earlier, most CAR-T cell therapies that are commercially available are approved only for cases where the cancer does not respond or has returned after the patient has received several lines of standard treatments such as chemotherapy. With each round of treatment, the functionality and quality of T cells decline. As CAR-T cell therapy uses the patient’s own T cells, obtaining healthy T cells for the therapy can be a real challenge. Currently, efforts are being made to deploy CAR-T cell therapy at an earlier stage of a patient’s disease. Stephen J. Forman, MD, director of the T-cell Therapeutics Research Laboratory at City of Hope Comprehensive Cancer Center has expressed the view that the strong efficacy of CAR-T cells in the treatment of advanced B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma begs the question of whether these cells could also be effective to treat patients at an earlier stage of their disease 42. Indeed, early data from a clinical trial indicate that patients with high-risk LBCL who receive CAR-T cell therapy as the initial treatment, show higher remission rates than those who receive it as third-line therapy43. Sattva Neelapu, the principal investigator of the trial, explained in an interview that the T cells are “younger, fitter cells” that can build a more potent attack against the cancer44. While it can be rightly argued that CAR-T cell therapy is currently very expensive, Forman explains that it can be a better bargain in the long run as it lowers the risks of disease relapse and “and all of the downstream costs that come with recurrent disease.42”
One of the main challenges faced when it comes to using CAR-T cell therapy as an earlier line of treatment, is the logistics of testing the therapy in a large patient group44. The personalized nature of the therapy means that it is necessary for CAR-T cell therapy to be manufactured individually for each individual patient. However, new research is focusing on creating CAR-T cells using T cells isolated from healthy individuals, instead of from a patient’s own T cells. Off-the-shelf CAR-T cell or “universal” CAR-T cell therapy, as this form of therapy is known, is ready to use when the patients need them, saving precious time. Moreover, an off-the-shelf product can be offered at more locations, increasing access to more patients. “Neelapu explained that by using off-the-shelf products, an apheresis center would not be required – only a freezer for product storage and competent personnel to administer the therapy intravenously are required. 44 This also makes CAR-T cell therapy more affordable, barring any holdups from insurance companies. Although, there have been doubts over the efficacy of off-the-shelf CAR-T therapies as compared to the personalized form, Ceylad, a CAR-T developer, is currently testing two of its off-the-shelf CAR-T products in clinical trials. So far, early results seem promising, with no significant toxicities reported to date45. Some of the clinical trials that are currently testing off-the-shelf CAR-T cells and recruiting patients with blood cancers are listed in the table below.
|Clinical trial identifier||Disease||Location|
|NCT03229876||Acute Lymphoblastic Leukemia, Non-Hodgkin Lymphoma||First Affliated Hospital of Zhengzhou University/ First Affliated Hospital of Zhejiang UniversityHangzhou|
|NCT03166878||B Cell Leukemia, B Cell Lymphoma||Biotherapeutic Department and Hematology Department of Chinese PLA General Hospital|
|NCT04502446||T Cell Lymphoma||Toronto, Ontario, Canada, M5G 2C1/ Sydney, New South Wales, Australia, 2050/ Salt Lake City, Utah, United States, 84112/ Houston, Texas, United States, 77030/ New York, New York, United States, 10065/ Bronx, New York, United States, 10467/ Miami, Florida, United States, 33124/ New Haven, Connecticut, United States, 06520/ Stanford, California, United States, 94305/ Duarte, California, United States, 91010|
|NCT03398967||B Cell Leukemia, B Cell Lymphoma||Biotherapeutic Department and Hematology Department of Chinese PLA General Hospital|
|NCT04288726||Extranodal Natural Killer/T-Cell Lymphoma, Nasal TypeClassical Hodgkin Lymphoma||Houston Methodist Hospital/ Texas Children’s Hospital|
|NCT04881240||Acute Lymphoblastic Leukemia, in RelapseAcute Lymphoblastic Leukemia, Refractory Pediatric ALL||St. Jude Children’s Research Hospital|
|NCT05127135||T-Acute Lymphoblastic, LeukemiaT-cell, Non-Hodgkin Lymphoma, T-cell Acute Lymphoblastic Lymphoma||The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Hefei, China/ Fundamenta Therapeutice Co.,Ltd, Suzhou, Jiangsu, China|
|NCT04601181||B Cell Malignancy||The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Hefei, Anhui, China, 230001|
|NCT05106946||Relapsed and/or refractory non-Hodgkin’s B cell lymphoma||The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China|
|NCT04173988||Relapsed/refractory acute lymphoblastic leukemia, Childhood B-cell malignancy||Children’s Hospital of Fudan University, Shanghai, Minhang, China, 201102|
Table 2 Some of the clinical trials that are currently recruiting blood cancer patients to test the efficacy and dosage of off-the-shelf CAR-Ts
However, Ceylad’s co-founder, Christian Homsy, highlighted that developing an off-the-shelf CAR-T therapy is a “scientifically challenging avenue”46. In fact, in October last year, Allogene, a clinical-stage biotechnology company, revealed that they detected chromosomal abnormalities in their off-the-shelf CAR-T product after this was administered to a lymphoma patient. This raises the possibility that gene editing during the manufacturing process can disrupt the T cell’s normal functions, making them capable of causing damage to the receiver. While Allogene’s entire clinical pipeline was put on hold, scientists are trying to understand how to overcome such technical difficulties47.
Another extremely important aspect of the treatment that scientists have been working on is the safety of CAR-T cells. “Once we let the CAR out, they’re like teenage kids,” said Marcela Maus, an immunologist and cell therapist at Mass General Cancer Center. “You can maybe watch, but you can’t really control them. So, there’s some desire to be able to turn them on or off at will.48” To this aim, researchers have devised control systems by engineering an additional genetic circuit into CAR-T cells which should in theory, allow clinicians to manually activate or deactivate the CAR-T cells, much like a remote control. “The goal is really getting our hands back on the steering wheel for a bit,” Maus said48. One such mechanism that has been created is the use of an emergency “kill” switch that could address the onset of severe CRS. The switch is only activated when a drug such as rimiducid is administered to the patient. The drug causes the infused CAR-T cells to self-destruct49. There are several other similar control systems that are currently being tested both in the lab and in clinical trials49. Some of these clinical trials that are recruiting patients with blood cancers are listed in the table below.
|Clinical trial identifier||Disease||Location|
|NCT03016377||ALL||Lineberger Comprehensive Cancer Center at University of North Carolina – Chapel Hill|
|NCT03696784||Lymphoma, B-Cell||Lineberger Comprehensive Cancer Center at University of North Carolina – Chapel Hill|
|NCT03373071||Relapsed/refractory B-ALL or NHL||Ospedale Pediatrico Bambino Gesù, Roma, Italy|
|NCT04844086||B-cell Acute Lymphoblastic Leukemia, Non-Hodgkin’s Lymphoma (Relapsed), Non-Hodgkin’s Lymphoma (Refractory), Primary Mediastinal Large B Cell Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma Mantle Cell Lymphoma, High-grade B-cell Lymphoma||National Taiwan University Hospital, Taipei, Taiwan|
Table 3 Some of the clinical trials that are currently recruiting blood cancer patients to test the efficacy and dosage of controllable CAR-Ts
More refined models of these controllable CAR-Ts are currently being designed. Unlike the “kill” switch approach, which deactivates CAR-T cells permanently, a team led by Shu Chien (PhD) and Yingxiao Wang (PhD) at the Univesity of California San Diego (UCSD) has engineered light-controllable CAR-T cells. These cells only become activated in the presence of blue light. In another example, T cells have been engineered in such a way that they only create and express the CAR protein on their surface in the presence of ultrasound radiation. “That way, it can be focused into a specific location,” said Yingxiao Wang48. “When the light or ultrasound is on the tumor locally, they can activate the CAR gene to trigger killing. Anywhere else, the CAR T-cells will be benign.” In this way, even if the CAR-T cells kill healthy cells when the activator signal is present, the damage will be limited only around the tumour. “But this is an infant field right now,” Wang added. “A lot of these studies are just proof of concepts to show that they’re technically achievable. If you want to move to clinical trials, all of the components must be optimized.” 48
CAR-T cell therapy represents an exciting advancement in the field of cancer and personalized medicine. It has truly transformed the treatment of patients with blood cancers such as lymphomas. However, many issues such as the high costs of the treatment, treatment-related toxicities, and decreased efficacy in the context of solid tumors still need to be addressed. However, with rapid advancements in technology and the launch of new initiatives to expand the number of centers that offer CAR-T cell therapy and to build expertise worldwide, there is hope that this treatment can be made accessible to far greater numbers of cancer patients and to treat a wider range of cancers in the foreseeable future.
For a list of centres that are authorised to administer the CAR-T cell therapy in England and USA, please visit: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/, https://www.yescarta.com/lbcl/find-a-treatment-center/, and https://www.us.kymriah.com/treatment-center-locator/
https://www.lls.org/support-resources/financial-support/susan-lang-pre-car-t-cell-therapy-travel-assistance-program (offers financial assistance such as lodging and transportation expenses for CAR-T cell patients, USA)
Clinicaltrials.gov (information about clinical trials worldwide)
https://moremomentsmorememories.org/ (provide grants that help people access oncology clinical trials for potentially life-saving treatment, offering more moments and more memories with loved ones, USA)
https://car-tcr-summit.com/patients-stories/ (some patient stories from around the world)
https://ascopost.com/issues/october-10-2021/tackling-a-growing-need-options-after-car-t-cell-therapy-for-lymphoma/ (treatment options after relapse from CAR-T cell therapy)
https://www.fredhutch.org/en/news/center-news/2019/12/repeat-dose-car-t-cells.html (repeat doses of CAR-T cell therapy: is it worth it?)
https://www.youtube.com/watch?v=ZZoeuBjSsUM&t=1683s (tips to help cope with the social and emotional challenges of going through CAR-T cell therapy)
https://www.youtube.com/watch?v=5cbu2wQlIcI&t=10s (Caring after CAR-T therapy: what you need to know; This program will offer information on CAR T-associated side effects and offer tips for coping as you support your loved one with the many different parts of the planning and therapy process)
https://www.youtube.com/watch?v=voQeppJc9o8&t=1s (Laura’s CAR-T story; a survivor of multiple myeloma talks about her experience with CAR-T cell therapy).
https://www.youtube.com/watch?v=RZE1oaKz-hI (Caregivers talk about their perspective and experience during CAR-T cell therapy).
- Wang, M., Yin, B., Wang, H. and Wang, R., 2014. Current advances in T-cell-based cancer immunotherapy. Immunotherapy, 6(12), pp.1265-1278.
- Miltenyi Biotec, n.d. Antigen specific activation of T cells. [image] Available at: <https://www.miltenyibiotec.com/SM-en/products/highlights-and-promotions/immuno-oncology-campaign-28923/enrichment-and-analysis-of-rare-antigen-specific-t-cells.html>
- Brentjens, R.J. and Curran, K.J., 2012. Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen. Hematology 2010, the American Society of Hematology Education Program Book, 2012(1), pp.143-151.
- June, C., 2016. Engineering T cells: moving beyond leukemia.
Available at: <https://videocast.nih.gov/Summary.asp?file=19892&bhcp=1>
- NIH National Cancer Institute, n.d. CAR T-cell therapy. [image] Available at: <https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy>
- Novartis, 2021. Kymriah® (tisagenlecleucel), first-in-class CAR-T therapy from Novartis, receives second FDA approval to treat appropriate r/r patients with large B-cell lymphoma. [online] Available at: https://www.novartis.com/news/media-releases/kymriah-tisagenlecleucel-first-class-car-t-therapy-from-novartis-receives-second-fda-approval-treat-appropriate-rr-patients-large-b-cell-lymphoma
- Neelapu, S., Locke, F., Bartlett, N., Lekakis, L., Miklos, D., Jacobson, C., Braunschweig, I., Oluwole, O., Siddiqi, T., Lin, Y., Timmerman, J., Stiff, P., Friedberg, J., Flinn, I., Goy, A., Hill, B., Smith, M., Deol, A., Farooq, U., McSweeney, P., Munoz, J., Avivi, I., Castro, J., Westin, J., Chavez, J., Ghobadi, A., Komanduri, K., Levy, R., Jacobsen, E., Witzig, T., Reagan, P., Bot, A., Rossi, J., Navale, L., Jiang, Y., Aycock, J., Elias, M., Chang, D., Wiezorek, J. and Go, W., 2017. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New England Journal of Medicine, 377(26), pp.2531-2544.
- Gilead Sciences, Inc., 2020. New Four-Year Data Show Long-Term Survival in Patients With Large B-Cell Lymphoma Treated With Yescarta® in ZUMA-1 Trial. [online] Available at: https://www.gilead.com/news-and-press/press-room/press-releases/2020/12/new-four-year-data-show-long-term-survival-in-patients-with-large-b-cell-lymphoma-treated-with-yescarta-in-zuma-1-trial
- Gilead Company, 2020. U.S. FDA Approves Kite’s Tecartus™, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma. [online] Available at: https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/us-fda-approves-kites-tecartus-the-first-and-only-car-t-treatment-for-relapsed-or-refractory-mantle-cell-lymphoma
- U.S. Food & Drug Administration, 2021. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. [online] Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-relapsed-or-refractory-large-b-cell-lymphoma
- U.S. Food & Drug Administration, 2021. FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma. [online] Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-multiple-myeloma
- Sterner, R. and Sterner, R., 2021. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal, 11(4).
- Mueller, K.T., Maude, S.L., Porter, D.L., Frey, N., Wood, P., Han, X., Waldron, E., Chakraborty, A., Awasthi, R., Levine, B.L., Melenhorst, J.J., Grupp, S.A., June, C.H. and Lacey, S.F., 2017. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood, 130(21), pp.2317–2325.
- Bartosch, J., 2022. Six years after CAR T-cell therapy for lymphoma, patient still cancer-free. [online] Uchicagomedicine.org. Available at: https://www.uchicagomedicine.org/forefront/cancer-articles/a-walking-miracle-car-t-cell-therapy
- Brudno, J.N. and Kochenderfer, J.N., 2016. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, The Journal of the American Society of Hematology, 127(26), pp.3321-3330.
- Maude, S.L., Laetsch, T.W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., Bader, P., Verneris, M.R., Stefanski, H.E., Myers, G.D. and Qayed, M., 2018. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), pp.439-448.
- Maude, S.L., Frey, N., Shaw, P.A., Aplenc, R., Barrett, D.M., Bunin, N.J., Chew, A., Gonzalez, V.E., Zheng, Z., Lacey, S.F. and Mahnke, Y.D., 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), pp.1507-1517.
- Lee, D.W., Gardner, R., Porter, D.L., Louis, C.U., Ahmed, N., Jensen, M., Grupp, S.A. and Mackall, C.L., 2014. Current concepts in the diagnosis and management of cytokine release syndrome. Blood, The Journal of the American Society of Hematology, 124(2), pp.188-195.
- Cambridge University Hospitals. 2022. Addenbrooke’s becomes first regional centre to offer CAR-T cell treatment for cancer patients. [online] Available at: https://www.cuh.nhs.uk/news/addenbrookes-becomes-first-regional-centre-to-offer-car-t-cell-treatment-for-cancer-patients/
- Neelapu, S.S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F.L., Komanduri, K.V., Lin, Y., Jain, N., Daver, N. and Westin, J., 2018. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nature reviews Clinical oncology, 15(1), pp.47-62.
- Susman, E., 2018. For Your Patients-Neurotoxicity Neurotoxicity May Arise from CAR-T Cancer Therapy. Neurology Today. [online] Available at: https://journals.lww.com/neurotodayonline/Fulltext/2018/06070/For_Your_Patients_Neurotoxicity__Neurotoxicity_May.3.aspx.
- Dholaria, B.R., Bachmeier, C.A. and Locke, F., 2019. Mechanisms and management of chimeric antigen receptor T-cell therapy-related toxicities. BioDrugs, 33(1), pp.45-60.
- Siegler, E.L. and Kenderian, S.S., 2020. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor t cell therapy: insights into mechanisms and novel therapies. Frontiers in immunology, 11, p.1973.
- Park, J.H., Rivière, I., Gonen, M., Wang, X., Sénéchal, B., Curran, K.J., Sauter, C., Wang, Y., Santomasso, B., Mead, E. and Roshal, M., 2018. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. New England Journal of Medicine, 378(5), pp.449-459.
- Cordeiro, A., Bezerra, E.D., Hirayama, A.V., Hill, J.A., Wu, Q.V., Voutsinas, J., Sorror, M.L., Turtle, C.J., Maloney, D.G. and Bar, M., 2020. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biology of Blood and Marrow Transplantation, 26(1), pp.26-33.
- Locke, F.L., Ghobadi, A., Jacobson, C.A., Miklos, D.B., Lekakis, L.J., Oluwole, O.O., Lin, Y., Braunschweig, I., Hill, B.T., Timmerman, J.M. and Deol, A., 2019. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. The lancet oncology, 20(1), pp.31-42.
- Hill, J.A., Giralt, S., Torgerson, T.R. and Lazarus, H.M., 2019. CAR-T–and a side order of IgG, to go?–Immunoglobulin replacement in patients receiving CAR-T cell therapy. Blood reviews, 38, p.100596.
- Blood Cancer UK, 2019. By the end of the programme, I didn’t feel despair. I felt hope. Available at: https://bloodcancer.org.uk/news/car-t-therapy-blood-cancer/
- UCL News. 2019. ‘War in the Blood’, a film about CAR T-cell therapy. [online] Available at: https://www.ucl.ac.uk/news/2019/jul/war-blood-film-about-car-t-cell-therapy
- Borgert, R., 2021. Improving outcomes and mitigating costs associated with CAR T-cell therapy. The American Journal of Managed Care, 27(13 Suppl), pp.S253-S261.
- Lyman, G.H., Nguyen, A., Snyder, S., Gitlin, M. and Chung, K.C., 2020. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma. JAMA network open, 3(4), pp.e202072-e202072.
- Institute for Clinical and Economic Review & California Technology Assessment Forum., 2018. Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value : final evidence report. [online] Boston, Massachusetts: Institute for Clinical and Economic Review. Available at: http://resource.nlm.nih.gov/101744954
- Snyder, S., Chung, K.C., Jun, M.P. and Gitlin, M., 2021. Access to chimeric antigen receptor T cell therapy for diffuse large B cell lymphoma. Advances in therapy, 38(9), pp.4659-4674.
- Dhulesia, A., Heskett, C., Ralph, L. and Kong, G., 2020. CAR-T: Unlocking Barriers to Adoption in Europe | L.E.K. Consulting. [online] Lek.com. Available at: https://www.lek.com/insights/ei/car-t-unlocking-barriers-adoption-europe
- Biospectrumasia.com. 2021. CAR-T therapy leads Singapore medical tourism within APAC. [online] Available at: https://www.biospectrumasia.com/analysis/34/17963/car-t-therapy-leads-singapore-medical-tourism-within-apac-.html
- Omnicom Public Relations Group, 2021. Novartis receives approval for Kymriah® (tisagenlecleucel) by Health Sciences Authority as Singapore’s first commercially approved CAR-T therapy | Novartis Singapore. [online] Novartis (Singapore) Pte. Ltd. Available at: https://www.novartis.com.sg/news/media-releases/novartis-receives-approval-kymriah-tisagenlecleucel-health-sciences-authority
- Wharton, J., 2022. Boy, 11, first to receive pioneering cancer treatment on NHS. Metro, [online] Available at: https://metro.co.uk/2019/01/31/boy-11-first-receive-pioneering-cancer-treatment-nhs-8420401/
- Cancer Research UK, 2019. First patient receives CAR T cell therapy on NHS. [online] Available at:https://news.cancerresearchuk.org/2019/01/31/first-patient-receives-car-t-cell-therapy-on-nhs/
- Tully, S., Feng, Z., Grindrod, K., McFarlane, T., Chan, K. and Wong, W., 2019. Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model. JCO Clinical Cancer Informatics, [online] (3), pp.1-9. Available at: <https://ascopubs.org/doi/full/10.1200/CCI.19.00086>.
- BiotechDispatch. 2021. TGA approves first Australian commercial CAR-T manufacturing site. [online] Available at: https://biotechdispatch.com.au/news/tga-approves-first-australian-commercial-car-t-manufacturing-sit
- Chalmers, V., 2021. Hopes of cancer ‘cure’ as stunning new therapy trains immune system to hunt and destroy disease. The Sun, [online] Available at: https://www.thesun.co.uk/news/14846222/hopes-cancer-cure-therapy-trains-immune-system-destroy-disease/
- Amorosi, D., 2021. The case for CAR T cells as earlier treatment requires more evidence. Cell Therapy Next, [online] Available at: https://www.healio.com/news/hematology-oncology/20210423/the-case-for-car-t-cells-as-earlier-treatment-requires-more-evidence
- MD Anderson Cancer Center, 2020. CAR T cell therapy effective as first-line treatment for high-risk large B-cell lymphoma. [online] Available at: https://www.mdanderson.org/newsroom/car-t-cell-therapy-effective-as-first-line-treatment-for-high-risk-large-b-cell-lymphoma.h00-159387468.html
- Carter, D., 2022. What’s new with CAR T cell therapy?. [online] MD Anderson Cancer Center. Available at: https://www.mdanderson.org/cancerwise/what-s-new-with-car-t-cell-therapy.h00-159464790.html
- Ceylad Oncology, 2021. Celyad Oncology Presents Updates on Allogeneic CAR T Clinical Candidates and shRNA-based Preclinical Concepts at Research & Development Day. [online] Available at: https://celyad.com/2021/07/20/celyad-oncology-presents-updates-on-allogeneic-car-t-clinical-candidates-and-shrna-based-preclinical-concepts-at-research-development-day/
- Fernández, C.R., 2021. A cure for cancer? how car-T cell therapy is revolutionizing oncology [Online] Available at: https://www.labiotech.eu/in-depth/car-t-therapy-cancer-review/
- Plieth, J. 2021. Allogene raises the spectre of a car-T nightmare [Online] Available at: https://www.evaluate.com/vantage/articles/news/trial-results/allogene-raises-spectre-car-t-nightmare
- Chen, A., 2022. Scientists are making CAR-T cells more clever. Here’s what the next generation could look like. STAT. Available at: https://www.statnews.com/2022/01/14/cancer-cart-cell-therapy-research/.
- Grossberg, H., 2019. A suicide switch for CAR-T? IQVIA. Available at: https://www.iqvia.com/blogs/2019/01/a-suicide-switch-for-car-t.