by Max Dakara
As breakthroughs in medicine are made over the decades, a greater quality of life can be brought about for those who suffer from potentially lethal diseases such as cancer. The field of oncology has undergone several breakthroughs over recent years by developing new treatments and providing more options for patients outside the usual choices of surgery, radiotherapy and chemotherapy.
One such option is immunotherapy which are treatments that involve reinforcing a patient's immune system for it to be capable enough to attack cancer cells, effectively improving their condition. CAR-T Therapy is a type of immunotherapy which relies on an approach known as adoptive cell transfer as it relies on a patient's own cells in order for it to work.
The process involves obtaining the patient's T-cells and sending it to a lab for it to be modified into a CAR-T cell and multiply in number. In order to receive the treatment, individuals have to undergo chemotherapy first in order to reduce the T-cell count within the body, in order to facilitate the expansion of CAR-T cells within the body. Once these modified T-cells are inserted, it will then start to detect the cancer cells and attack them.
The genetic modification of the T-cells into a CAR-T cell involves the production of an artificial receptor within them that enables the detection of cancer cells which would normally reduce human leukocyte antigen expression to avoid being sensed by T-cells. This is done through the implementation of the CAR onto the T-cell which is composed of fragments or domains of synthetic antibodies. Depending on those domains, the ability of these modified cells to identify and bind to the antigen present on the cancer cells would alter. For the overall function of recognising and binding to an antigen on malignant B cells such as CD-19, it leans on domains within the cell itself that can enable the function of the CAR-T cells.
A major reason as to why CAR-T Therapy is considered an important stepping stone for cancer treatment is how it reduces the likelihood of recurrence as shown through studies. Results such as more than 80% of adult patients suffering from B-ALL (B-acute lymphoblastic leukaemia) who had previously relapsed had undergone a complete remission with 50-86% of those patients still alive after a year since their treatment. Other cancers such as follicular lymphoma showed similar results, seeing a 71% complete remission rate but some show comparatively lower complete remission rates such as diffuse large B-cell lymphoma at 43%. This however can be attributed to how this form of therapy is still relatively new to the market and means that it may need some more time for advancements to be made within the industry for a more consistent result amongst patients.
Despite the promising aspect of CAR-T, it may bring about serious side effects just like some cancer treatments. One of utmost concern is Cytokine Release Syndrome (CRS), the absence of it indicates the failure of CAR-T cells to expand which is a bad thing but the presence of it can prove fatal. Occurring in 57-97% of patients across different studies, it's a result of these modified cells being overstimulated leading to a greater secretion of cytokines (chemical messengers that initiate and steers the immune response) in the body which can lead to fevers running at high temperatures and a reduction in the blood pressure of the patient. More serious instances of CRS can lead to individuals developing concerning multisystem complications such as liver failure, acute kidney injury and cardiac myopathy among others. This is attributed to a particular cytokine being released known as Interleukin 6 (IL-6) in high amounts which has been suggested that it leads to organ toxicity.
STRUCTURE OF IL-6
Another possible result of the treatment is Cell-Related Encephalopathy Syndrome (CRES) which ranges from mild confusion, disorientation and dysphasia to more serious symptoms such as seizures. Fatal cerebral oedema is a possible symptom of CRES which can be lethal as a result of compression and herniation of the brain and brainstem. In addition to that, these CAR-T cells may reach cerebrospinal fluid as seen in some patients but the reasoning behind it has not been understood entirely by researchers.
A combination of those previously mentioned symptoms, CRS and CRES, can lead to permanent damage or even death. However, systems are being developed and in place in order to respond to adverse side effects that are seen in patients. Protocols or procedures have been kept in place in order to adequately respond to such instances. Some protocols require the administering of drugs such as an IL-6 receptor antagonist like Tociluzimab to combat severe CRS or a high dosage of corticosteroids in order to alleviate a raised intracranial pressure brought about by CRES. For these procedures to be carried out immediately, it's been suggested that hospitals providing CAR-T Therapy should have a team of specialists ranging from different fields in order for a diagnosis to be carried out as soon as possible. This team would include Bone Marrow Transplant units that are certified to be carrying out treatments that concern cellular therapy as well as neurologists, cardiologists, and experts in renal medicine among other disciplines. It's also suggested that in order for a fast response, intensive care units should be made aware of patients who have taken up on the treatment as well as when they are having the CAR-T cells infused.
PROPOSED TEAM STRUCTURE FOR A CAR-T THERAPY TEAM
Another hurdle that poses a problem in CAR-T Therapy are the antigens that are present on these cancer cells, as for most of these trials they have been only targeting the antigen CD-19. This has become a problem as it's been observed that a few patients suffering from ALL have seen recurrences in their cancers and this has been linked to how these ALL cells have undergone antigen loss of CD-19 meaning it has halted the expression of CD-19. As a result of this, identifying new antigen targets have become a priority for researchers working on the treatment such as identifying CD-22 on ALL, CD-123 on leukaemia and BCMA protein on multiple myeloma. However, these antigens are susceptible to reduce their expression as seen with CD-22 targeted treatment patients seeing a relapse in condition. This problem of antigen loss can be circumvented through targeting multiple antigens at once which hypothetically may stall the process of antigen loss or even prevent it from occurring. There have been studies that generated results that support this hypothesis, this being studying a CAR-T cell that targets both CD-19 and CD-123 which are antigens found on leukaemia. Conducted through animal models, these studies suggested that it may prevent the entire process completely and hence with time, this particular issue will be solved.
In terms of accessibility, this treatment is barred off by the exorbitant price tag it possesses at US$475,000 which creates a barrier which blocks many who are suffering from cancer from getting adequate treatment, especially those who had no success with other forms of cancer treatments. A reason for such a price can be linked to several reasons such as the treatment being relatively new in terms of development and approval as well as the production process involving collection, modifying, and delivering back which makes it labour intensive. It being a treatment rather than a drug means it cannot be manufactured at a large scale at a low price and the high costs of research and development compounded with the uncertainty of approval makes treatments such as CAR-T Therapy inaccessible to many. Time taken to modify the cells have reduced from several weeks to just a week and may be faster if new technology is developed specific to it as well as some governments and insurance firms may increase accessibility by covering some of the cost that comes with CAR-T Therapy.
As of the writing of this piece, there have been 5 different CAR-T Therapies that have been approved (Abecma, Breyanzi, Kymriah, Tecartus and Yescarta) with each focusing on a particular type of cancer. These treatments are limited to a few types that being DLBCL, follicular lymphoma, mantle cell lymphoma, multiple myeloma and ALL under different circumstances such as reappearance of the patient's cancer after a number of treatments. This limited list and the difficulties posed by unsuccessful attempts at treating solid tumours is a sign of the treatment still taking its initial steps and that several more breakthroughs within the development of the treatment being required.
So what exactly is the future of cancer treatment and will CAR-T Therapy be a major proponent of it? That's a difficult question to answer if we were to look at its current state now of serious side effects and relative inaccessibility, it may seem bleak but a major factor to consider is that it's still in its infancy with any type of treatment relating to CAR-T Therapy being approved in 2019 by the FDA. As a result, the path that lies ahead for this treatment is long but the rate at which both progress and approvals are being made brings about a glimmer of hope for it to be a staple of cancer treatment.
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