Chimeric Antigen Receptor T-Cells: The First Step Against Lymphoma

In the body, cells constantly go through mitosis to divide into two identical daughter cells. Such cells include lymphocytes; leukocytes present in lymph. However, cell division makes errors, resulting in mutations within the DNA whilst being copied. Cancer is caused by several mutations in genes: specifically the proto-oncogenes and tumor suppressor genes (Nature). Proto-oncogenes regulate transitions between the cell cycle whereas tumor suppressor genes regulate the speed of cell division, and command cells when to die (Nature). As these genes malfunction due to mutations, cells are able to divide and grow rapidly, and have extended lifespans as there is no gene controlling their death. Lymphoma is a cancer which targets cells of the immune system called lymphocytes. It occurs when lymphocytes rapidly divide and have longer lifespans, due to mutations which affect the proto-oncogenes and tumor suppressor genes, resulting in rapid division and longer lifespans (Cancer). As lymphoma progresses and affects healthy cells, the amount of healthy lymphocytes decreases in the immune system, leaving one vulnerable to disease (Causes). Additionally, lymphoma is able to infect parts of the lymphatic system, including lymph nodes and the spleen (Causes). By genetically modifying chimeric antigen receptors [CAR] onto a T-Cell, CAR T-Cells may be the solution to lymphoma.
CAR T-Cells are T-Cells with the addition of a CAR which is able to attach to proteins displayed on the surface of cancerous lymphocytes. Cytotoxic T-Cells [TC] have T-Cell receptors which recognize processed antigens mixed with MHC-I, which then results in costimulation and proliferation of the T-Cell. However, cancerous lymphocytes evade TC cells by degrading the MHC-I complex, allowing the cancerous cell to be undetectable to the immune system. The addition of a CAR allows TC cells to detect cancerous lymphocytes by targeting proteins found on the membrane of the cell; ultimately destroying the lymphocyte. The ectodomain portion of the CAR recognizes and binds to certain antigens present on the plasma membrane of cancerous lymphocytes, such as CD-19 (Adoptive). The antigen recognition domain consists of the variable segment of a monoclonal antibody [moAB] and a single-chain variable fragment [scFv](The). A scFv is a chimeric protein which contains VL and VH chains; chosen based on the ability to bind onto the target antigen, connected by a short peptide chain (Davila). The hinge region located beneath increases the flexibility of the scFv, as well as increases space between the CAR and the antigen; encouraging antigen binding to occur between the CAR T-Cell and cancerous lymphocyte. Additionally, the hinge region controls T-Cell cytokine production; a vital protein involved in the activation and proliferation of T-Cells (Adoptive). Upon attachment to the target antigen, the transmembrane domain stabilizes the receptor in the plasma membrane of the CAR T-Cell. The costimulary region impacts T-Cell endurance, expansion, and metabolic profile (Adoptive). CD-28 transmembrane domains are commonly utilized as the domain enhances effector function, and increases amounts of effector memory T-Cells, which differentiate into effector T-Cells (Adoptive). Stimulatory regions transmit primary activation signaling within the CAR T-Cell, and are deprived of CD3-ζ, as it mirrors the activation of TC cells by immunoreceptor tyrosine-based activation motifs [ITAM] in the cytoplasmic domain of CD3-ζ (Liu). CARs which contain both costimulatory and stimulatory domains are termed 2nd generation receptors, capable of delivering primary activation signaling as well as costimulatory signaling. Both domains fully activate the CAR T-Cell, which causes it to release perforin and granzymes; two toxic chemicals which cause cytolysis within the cancerous cell (Adoptive). Additionally, the CAR T-Cell releases cytokines, which ensure nominal T-Cell health and activate inactive lymphocytes as well as stimulate apoptosis within cancerous lymphocytes (Lui).
Studies conducted by Gilead states that 72% of adult lymphoma patients were in remission 15 months after CAR T-Cell therapy, with signs of weakening lymphoma (Fernández). Additionally, unlike other therapies for lymphoma such as chemotherapy which have one-time effects, CAR T-Cells are able to function as a part of the immune system for years, and are able to be activated whenever lymphoma occurs in the body again (Advantages). Furthermore, CAR T-Cell insertion is a one-time appointment which takes 30-90 minutes, whereas other lymphoma treatments such as radiation therapy include 10 minute daily periods over a span of 4-5 weeks (Advantages). As CAR T-Cells are genetically modified with receptors produced for a specific antigen, CARs have higher affinity rates for the target antigen than standard T-Cell receptors (Questions). Unfortunately, the implantation of CAR T-Cell carries the possibility of cytokine release syndrome [CRS], or immune effector cell-associated neurotoxicity syndrome [ICANS] (NCI). It was seen that 58% out of the 101 subjects experienced recommission, with signs of increasing health against lymphoma (Neelapu). Even as the majority of CRS and ICANS present in subjects were severties between grade 1 and 2, 42% of the subjects were found to have grade 3 or higher effects; 13% of which were affected with CRS and 29% of which were affected with ICANs (Neelapu). CRS symptoms span between fever to mortality, and occur due to over-excessive production of inflammatory cytokines such as interleukin and interferon-(NCI). ICANs occur due to the production of neurotoxicants, which are able to disrupt synapses passed through the nervous system and kill neurons (Siegler).
Despite being capable of having high remission rates as seen from trials, CAR T-Cell therapy is the most expensive form of therapy for lymphoma treatment. It is estimated that CAR T-Cells cost about 375,000 dollars; a 275% increase from brentuximab vedotin, which costs around 100,000 dollars. However, CAR T-Cell therapy is estimated to have a compound annual growth rate of 35% between 2020-2028 (CAR). Additionally, predictions conclude that CD-19 CARs will possess the majority of the shares in the therapeutic market, due to numerous cancer cells possessing the CD-19 antigen (CAR). Experts expect the global CAR T-Cell therapy market to surpass $8.92 billion by 2026, making it one of the most successful immunotherapeutic industries globally (Market). The industry of CAR T-Cell therapy is mainly driven by the rapidly increasing cases of cancer as the world population continues to rise, as well as the failures of other immunotherapies such as radiotherapy on patients with lymphoma (Coherent). Additionally, the FDA’s approval of Kite Pharma’s CAR T-Cell therapy targeting specifically mantle-cell lymphoma is expected to increase the economy and CAR T-Cell therapy success rates as ween by ZUMA-2, which the success rate of the therapy was 93% out of the 60 subjects involved; an evident success rate increase of trials conducted by ZUMA-1 (Wang;U.S.).
As the population continues to rise, blood cancers such as lymphoma are expected to be increasingly prevalent throughout countries. However, as the field of immunotherapy continues to expand and develop, CAR T-Cells may be the solution to fight against cancerous lymphocytes. CAR T-Cells have been proven to successfully recommission patients, and have success rates which increase by every trial; shown by the set of ZUMA trials. Being time efficient, having high affinity rates, and being able to be activated numerous times if lymphoma is present in the body again, CAR T-Cell therapy usage is expected to increase as the treatment develops and success rates near perfect for every patient (Advantages).

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