CAR T Cells - Groundbreaking Cancer Therapy: Hopes And Challenges

Topic: ‘CAR T cells – Groundbreaking cancer therapy at groundbreaking costs: hopes and challenges’.

The purpose of this assignment is for you to learn how to summarize the information gathered from several academic (e.g. review articles or primary articles from scientific journals) and non- academic sources (e.g. science news articles from reputable magazines [The Scientist, Scientific American, etc.], or newspapers [New York Times, The Guardian, etc.], reports from government and institution science websites [NIH, Health Canada, WHO, etc.], science blogs, podcasts, etc.). From your collected material you will build a “story” for a general reader with or without a background in science. In other words, we want you to submit a piece of science writing using a journalistic approach. Some academic and non-academic references will be provided but you are encouraged to find your own sources of information and inspiration depending on the angle you decide to give to your article.

What are CAR T cells and how do they function?

The field of science and technology is witnessing remarkable development in terms of advancement and innovation. It is worth mentioning here that the human race has been affected with a number of life-threatening diseases such as Cancer and autoimmune disorders. Till the last decade, the human race struggled to fight against the quagmire but there was no absolute treatment available for the life-threatening disease cancer. However, recently there has been ground breaking inventions in the field of molecular biology that has changed the fate of the scenario. Till date chemotherapy had been considered as the most obvious treatment for cancer at initial or advanced stages but the medical cost associated with the treatment procedure elevated the plight of the patients. Scientists have now come up with the concept of CAR T CELLS that are thought to be extremely effective for treating cancer. This paper intends to discuss the efficacy of CAR T CELLS in the treatment process of cancer. It would also elaborate the properties of the therapy and talk about the associated advantages that makes it a boon to the mankind.

The CAR T CELL therapy can be defined as a therapeutic procedure that involves the redesigning of the T cells of the patient so that it targets the cancerous cells and destroys them (Brentjens et al., 2013). It is more like an army training being imparted to the T cells of the human body in order to prepare them to fight against the opponent party. The procedure proceeds with the isolation of the T-cells from the human blood. After the procedure of isolation, the gene that contains the receptor for binding the proteins expressed by the cancer cells is modified within the laboratory. The receptor is known as the Cheminergic receptor which is popularly known as the CAR. A large number of CAR T cells are thus grown in the laboratory that is administered to the patient through the process of infusion (Davila et al., 2014). The injected CAR T cells thus target the cancerous cells and destroy them so as to prevent the tumour growth.  The therapy has been found to be effective against two cancer types majorly that includes Leukemia and Non-Hodgkin Lymphoma (Hinrichs& Rosenberg, 2014).

Fig: CAR T CELL THERAPY

Source: Kakarla & Gottschalk (2014)

CAR T CELL therapy procedure proceeds with the collection of intravenous blood from the patient’s arm which passes through a tube to an apheresis machine. The machine disintegrates the blood and segregates the white blood cells along with the T cells and send the remaining amount of blood back to patient’s body (Kalos & June, 2014). Once the T-cells are isolated the CAR are inserted into the T cells within the laboratory. Millions of T cells are grown and transferred to the human body through the process of infusion. The CAR T cells once infused inside the human body bind to the antigen on the cancerous cells and proceed with the killing of the cells.

The T-cell lymphocytes play a central role in eliciting the T-cell mediated immune response. The T cells mature from the thymus and possess a T-cell receptor on the surface of the cells. A major proportion of the T-cells are termed as alpha beta T cells that form an integral part of the adaptive immune response. The alpha beta cells rearrange their alpha beta chains in accordance with the functional property (Kochenderfer et al., 2015). It should be noted here that a group of specialized gamma delta T cells possess T cell receptors with restricted diversity that can potentially present antigen to other T cells. On the other hand, CARS can be considered as the recombinant constructs of T cell receptors (Koneru et al., 2015). The recombinant receptor is then joined to a spacer peptide and a transmembrane domain that is consecutively linked to the T-cell signalling g domains of the T-cell receptor intracellularly. Hence in this regard, it can be said that the CAR T cells are modified forms of T cells that possess the combination and specificity of an antibody with the memory and the cytotoxic property of the T-cells (Qasim et al.,2017).

Efficacy of CAR T cells in treating cancer

In the year 1992, Michael Sadelain was the first person to use biotechnological tools in order to introduce the genes into the T cells so as to stimulate cancer fighter cells. The year 1993, witnessed the first generation of the CAR-S. The renowned immunologist ZeligEshhar modified the T-cells with the initial chimeric molecule that formed a part of the antibody that fused with the T-cell receptor. However, the clinical effectiveness of the first generation of CAR was not of much significance. In the year 1994, the virus specific T-cells were used for the first time in stem cell transplants. The year 1998, witnessed the second generation CARS that showed a unique property which proved that introduction of a co-stimulatory molecule can facilitate pertinent activeness of the engineered T-cells (Rosenberg & Restifo, 2015). In the year 2002, the second generation CAR T cells were successfully used against a Prostate cancer antigen. In the year 2003, Dr Sadelain and his team worked to design CARS against CD19 (Rosenberg &Restifo, 2015). In the year, 2009, published the protocol of the manufacturing process of CD19 CAR cells which was found to be effective in treating Leukemia in patients with recurrent cancer symptoms after chemotherapy (Qasim et al., 2017) .In the year 2014, the CAR T therapy was designated as the major breakthrough therapy in the history of molecular biology. Mesothilin directed CARS were developed that helped in the identification of solid tumours also known as Mesothilin (Qasim et al., 2017). In the year 2015, armored CARS were developed as a potential therapy for ovarian cancer. The first half of the year 2017, witnessed another revolution in the field of Molecular Biology that popularised the concept of CRISPR technology to place CAR at a specific location so as to improvise the functioning of T-cells. CAR T therapy was approved by the FDA in 2017 and was designated as the standard treatment therapy for lymphoblastic lymphoma in children and adults (Qasim et al., 2017).

The procedure of administering CAR T cell therapy is invasive. The procedure takes about a few weeks. The initial step includes performing leukapheresis. The patient is either made to sit comfortably or lie down and two IV needles are then inserted. One carries the blood back to the body and the other removes the blood from the body. A central intravenous catheter is sometimes inserted that comprises of both the intravenous needles. The patient is supposed to remain still for a time period of approximately 2 hours. During the procedure, the patient might feel numbness in the muscles which happens because of reduced calcium levels. This is treated by administering calcium through the IV catheter (Turtle et al., 2016). Finally the WBC is extracted from the patient’s blood sample and sent to the laboratory for the further steps. At present, three CAR T therapies have been approved in the United States of America, that include the treatment of acute lymphoblastic Leukemia in children and adults, B-cell lymphoma and non-Hodgkin’s lymphoma. The CAR T therapy has shown positive results in the clinical trials of the mentioned types of cancer (Turtle et al., 2016). It should be noted here that the CAR T therapy has been associated with a number of severe side-effects pertaining to the fact the CAR T cells multiply inside the human body to effectively fight against cancer. Some of the serious side-effects include, high temperature and low blood pressure. Further, other invasive side-effects include, neurotoxicity and changes in the brain functioning (Carpenter et al., 2013). The changes in the brain functioning is characterized by, confusion, seizures and serious headaches. Serious infections, lower RBC count and a weakened immune response have also been attributes as major side-effects which cause life-threatening risks.

History of CAR T cells and its advancements

Some of the most prevalent clinical challenges associated with CAR T therapy includes proper management of the side effects and stringent monitoring so as to avoid the worsening of the side-effects. Other clinical challenges also include, promoting continuity in patients undergoing CAR T cell therapy. Studies reveal that on many occasions the CART cells end up killing off target healthy B cells in patients with Leukemia (The Alliance of Advanced BioMedical Engineering, 2018). This leads to the creation of adverse situation that might even lead to fatal death. In addition to this, it should further be noted that high medical cost expenditure involved in availing the therapy has served to be the main reason why the therapy has not emerged out to be a popular one. Despite the enhance effectiveness of the therapy, it is still not popular among a major proportion of the global population (Carpenter et al., 2013). Hence, there is a need to adapt measures to spread awareness and popularise the therapeutic process. The two approve CAR T therapy are associated with a heavy financial expenditure of almost $400,000 dollars each. Studies have revealed that the effective intervention for the management of side-effects include, administration of tocilizumab which involves expenditure up to $2500 per dose (The Alliance of Advanced BioMedical Engineering, 2018). In order to make the treatment intervention feasible the provider of the Medicare Advantage plan aimed at launching a coverage policy for CAR-T therapy so as to ensure adequate access to treatment opportunities for all. The law intends to help patients who are 65 years and above and intends to impart treatment at a feasible rate (The Alliance of Advanced BioMedical Engineering, 2018).

Hence, it can be hoped that with the passing years the technological innovation would revolutionise the CAR T therapeutic intervention and completely cure cancer of all types. Further, researchers are also trying to develop methodologies by virtue of which the side-effects can be treated automatically and the CAR T cells could automatically deactivate itself once it kills the cancerous cells.  With respect to the medical scenario in Canada, it can be said that the CAR T therapy is gaining wide popularity. The government of Canada has collaborated with GE life sciences to develop an innovative research hub that would primarily focus on developing CAR T therapies and other associated cellular therapies. The Canadian government has extended a $ 20 million grant from Canada’s Federal Economic Development Agency for Southern Ontario in order to encourage research and innovation in the development of therapeutic cell technologies (The Alliance of Advanced BioMedical Engineering, 2018).

Therefore, to conclude it can be said that CAR T therapy has emerged out to be a live therapy that modified the immune system so as to stop tumour growth. At this phase, the therapy has been found effective in treating a limited number of cancerous disorders, however the research is area is promising and soon it would serve as an ultimate respite for all types of cancer.

References:

Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., ...&Borquez-Ojeda, O. (2013). CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science translational medicine, 5(177), 177ra38-177ra38.

Carpenter, R. O., Evbuomwan, M. O., Pittaluga, S., Rose, J. J., Raffeld, M., Yang, S., ...&Kochenderfer, J. N. (2013). B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clinical cancer research.

Davila, M. L., Riviere, I., Wang, X., Bartido, S., Park, J., Curran, K., ...& Qu, J. (2014). Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science translational medicine, 6(224), 224ra25-224ra25.

Hinrichs, C. S., & Rosenberg, S. A. (2014). Exploiting the curative potential of adoptive T?cell therapy for cancer. Immunological reviews, 257(1), 56-71.

Kakarla, S., & Gottschalk, S. (2014). CAR T cells for solid tumors: armed and ready to go?. Cancer journal (Sudbury, Mass.), 20(2), 151.

Kalos, M., & June, C. H. (2013). Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity, 39(1), 49-60.

Kochenderfer, J. N., Dudley, M. E., Kassim, S. H., Somerville, R. P., Carpenter, R. O., Stetler-Stevenson, M., ... &Raffeld, M. (2015). Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. Journal of Clinical Oncology, 33(6), 540.

Koneru, M., O’Cearbhaill, R., Pendharkar, S., Spriggs, D. R., &Brentjens, R. J. (2015). A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16 ecto directed chimeric antigen receptors for recurrent ovarian cancer. Journal of translational medicine, 13(1), 102.

Qasim, W., Zhan, H., Samarasinghe, S., Adams, S., Amrolia, P., Stafford, S., ...&Ghorashian, S. (2017). Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Science translational medicine, 9(374), eaaj2013.

Rosenberg, S. A., &Restifo, N. P. (2015). Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348(6230), 62-68.

The Alliance of Advanced BioMedical Engineering (2018). Canada Joins the CAR T-Cell Club. [online] The Alliance of Advanced BioMedical Engineering. Available at: https://aabme.asme.org/posts/canada-joins-the-car-t-club [Accessed 5 Nov. 2018].

Turtle, C. J., Hanafi, L. A., Berger, C., Gooley, T. A., Cherian, S., Hudecek, M., ...& Robinson, E. (2016). CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. The Journal of clinical investigation, 126(6), 2123-2138.