CAR-T CELL THERAPY (part4)

2.9 Safety
Due to the injection of CAR-T cells into the body, it creates some side effects. these are cytokine release syndrome and neurological toxicity. There is little data on the long-term effects of CAR-T cell therapy, as it is a new therapy. When the CAR-T cell recognizes the healthy antigen, it can express it in non-pathogenic tissue. Excessive toxicity may occur due to this unfavorable situation because it attacks the wrong tissue [19,23]. The most common problem after treatment with CAR-T cells is cytokine release syndrome (CRS). CRS is when the immune system is activated, it releases an increasing number of inflammatory cytokines. The clinical manifestation of this syndrome is similar to sepsis with high fever, fatigue, myalgia, nausea, capillary leaks, tachycardia and other cardiac dysfunctions, hepatic failure and renal failure [21]. CRS occurs in almost all patients treated with CAR-T cell therapy; in fact, the presence of CRS is a diagnostic marker that CAR-T cells are working towards killing cancer cells. however, greater severity of CRS may result in higher disease burden. Neurological toxicity can also be seen in CAR-T cell therapy. The underlying mechanism is not fully understood and may or may not be associated with CRS. Clinical manifestations include delirium, partial loss of coherent speech while having the ability to interpret language (expressive aphasia), low alertness (obtundation), and seizures [19].
2.10 Economy
The cost of CAR T cell therapies has been criticized, with initial costs of tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) being $375,000 and $475,000, respectively. The high cost of CAR T therapies is due to complex cellular production in specialized Good Manufacturing Practice (GMP) facilities and the high level of hospital care required after CAR T cells are administered due to risks such as cytokine release syndrome. In the United States, CAR T cell therapies are covered by many private insurance companies [24].
3.         Conclusion
Although the initial results of CAR -T cell therapies are impressive, this treatment approach still has room for development in many respects. A priority for future studies is to better understand the significance of CAR -T cell persistence. The goal of therapy is to achieve sustained, ideally permanent, remission of disease in patients, and two general hypotheses may explain how CAR -T cell therapy can achieve this goal. First, a strong CART cell response eliminates all malignant cells immediately after infusion, so long-term cell persistence is not required. Second, a limited number of malignant cells are eliminated, so long-term CAR -T cell persistence is required. Indeed, CAR -T cell continuity is more important in the tumor area than in the circulation, and activation-induced cell death (AICD) is an important factor limiting CAR -T cell survival. Immunological rejection against peptides and amino acids in the structure of CARs, loss of expression of the target antigen, defined as "antigen escape", and of course very high treatment costs are other limiting points of CAR -T cell therapy. Adaptive T-cell transfer has been used to treat malignancies and can be considered a biopharmaceutical for cancer treatment. A biopharmaceutical is defined as a product that is originally natural or derived from biological sources with industrial additives. The main goals of T-cell engineering are to target tumor antigens and increase antitumor functions. CAR T-cell therapies are powerful breakthrough treatments, but several challenges remain to be overcome. The optimal design of CARs remains an area of research. To be of benefit in other disease types, tumor-specific targets in solid tumors need to be identified. Adoptive immunotherapy with CAR T cells has proven successful in clinical trials, and the ultimate goal is to induce immunity that is resistant to disease progression without severe side effects. Whether this treatment option will replace or serve as a bridge to HSCT in the near future remains an open question. For the treatment to be used routinely, automation and robotic culture techniques should be used instead of manual cell culture techniques in the production process.


4.         REFERENCES
1.    Anonymous. (2017). https://hsgm.saglik.gov.tr/tr/kanser-nedir-belirtileri
2.    Prof. Dr. Şeref Kömürcü. (2017) https://www.anadolusaglik.org/blog/kanser
3.    Mustafa ÇETİN, Neslihan MANDACI ŞANLI, Turkiye Klinikleri J Med Oncol-Special Topics 2017;10(2):180-5
4.    Tang XJ, Sun XY, Huang KM, Zhang L, Yang ZS, Zou DD, Wang B, Warnock GL, Dai LJ, Luo J (December 2015).
5.    Fox M (July 12, 2017). "New Gene Therapy for Cancer Offers Hope to Those With No Options Left". NBC News.
6.    Zijun Zhao , Yu Chen , Ngiambudulu M Francisco 1, Yuanqing Zhang , Minhao Wu, The application of CAR-T cell therapy in hematological malignancies: advantages and challenges, DOI: 10.1016/j.apsb.2018.03.001
7.    Research, Center for Biologics Evaluation and (2019-04-05). "KYMRIAH (tisagenlecleucel)
8.    Kuwana, Y.; Asakura, Y.; Utsunomiya, N.; Nakanishi, M.; Arata, Y.; Itoh, S.; Nagase, F.; Kurosawa, Y. (1987-12-31)
9.    Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Ann Rev Immunol. 2004;22:329–360.
10. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001
11. Wieczorek A, Uharek L. Genetically modified T cells for the treatment of malignant disease. Transfus Med Hemother. 2013
12. Deniz GÖREN ŞAHİN, Olga MELTEM AKAY. Car-T Cell Therapy. 2019; DOI: 10.5336.
13.  Jensen MC, Clarke P, Tan G, Wright C, Chung-Chang W, Clark TN, Zhang F, Slovak ML, Wu AM, Forman SJ, Raubitschek A. Human T lymphocyte genetic modification with naked DNA. Mol Ther. 2000
14. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer. 2012
15. Chandran SS, Klebanoff CA (9 May 2019). "T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance
16.    Dotti G, Gottschalk S, Savoldo B, Brenner MK (January 2014). "Design and development of therapies using chimeric antigen receptor-expressing T cells''
17.    Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, Jensen MC, Riddell SR (Feb 2015). "The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity"
18.    Zhang C, Liu J, Zhong JF, Zhang X (2017-06-24). "Engineering CAR-T cells". Biomarker Research. 5: 22. doi:10.1186/s40364-017-0102-y
19.    Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ (2016). "Toxicity and management in CAR-T cell therapy". Molecular Therapy: Oncolytics. 3: 16011. doi:10.1038/mto.2016.11
20.    Kueberuwa G, Kalaitsidou M, Cheadle E, Hawkins RE, Gilham DE (March 2018)
21.    Wilkie S, van Schalkwyk MC (2012). "Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling". Clin Immunol.
22.    Frankel SR (2013). "Targeting T cells to tumor cells using bispecific antibodies". Curr Opin Chem Biol
23.    von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol 2016
24.    Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018
25. Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 2016
26. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 2017
27. Miliotou AN, Lefkothea PC. CAR T-cell therapy: A new era in cancer immunotherapy. Curr Pharm Biotechnol 2018
28. Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q. The addition of the BTK inhibitor ibrutinib to anti-CD19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma. Clin Cancer Res 2016
29. Makita S, Yoshimura K, Tobinai K (June 2017). "Clinical development of anti-CD19 chimeric antigen receptor T cell therapy for B-cell non-Hodgkin lymphoma"
Breslin S (February 2007). "Cytokine-release syndrome: overview and nursing implications". Clinical Journal of Oncology Nursing. 11 (1 Suppl): 37–42.