Immune-Cell-Mediated Cancer Treatment: Advantages, Drawbacks And Future Direction

Ohn Mar Lwin; Atif Amin Baig; Nurul Akmal Jamaludin; Thin Thin Aung; Haziq Hazman Norman; Aung Myo Oo

doi:10.18006/2023.11(4).625.639

Authors

Ohn Mar Lwin Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia https://orcid.org/0000-0002-4071-2999
Atif Amin Baig University Institute of Public Health, Faculty of Allied Health Sciences & Institute of Molecular Biology and Biotechnology, The University of Lahore, Pakistan https://orcid.org/0000-0001-5892-3674
Nurul Akmal Jamaludin Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia https://orcid.org/0000-0002-3410-8699
Thin Thin Aung Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia https://orcid.org/0000-0002-0717-9360
Haziq Hazman Norman Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia https://orcid.org/0000-0001-9703-8598
Aung Myo Oo Faculty of Medicine, Universiti Sultan Zainal Abidin (UniSZA), Terengganu, Malaysia, and International Medical School, Management and Science University, Selangor, Malaysia https://orcid.org/0000-0002-2961-9697

DOI:

https://doi.org/10.18006/2023.11(4).625.639

Keywords:

Immunotherapy, Cancer, T cell, Natural killer cell, Chimeric antigen receptor

Abstract

Cancer ranks as the most lethal and prevalent non-communicable disease in clinical settings. Therapeutic options for cancer comprise chemotherapy, radiotherapy, surgery, and combined treatment. Cancer remission and relapse cases are widespread despite having various advanced medications and sophisticated dissection techniques. A new approach involving immune-cell-mediated cancer therapy has been adopted extensively for cancer treatments by utilizing immune cells. Immunotherapy has gained much attention to prevent and treat various types of cancer. Immunotherapy treatments operate in multiple contexts. Several immunotherapy therapeutic interventions assist the immune function in halting or reducing the advancement of cancer cells. Many also facilitate the immune cells in destroying cancerous cells or safeguarding against cancer from disseminating to certain other regions of the human body. Among other methods, genetic manipulation of immune cells offers hope for innovative anticancer treatment. T lymphocytes and natural killer cells have become the most extensively documented immune cells for immunotherapy. Chimeric antigen receptor T-cell therapy exhibits the most promising blood cancer treatment. However, adoptive NK cell transfer therapy displays potential anticancer treatment options, although more research is needed to be carried out. In addition, cytokine-induced immunomodulation is also plausible for cancer immunotherapy. This review will highlight the most comprehensive information, observations, and consequences associated with different cancer immunotherapy initiatives.

Author Biographies

Ohn Mar Lwin, Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia

Aung Myo Oo, Faculty of Medicine, Universiti Sultan Zainal Abidin (UniSZA), Terengganu, Malaysia, and International Medical School, Management and Science University, Selangor, Malaysia

Faculty of Medicine, International Medical School, Management and Science University, Selangor, Malaysia

References

Alabanza, L., Pegues, M., Geldres, C., Shi, V., et al. (2017). Function of novel Anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Molecular Therapeutics, 25(11), 2452–65. DOI: https://doi.org/10.1016/j.ymthe.2017.07.013

Bachanova, V., Cooley, S., Defor, T.E., Verneris, M.R., et al. (2014). Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood, 123(25), 3855-63. doi: 10.1182/blood-2013-10-532531. DOI: https://doi.org/10.1182/blood-2013-10-532531

Basar, R., Daher, M., & Rezvani, K. (2020). Next-generation cell therapies: the emerging role of CAR-NK cells. Blood Advances, 4(22), 5868–76. DOI: https://doi.org/10.1182/bloodadvances.2020002547

Becknell, B., & Caligiuri, M.A. (2005). Interleukin-2, interleukin-15, and their roles in human natural killer cells. Advance inImmunology, 86, 209–39. DOI: https://doi.org/10.1016/S0065-2776(04)86006-1

Bouchkouj, N., Kasamon, Y.L., de Claro, R.A., George, B., et al. (2019). FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma. Clinical Cancer Research, 25(6),1702-1708. doi: 10.1158/1078-0432.CCR-18-2743. DOI: https://doi.org/10.1158/1078-0432.CCR-18-2743

Brudno, J.N., & Kochenderfer, J.N. (2016). Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 127(26), 3321–30. DOI: https://doi.org/10.1182/blood-2016-04-703751

Cerrano, M., Ruella, M., Perales, M. A., Vitale, C., Faraci, D. G., et al. (2020). The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice. Frontiers in immunology, 11, 888. https://doi.org/10.3389/fimmu.2020.00888 DOI: https://doi.org/10.3389/fimmu.2020.00888

Chen, K.H., Wada, M., Firor, A.E., Pinz, K.G., et al. (2016). Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget, 7(35), 56219–32. DOI: https://doi.org/10.18632/oncotarget.11019

Cherkassky, L., Morello, A., Villena-Vargas, J., Feng, Y., et al. (2016). Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. Journal of Clinical Investigation,126(8), 3130-44. doi: 10.1172/JCI83092. DOI: https://doi.org/10.1172/JCI83092

Chhabra, N., & Kennedy, J. (2021). A Review of Cancer Immunotherapy Toxicity II: Adoptive cellular therapies, kinase inhibitors, monoclonal antibodies, and oncolytic viruses. Journal of Medical Toxicology, 18(1), 43-55. doi: 10.1007/s13181-021-00835-6 DOI: https://doi.org/10.1007/s13181-021-00835-6

Davis, Z.B., Felices, M., Verneris, M.R., & Miller, J.S. (2015). Natural Killer Cell Adoptive Transfer Therapy. The Cancer Journal, 21(6), 486–91. DOI: https://doi.org/10.1097/PPO.0000000000000156

Dholaria, B.R., Bachmeier, C.A., & Locke, F. (2018). Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities. BioDrugs, 33(1), 45–60.

Dholaria, B.R., Bachmeier, C.A., & Locke, F. (2019). Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities. BioDrugs, 33(1), 45-60. doi: 10.1007/s40259-018-0324-z. DOI: https://doi.org/10.1007/s40259-018-0324-z

Du, H., Hirabayashi, K., Ahn, S., Kren, N.P., et al. (2019). Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. Cancer Cell, 11, 35(2), 221-237.e8. doi: 10.1016/j.ccell.2019.01.002. DOI: https://doi.org/10.1016/j.ccell.2019.01.002

Fischer, J. W., & Bhattarai, N. (2021). CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities. Frontiers in immunology, 12, 693016. https://doi.org/10.3389/fimmu.2021.693016 DOI: https://doi.org/10.3389/fimmu.2021.693016

Franks, S. E., Wolfson, B., & Hodge, J. W. (2020). Natural Born Killers: NK Cells in Cancer Therapy. Cancers, 12(8), 2131. https://doi.org/10.3390/cancers12082131 DOI: https://doi.org/10.3390/cancers12082131

Fried, S., Avigdor, A., Bielorai, B., Meir, A., et al.(2019). Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant, 54(10), 1643-1650. doi: 10.1038/s41409-019-0487-3. DOI: https://doi.org/10.1038/s41409-019-0487-3

Gardner, R. A., Ceppi, F., Rivers, J., Annesley, C., Summers, C., et al. (2019). Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood, 134(24), 2149–2158. https://doi.org/10.1182/ blood.2019001463. DOI: https://doi.org/10.1182/blood.2019001463

Geller, M.A., & Miller, J.S. (2011). Use of allogeneic NK cells for cancer immunotherapy. Immunotherapy, 3(12), 1445–59. DOI: https://doi.org/10.2217/imt.11.131

Giavridis, T., van der Stegen, S.J.C., Eyquem, J., Hamieh, M., et al. (2018). CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nature Medicine, 24(6), 731-738. doi: 10.1038/s41591-018-0041-7. DOI: https://doi.org/10.1038/s41591-018-0041-7

Gleichmann, N. (2020). Innate Vs Adaptive Immunity. From Technology Networks. Retrieved from: https://www.technologynetworks.com/immunology/articles/innate-vs-adaptive-immunity-335116

Glienke, W., Esser, R., Priesner, C., Suerth, J. D., Schambach, A., et al. (2015). Advantages and applications of CAR-expressing natural killer cells. Frontiers in pharmacology, 6, 21. https://doi.org/10.3389/fphar.2015.00021 DOI: https://doi.org/10.3389/fphar.2015.00021

Grigore, A. (2017). Plant Phenolic Compounds as Immunomodulatory Agents. In M., Soto-Hernandez, M., Palma-Tenango, & M. R., Garcia-Mateos (Eds.) Phenolic Compounds - Biological Activity. IntechOpen. http://dx.doi.org/10.5772/66112. DOI: https://doi.org/10.5772/66112

Guedan, S., Posey, A.D. Jr., Shaw, C., Wing, A., et al. (2018). Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight, 3(1), e96976. doi: 10.1172/jci.insight.96976. DOI: https://doi.org/10.1172/jci.insight.96976

Gust, J., Hay, K.A., Hanafi, L.A., Li, D., et al.(2017). Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discovery,7(12), 1404-1419. doi: 10.1158/2159-8290. DOI: https://doi.org/10.1158/2159-8290.CD-17-0698

Hay, K. A., Hanafi, L. A., Li, D., Gust, J., Liles, W. C., Wurfel, M. M., et al. (2017). Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood, 130(21), 2295–2306. https://doi.org/ 10.1182/blood-2017-06-793141. DOI: https://doi.org/10.1182/blood-2017-06-793141

Hirayama, A.V., Gauthier, J., Hay, K.A., Sheih, A., et al. (2018). Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma. Blood,132(Supplement 1), 1680–0. DOI: https://doi.org/10.1182/blood-2018-99-116745

Hu, Y., Feng, J., Gu, T., Wang, L., et al. (2022). CAR T-cell therapies in China: rapid evolution and a bright future. The Lancet Haematology, 9(12), e930–e941. https://doi.org/10.1016/S2352-3026(22)00291-5 DOI: https://doi.org/10.1016/S2352-3026(22)00291-5

Jacobson, C.A., Locke, F.L., Miklos, D.B., Zheng, L., et al. (2018). End of phase 1 results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in combination with atezolizumab for the treatment of patients with refractory diffuse large B Cell Lymphoma. Blood, 132(Supplement 1), 4192–2. DOI: https://doi.org/10.1182/blood-2018-99-111523

Jiang, H., Zhang, W., Shang, P., Zhang, H., Fu, W., et al. (2014). Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Molecular oncology, 8(2), 297–310. https://doi.org/10.1016/j.molonc.2013.12.001 DOI: https://doi.org/10.1016/j.molonc.2013.12.001

Jiang, T., Zhou, C., & Ren, S. (2016). Role of IL-2 in cancer immunotherapy. Oncoimmunology, 5(6), e1163462. https://doi.org/10.1080/2162402X.2016.1163462. DOI: https://doi.org/10.1080/2162402X.2016.1163462

Karre, K. (2002). NK Cells, MHC Class I Molecules and the Missing Self. Scandinavian Journal of Immunology, 55(3), 221–8. DOI: https://doi.org/10.1046/j.1365-3083.2002.01053.x

Karschnia, P., Jordan, J. T., Forst, D. A., Arrillaga-Romany, I. C., Batchelor, T. T., et al. (2019). Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood, 133(20), 2212–2221. https://doi.org/ 10.1182/blood-2018-12-893396. DOI: https://doi.org/10.1182/blood-2018-12-893396

Kilgour, M. K., Bastin, D. J., Lee, S. H., Ardolino, M., McComb, S., & Visram, A. (2023). Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy. Frontiers in immunology, 14, 1166038. https://doi.org/10.3389/ fimmu.2023.1166038. DOI: https://doi.org/10.3389/fimmu.2023.1166038

Klingemann, H. (2014). Are natural killer cells superior CAR drivers?. Oncoimmunology, 3, e28147. https://doi.org/10.4161/ onci.28147 DOI: https://doi.org/10.4161/onci.28147

Laskowski, T. J., Biederstädt, A., & Rezvani, K. (2022). Natural killer cells in antitumour adoptive cell immunotherapy. Nature reviews. Cancer, 22(10), 557–575. https://doi.org/10.1038/s41568-022-00491-0 DOI: https://doi.org/10.1038/s41568-022-00491-0

Lawler, S. E., Speranza, M. C., Cho, C. F., & Chiocca, E. A. (2017). Oncolytic Viruses in Cancer Treatment: A Review. JAMA oncology, 3(6), 841–849. https://doi.org/10.1001/jamaoncol.2016.2064 DOI: https://doi.org/10.1001/jamaoncol.2016.2064

Lee, D.W., Santomasso, B.D., Locke, F.L., Ghobadi, A., et al. (2019). ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biology of Blood Marrow Transplant,25(4), 625-638. doi: 10.1016/j.bbmt.2018.12.758 DOI: https://doi.org/10.1016/j.bbmt.2018.12.758

Leyfman, Y.(2018). Chimeric antigen receptors: unleashing a new age of anticancer therapy. Cancer Cell International, 18, 182. doi: 10.1186/s12935-018-0685-x. DOI: https://doi.org/10.1186/s12935-018-0685-x

Liu, E., Tong, Y., Dotti, G., Shaim, H., et al. (2018). Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia, 32(2), 520-531. doi: 10.1038/leu.2017.226. DOI: https://doi.org/10.1038/leu.2017.226

Liu, S., Deng, B., Yin, Z., Pan, J., et al. (2020). Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia. Blood Cancer Journal,10(2), 15. doi: 10.1038/s41408-020-0280-y. DOI: https://doi.org/10.1038/s41408-020-0280-y

Locke, F.L., Ghobadi, A., Jacobson, C.A., Miklos, D.B., et al. (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. Lancet Oncology, 20(1), 31-42. doi: 10.1016/S1470-2045(18)30864-7 DOI: https://doi.org/10.1016/S1470-2045(18)30864-7

Lupo, K.B., & Matosevic, S.(2019). Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy. Cancers, 11(6), 769. DOI: https://doi.org/10.3390/cancers11060769

Marofi, F., Al-Awad, A.S., Sulaiman, H.R., Markov, A., et al. (2021). CAR-NK Cell: A New Paradigm in Tumor Immunotherapy. Frontiers in Oncology,11, 673276. doi: 10.3389/fonc.2021.673276. DOI: https://doi.org/10.3389/fonc.2021.673276

Martino, M., Alati, C., Canale, F. A., Musuraca, G., Martinelli, G., & Cerchione, C. (2021). A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia. International journal of molecular sciences, 22(4), 2150. https://doi.org/10.3390/ijms22042150. DOI: https://doi.org/10.3390/ijms22042150

Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., et al. (2018). Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. The New England journal of medicine, 378(5), 439–448. https://doi.org/10.1056/NEJMoa1709866. DOI: https://doi.org/10.1056/NEJMoa1709866

Mehta, R. S., & Rezvani, K. (2018). Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer. Frontiers in immunology, 9, 283. https://doi.org/10.3389/ fimmu.2018.00283. DOI: https://doi.org/10.3389/fimmu.2018.00283

Moon, E. K., Ranganathan, R., Eruslanov, E., Kim, S., Newick, K., et al. (2016). Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(2), 436–447. https://doi.org/10.1158/1078-0432.CCR-15-1070. DOI: https://doi.org/10.1158/1078-0432.CCR-15-1070

Morgan, R.A., Yang, J.C., Kitano, M., Dudley, M.E., Laurencot, C.M., & Rosenberg, S.A.(2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapeutics,18(4), 843–51. DOI: https://doi.org/10.1038/mt.2010.24

Mostafa, A. A., & Morris, D. G. (2014). Immunotherapy for Lung Cancer: Has it Finally Arrived?. Frontiers in oncology, 4, 288. https://doi.org/10.3389/fonc.2014.00288 DOI: https://doi.org/10.3389/fonc.2014.00288

Neelapu, S.S., Locke, F.L., Bartlett, N.L., Lekakis, L.J., et al. (2017). Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New England Journal Medicine, 377(26), 2531-2544. doi: 10.1056/NEJMoa1707447 DOI: https://doi.org/10.1056/NEJMoa1707447

Neelapu, S.S. (2019). Managing the toxicities of CAR T‐cell therapy. Haematological Oncology, 37(S1):48–52. DOI: https://doi.org/10.1002/hon.2595

Norelli, M., Camisa, B., Barbiera, G., Falcone, L., et al. (2018). Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and Neurotoxicity due to CAR T cells. Nature Medicine, 24(6), 739-748. doi: 10.1038/s41591-018-0036-4. DOI: https://doi.org/10.1038/s41591-018-0036-4

Obstfeld, A.E., Frey, N.V., Mansfield, K., Lacey, S.F., et al .(2017). Cytokine release syndrome associated with chimeric-antigen receptor T-cell therapy: clinicopathological insights. Blood, 130(23), 2569-2572. doi: 10.1182/blood-2017-08-802413. DOI: https://doi.org/10.1182/blood-2017-08-802413

Park, H., Awasthi, A., Ayello, J., Chu, Y., et al.(2017). ROR1-Specific chimeric antigen receptor (CAR) NK cell immunotherapy for high-risk neuroblastomas and sarcomas. Biology of Blood and Marrow Transplant, 23(3), S136–7. DOI: https://doi.org/10.1016/j.bbmt.2017.01.056

Parkhurst, M.R., Riley, J.P., Dudley, M.E., & Rosenberg, S.A. (2011). Adoptive Transfer of Autologous Natural Killer Cells Leads to High Levels of Circulating Natural Killer Cells but Does Not Mediate Tumor Regression. Clinical Cancer Research, 17(19), 6287–97. DOI: https://doi.org/10.1158/1078-0432.CCR-11-1347

Quintarelli, C., Sivori, S., Caruso, S., Carlomagno, S., et al. (2019). Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. Leukemia, 34(4), 1102-1115. doi: 10.1038/s41375-019-0613-7. DOI: https://doi.org/10.1038/s41375-019-0613-7

Rafiq, S., Hackett, C.S., & Brentjens, R.J. (2020). Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nature Review Clinical Oncology, 17(3), 147–67. DOI: https://doi.org/10.1038/s41571-019-0297-y

Raftery, M. J., Franzén, A. S., & Pecher, G. (2023). CAR NK Cells: The Future is Now. Annual Reviews of Cancer Biology, 7(1). https://doi.org/10.1146/annurev-cancerbio-061521-082320 DOI: https://doi.org/10.1146/annurev-cancerbio-061521-082320

Rey, J., Veuillen, C., Vey, N., Bouabdallah, R., & Olive, D. (2009). Natural killer and γδ-T cells in haematological malignancies: enhancing the immune effectors. Trends in Molecular Medicine, 15(6), 275–84. DOI: https://doi.org/10.1016/j.molmed.2009.04.005

Robert C. (2020). A decade of immune-checkpoint inhibitors in cancer therapy. Nature communications, 11(1), 3801. https://doi.org/10.1038/s41467-020-17670-y DOI: https://doi.org/10.1038/s41467-020-17670-y

Romanski, A., Uherek, C., Bug, G., Seifried, E., et al. (2016). CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Journal of Cellular and Molecular Medicine, 20(7), 1287-94. doi: 10.1111/jcmm.12810. DOI: https://doi.org/10.1111/jcmm.12810

Santomasso, B.D., Park, J.H., Salloum, D., Riviere, I., et al. (2018). Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia. Cancer Discovery, 8(8), 958-971. doi: 10.1158/2159-8290.CD-17-1319. DOI: https://doi.org/10.1158/2159-8290.CD-17-1319

Saxena, M., van der Burg, S.H., Melief, C.J.M.,& Bhardwaj, N. (2021). Therapeutic cancer vaccines., Nature Review Cancer, 21(6), 360–78. DOI: https://doi.org/10.1038/s41568-021-00346-0

Schuster, S.J., Bishop, M.R., Tam, C.S., Waller, E.K., et al. (2019). Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. New England Journal Medicine, 380(1), 45-56. doi: 10.1056/NEJMoa1804980. DOI: https://doi.org/10.1056/NEJMoa1804980

Shah, N., Martin-Antonio, B., Yang, H., Ku, S., et al. (2013). Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One, 8(10), e76781. doi: 10.1371/journal.pone.0076781. DOI: https://doi.org/10.1371/journal.pone.0076781

Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H.J., et al. (2018). Cytokine release syndrome. Journal of Immunotherapy and Cancer, 6(1), 56. doi: 10.1186/s40425-018-0343-9. DOI: https://doi.org/10.1186/s40425-018-0343-9

Siddiqi, T., Abramson, J.S., Lee, H.J., Schuster, S., Hasskarl J.,et al. (2019). Safety of lisocabtagene maraleucel given with durvalumab in patients with relapsed/refractory aggressive b-cell non-Hodgkin lymphoma: first results from the platform study. Haematological Oncology, 37, 171–2. DOI: https://doi.org/10.1002/hon.128_2629

Simon, B., & Uslu,U. (2018). CAR‐T cell therapy in melanoma: A future success story? Experimental Dermatology, 27(12), 1315–21. DOI: https://doi.org/10.1111/exd.13792

Simonetta, F., Alvarez, M., & Negrin, R. S. (2017). Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation. Frontiers in immunology, 8, 465. https://doi.org/10.3389/fimmu.2017.00465 DOI: https://doi.org/10.3389/fimmu.2017.00465

Smyth, M.J., Cretney, E., Kershaw, M.H.,& Hayakawa, Y. (2004). Cytokines in cancer immunity and immunotherapy. Immunological Reviews, 202, 275–93. DOI: https://doi.org/10.1111/j.0105-2896.2004.00199.x

Sterner, R.C., & Sterner, R.M. (2021). CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal,11(4), 1–11. DOI: https://doi.org/10.1038/s41408-021-00459-7

Sterner, R.M., Sakemura, R., Cox, M.J., Yang, N., et al. (2019). GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood, 133(7), 697-709. doi: 10.1182/blood-2018-10-881722. DOI: https://doi.org/10.1182/blood-2018-10-881722

Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer Journal of Clinician, 71(3), 209-249. doi: 10.3322/caac.21660 DOI: https://doi.org/10.3322/caac.21660

Tang, X., Yang, L., Li, Z., Nalin, A. P., Dai, H., et al. (2018). First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. American journal of cancer research, 8(6), 1083–1089.

Taraseviciute, A., Tkachev, V., Ponce, R., Turtle, C.J., et al. (2018). Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discovery, 8(6), 750-763. doi: 10.1158/2159-8290. DOI: https://doi.org/10.1158/2159-8290.CD-17-1368

Tariq, S.M., Haider, S.A., Hasan, M., Tahir, A., Khan, M., Rehan, A., & Kamal, A. (2018). Chimeric Antigen Receptor T-Cell Therapy: A Beacon of Hope in the Fight Against Cancer. Cureus,10(10), e3486. doi: 10.7759/cureus.3486. DOI: https://doi.org/10.7759/cureus.3486

Tomasik, J., Jasiński, M., & Basak, G. W. (2022). Next generations of CAR-T cells - new therapeutic opportunities in hematology? Frontiers in Immunology, 13, 1034707. https://doi.org/10.3389/fimmu.2022.1034707 DOI: https://doi.org/10.3389/fimmu.2022.1034707

van Vliet, A.A., Georgoudaki, A-M., Raimo, M., de Gruijl, T.D., & Spanholtz, J. (2021). Adoptive NK cell therapy: A promising treatment prospect for metastatic melanoma. Cancers, 13(18), 4722. DOI: https://doi.org/10.3390/cancers13184722

Veluchamy, J. P., Kok, N., van der Vliet, H. J., Verheul, H. M. W., de Gruijl, T. D., & Spanholtz, J. (2017). The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments. Frontiers in immunology, 8, 631. https://doi.org/10.3389/fimmu.2017.00631 DOI: https://doi.org/10.3389/fimmu.2017.00631

Verneris M. R. (2013). Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL. Hematology. American Society of Hematology. Education Program, 2013, 335–341. https://doi.org/10.1182/asheducation-2013.1.335 DOI: https://doi.org/10.1182/asheducation-2013.1.335

World Health Organization (2020). Palliative Care. Available from: https://www.who.int/news-room/fact-sheets/detail/palliative-care

World Health Organization (2022). Cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer

Zahavi, D., & Weiner, L. (2020). Monoclonal antibodies in cancer therapy. Antibodies, 9(3), 34. DOI: https://doi.org/10.3390/antib9030034

Zhang, G., Wang, L., Cui, H., Wang, X., Zhang, G., et al. (2014). Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor. Scientific reports, 4, 3571. https://doi.org/10.1038/srep03571 DOI: https://doi.org/10.1038/srep03571

Zhang, Q., Ping, J., Huang, Z., Zhang, X., Zhou, J., Wang, G., Liu, S., & Ma, J. (2020). CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead. Journal of immunology research, 2020, 1924379. https://doi.org/10.1155/2020/1924379 DOI: https://doi.org/10.1155/2020/1924379

Zhang, T., Jou, T.H., Hsin, J., Wang, Z., et al. (2023). Talimogene Laherparepvec (T-VEC): A Review of the Recent Advances in Cancer Therapy. Journal of Clinical Medicine,12(3):1098. doi: 10.3390/jcm12031098. DOI: https://doi.org/10.3390/jcm12031098

Zhao, Q., Ahmed, M., Tassev, D.V., Hasan, A., et al. (2015). Affinity maturation of T-cell receptor-like antibodies for Wilms tumour 1 peptide greatly enhances therapeutic potential. Leukaemia, 29(11), 2238–47. DOI: https://doi.org/10.1038/leu.2015.125