open access

Vol 53, No 4 (2022)
Review article
Submitted: 2022-05-15
Accepted: 2022-06-12
Published online: 2022-07-28
Get Citation

A living drug: application of CAR-T therapy for lymphoid malignancies and beyond

Anna Strzelec1, Anna Klima1, Natalia Gawlik-Rzemieniewska1, Grzegorz Helbig1
DOI: 10.5603/AHP.a2022.0032
·
Acta Haematol Pol 2022;53(4):241-248.
Affiliations
  1. Faculty of Medicine in Katowice, Medical University of Silesia, Department of Hematology and Bone Marrow Transplantation, Katowice, Poland

open access

Vol 53, No 4 (2022)
REVIEW ARTICLE
Submitted: 2022-05-15
Accepted: 2022-06-12
Published online: 2022-07-28

Abstract

The ongoing development of novel personalized cancer therapies has resulted in the implementation of T cells enriched with synthetic chimeric antigen receptors, known as chimeric antigen receptors T cell (CAR-T) cells, into clinical practice. CAR-T cells are able to recognize and bind specific antigens present on the surface of target cells — so-called tumor-associated antigens. This innovative method has been approved for the treatment of hematological malignancies and may also serve as a bridge to hematopoietic stem cell transplantation. The production of the drug containing modified T cells consists of several steps — leukapheresis, T cell activation, transduction and expansion of the final CAR-T cells. Activation of CAR-T cells occurs through a pathway independent of the major histocompatibility complex, which is often associated with uncontrolled responses from the immune system and adverse reactions such as cytokine release syndrome. CAR-T therapy can only be performed in certified centers, and requires close cooperation between experienced specialists of different medical disciplines. This is what determines its effectiveness. Every step from collection and cryopreservation, through transport and modification, to thawing and infusion is strictly controlled because it has a critical impact on the quality and efficiency of the drug. Despite its proven benefits, CAR-T therapy remains available only to patients who meet well-defined criteria. These however are liable to change with the emergence of new indications.

Abstract

The ongoing development of novel personalized cancer therapies has resulted in the implementation of T cells enriched with synthetic chimeric antigen receptors, known as chimeric antigen receptors T cell (CAR-T) cells, into clinical practice. CAR-T cells are able to recognize and bind specific antigens present on the surface of target cells — so-called tumor-associated antigens. This innovative method has been approved for the treatment of hematological malignancies and may also serve as a bridge to hematopoietic stem cell transplantation. The production of the drug containing modified T cells consists of several steps — leukapheresis, T cell activation, transduction and expansion of the final CAR-T cells. Activation of CAR-T cells occurs through a pathway independent of the major histocompatibility complex, which is often associated with uncontrolled responses from the immune system and adverse reactions such as cytokine release syndrome. CAR-T therapy can only be performed in certified centers, and requires close cooperation between experienced specialists of different medical disciplines. This is what determines its effectiveness. Every step from collection and cryopreservation, through transport and modification, to thawing and infusion is strictly controlled because it has a critical impact on the quality and efficiency of the drug. Despite its proven benefits, CAR-T therapy remains available only to patients who meet well-defined criteria. These however are liable to change with the emergence of new indications.

Get Citation

Keywords

CAR-T, efficacy, CRS, ICANS, side effects

About this article
Title

A living drug: application of CAR-T therapy for lymphoid malignancies and beyond

Journal

Acta Haematologica Polonica

Issue

Vol 53, No 4 (2022)

Article type

Review article

Pages

241-248

Published online

2022-07-28

Page views

1610

Article views/downloads

171

DOI

10.5603/AHP.a2022.0032

Bibliographic record

Acta Haematol Pol 2022;53(4):241-248.

Keywords

CAR-T
efficacy
CRS
ICANS
side effects

Authors

Anna Strzelec
Anna Klima
Natalia Gawlik-Rzemieniewska
Grzegorz Helbig

References (48)
  1. Han D, Xu Z, Zhuang Y, et al. Current progress in CAR-T cell therapy for hematological malignancies. J Cancer. 2021; 12(2): 326–334.
  2. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012; 4(5): 511–527.
  3. Chen Y, You F, Jiang L, et al. Gene-modified NK-92MI cells expressing a chimeric CD16-BB-ζ or CD64-BB-ζ receptor exhibit enhanced cancer-killing ability in combination with therapeutic antibody. Oncotarget. 2017; 8(23): 37128–37139.
  4. Kuwana Y, Asakura Y, Utsunomiya N, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun. 1987; 149(3): 960–968.
  5. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA. 1989; 86(24): 10024–10028.
  6. FDA. Cellular and Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products (April 10, 2022).
  7. Zhang C, Liu J, Zhong JF, et al. Engineering CAR-T cells. Biomark Res. 2017; 5: 22.
  8. Abate-Daga D, Davila ML. CAR models: next-generation CAR modifications for enhanced T-cell function. Mol Ther Oncolytics. 2016; 3: 16014.
  9. Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015; 28(4): 415–428.
  10. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020; 17(3): 147–167.
  11. Golubovskaya V. CAR-T cells targeting immune checkpoint pathway players. Front Biosci (Landmark Ed). 2022; 27(4): 121.
  12. Gee AP. GMP CAR-T cell production. Best Pract Res Clin Haematol. 2018; 31(2): 126–134.
  13. Nastoupil LJ. The evolving use of CAR T-cell therapy in follicular lymphoma. Clin Adv Hematol Oncol. 2021; 19(11): 684–686.
  14. Piscopo NJ, Mueller KP, Das A, et al. Bioengineering solutions for manufacturing challenges in CAR T cells. Biotechnol J. 2018; 13(2).
  15. Abou-El-Enein M, Elsallab M, Feldman SA, et al. Scalable manufacturing of CAR T cells for cancer immunotherapy. Blood Cancer Discov. 2021; 2(5): 408–422.
  16. Lee G, Arepally GM. Anticoagulation techniques in apheresis: from heparin to citrate and beyond. J Clin Apher. 2012; 27(3): 117–125.
  17. Poorebrahim M, Sadeghi S, Fakhr E, et al. Production of CAR T-cells by GMP-grade lentiviral vectors: latest advances and future prospects. Crit Rev Clin Lab Sci. 2019; 56(6): 393–419.
  18. Stock S, Schmitt M, Sellner L. Optimizing manufacturing protocols of chimeric antigen receptor T Cells for improved anticancer immunotherapy. Int J Mol Sci. 2019; 20(24).
  19. Kymriah. Therapy for leukaemia/lymphoma. https://www.us.kymriah.com (April 21, 2022).
  20. Master A, O’Connor RS. T Cell media: a comprehensive guide to key components. https://cellculturedish.com/t-cell-media-comprehensive-guide-key-components/ (April 21, 2022).
  21. Stock S, Hoffmann JM, Schubert ML, et al. Influence of retronectin-mediated T-cell activation on expansion and phenotype of CD19-specific chimeric antigen receptor T cells. Hum Gene Ther. 2018; 29(10): 1167–1182.
  22. Ghorashian S, Pule M, Amrolia P. CD19 chimeric antigen receptor T cell therapy for haematological malignancies. Br J Haematol. 2015; 169(4): 463–478.
  23. Ramanayake S, Bilmon I, Bishop D, et al. Low-cost generation of Good Manufacturing Practice-grade CD19-specific chimeric antigen receptor-expressing T cells using piggyBac gene transfer and patient-derived materials. Cytotherapy. 2015; 17(9): 1251–1267.
  24. Ivics Z, Hackett PB, Plasterk RH, et al. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997; 91(4): 501–510.
  25. Lin Z, Liu X, Liu T, et al. Evaluation of nonviral piggyBac and lentiviral vector in functions of CD19+ chimeric antigen receptor T cells and their antitumor activity for CD19 tumor cells. Front Immunol. 2021; 12: 802705.
  26. Mirones I, Moreno L, Patiño-García A, et al. Grupo de Inmunoterapia y Terapias Avanzadas de la Sociedad Española de Hematología y Oncología Pediátricas, Grupo de Inmunoterapia y Terapias Avanzadas de la Sociedad Española de Hematología y Oncología Pediátricas. [Immunotherapy with CAR-T cells in paediatric haematology-oncology]. An Pediatr (Engl Ed). 2020; 93(1): 59.e1–59.e10.
  27. Freitag F, Maucher M, Riester Z, et al. New targets and technologies for CAR-T cells. Curr Opin Oncol. 2020; 32(5): 510–517.
  28. Razeghian E, Nasution MKM, Rahman HS, et al. A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies. Stem Cell Res Ther. 2021; 12(1): 428.
  29. Miltenyi Biotec. Engineering of CAR T cells for research use. https://www.miltenyibiotec.com/_Resources/Persistent/761c3be7be470fc995206924676e45625273581a/IM0022471.pdf (May 05, 2022).
  30. Vormittag P, Gunn R, Ghorashian S, et al. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018; 53: 164–181.
  31. Liebers N, Duell J, Fitzgerald D, et al. Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas. Blood Adv. 2021; 5(13): 2707–2716.
  32. FDA. Package Insert: Kymriah. https://www.fda.gov/media/107296/download (April 21, 2022).
  33. FDA. Package Insert: Yescarta. https://www.fda.gov/media/108377/download (April 21, 2022).
  34. Benmebarek MR, Karches CH, Cadilha BL, et al. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019; 20(6).
  35. Cartellieri M, Bachmann M, Feldmann A, et al. Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. J Biomed Biotechnol. 2010; 2010: 956304.
  36. Lin JK, Muffly LS, Spinner MA, et al. Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol. 2019; 37(24): 2105–2119.
  37. Clinical trials. CAR-T. https://www.clinicaltrials.gov/ct2/results?cond=car-t (April 04, 2022).
  38. Van Norman GA. Drugs and devices: comparison of European and U.S. approval processes. JACC Basic Transl Sci. 2016; 1(5): 399–412.
  39. Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2021; 56(3): 552–566.
  40. Giavridis T, van der Stegen SJC, Eyquem J, et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018; 24(6): 731–738.
  41. Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015; 28(4): 415–428.
  42. Abbott RC, Hughes-Parry HE, Jenkins MR. To go or not to go? Biological logic gating engineered T cells. J Immunother Cancer. 2022; 10(4).
  43. Beider K, Itzhaki O, Schachter J, et al. Molecular and functional signatures associated with CAR T cell exhaustion and impaired clinical response in patients with B cell malignancies. Cells. 2022; 11(7).
  44. Titov A, Kaminskiy Y, Ganeeva I, et al. Knowns and unknowns about CAR-T cell dysfunction. Cancers (Basel). 2022; 14(4).
  45. Chong EA, Alanio C, Svoboda J, et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. Blood. 2022; 139(7): 1026–1038.
  46. Miliotou AN, Papadopoulou LC. CAR T-cell therapy: a new era in cancer immunotherapy. Curr Pharm Biotechnol. 2018; 19(1): 5–18.
  47. Khurana A, Lin Yi. Allogeneic chimeric antigen receptor therapy in lymphoma. Curr Treat Options Oncol. 2022; 23(2): 171–187.
  48. Lin H, Cheng J, Mu W, et al. Advances in universal CAR-T cell therapy. Front Immunol. 2021; 12: 744823.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., Grupa Via Medica, ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
phone: +48 58 320 94 94, fax: +48 58 320 94 60, e-mail: viamedica@viamedica.pl