CAR T cell
{{Short description|Genetically engineered T cell}}
In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.
CAR T cell therapy uses T cells engineered with CARs to treat cancer. T cells are modified to recognize cancer cells and destroy them. The standard approach is to harvest T cells from patients, genetically alter them, then infuse the resulting CAR T cells into patients to attack their tumors.{{cite web |date=July 12, 2017 |work=NBC News |url=https://www.nbcnews.com/health/health-news/new-gene-therapy-cancer-offers-hope-those-no-options-left-n741326 |title=New Gene Therapy for Cancer Offers Hope to Those With No Options Left | vauthors = Fox M }}
CAR T cells can be derived either autologously from T cells in a patient's own blood or allogeneically from those of a donor. Once isolated, these T cells are genetically engineered to express a specific CAR, using a vector derived from an engineered lentivirus such as HIV (see Lentiviral vector in gene therapy). The CAR programs the T cells to target an antigen present on the tumor cell surface. For safety, CAR T cells are engineered to be specific to an antigen that is expressed on a tumor cell but not on healthy cells.{{cite journal | vauthors = Srivastava S, Riddell SR | title = Engineering CAR-T cells: Design concepts | journal = Trends in Immunology | volume = 36 | issue = 8 | pages = 494–502 | date = August 2015 | pmid = 26169254 | pmc = 4746114 | doi = 10.1016/j.it.2015.06.004 }}
After the modified T cells are infused into a patient, they act as a "living drug" against cancer cells. When they come in contact with their targeted antigen on a cell's surface, T cells bind to it and become activated, then proceed to proliferate and become cytotoxic.{{cite journal | vauthors = Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ | title = Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts | journal = EMBO Molecular Medicine | volume = 9 | issue = 9 | pages = 1183–1197 | date = September 2017 | pmid = 28765140 | pmc = 5582407 | doi = 10.15252/emmm.201607485 }} CAR T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity), and by causing the increased secretion of factors that can affect other cells such as cytokines, interleukins and growth factors.{{cite journal | vauthors = Tang XJ, Sun XY, Huang KM, Zhang L, Yang ZS, Zou DD, Wang B, Warnock GL, Dai LJ, Luo J | display-authors = 6 | title = Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy | journal = Oncotarget | volume = 6 | issue = 42 | pages = 44179–44190 | date = December 2015 | pmid = 26496034 | pmc = 4792550 | doi = 10.18632/oncotarget.6175 }}
The surface of CAR T cells can bear either of two types of co-receptors, CD4 and CD8. These two cell types, called CD4+ and CD8+, respectively, have different and interacting cytotoxic effects. Therapies employing a 1-to-1 ratio of the cell types apparently provide synergistic antitumor effects.{{cite journal | vauthors = Zhang H, Zhao P, Huang H | title = Engineering better chimeric antigen receptor T cells | journal = Experimental Hematology & Oncology | volume = 9 | issue = 1 | pages = 34 | date = December 2020 | pmid = 33292660 | pmc = 7709221 | doi = 10.1186/s40164-020-00190-2 | doi-access = free }}
History
The first chimeric receptors containing portions of an antibody and the T cell receptor was described in 1987 by Yoshihisa Kuwana et al.{{cite journal | vauthors = Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y | display-authors = 6 | title = Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions | journal = Biochemical and Biophysical Research Communications | volume = 149 | issue = 3 | pages = 960–968 | date = December 1987 | pmid = 3122749 | doi = 10.1016/0006-291x(87)90502-x }} at Fujita Health University and Kyowa Hakko Kogyo, Co. Ltd. in Japan, and independently in 1989 by Gideon Gross and Zelig Eshhar{{cite journal | vauthors = Gross G, Gorochov G, Waks T, Eshhar Z | title = Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity | journal = Transplantation Proceedings | volume = 21 | issue = 1 Pt 1 | pages = 127–130 | date = February 1989 | pmid = 2784887 }}{{cite journal | vauthors = Rosenbaum L | title = Tragedy, Perseverance, and Chance - The Story of CAR-T Therapy | journal = The New England Journal of Medicine | volume = 377 | issue = 14 | pages = 1313–1315 | date = October 2017 | pmid = 28902570 | doi = 10.1056/NEJMp1711886 | s2cid = 205114161 }} at the Weizmann Institute in Israel.{{cite journal | vauthors = Gross G, Waks T, Eshhar Z | title = Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 24 | pages = 10024–10028 | date = December 1989 | pmid = 2513569 | pmc = 298636 | doi = 10.1073/pnas.86.24.10024 | bibcode = 1989PNAS...8610024G | doi-access = free | jstor = 34790 }} Originally termed "T-bodies", these early approaches combined an antibody's ability to specifically bind to diverse targets with the constant domains of the TCR-α or TCR-β proteins.{{cite journal | vauthors = Eshhar Z, Bach N, Fitzer-Attas CJ, Gross G, Lustgarten J, Waks T, Schindler DG | title = The T-body approach: potential for cancer immunotherapy | journal = Springer Seminars in Immunopathology | volume = 18 | issue = 2 | pages = 199–209 | date = 1996 | pmid = 8908700 | doi = 10.1007/BF00820666 | s2cid = 19872173 }}
In 1991, chimeric receptors containing the intracellular signaling domain of CD3ζ were shown to activate T cell signaling by Arthur Weiss at the University of California, San Francisco.{{cite journal | vauthors = Irving BA, Weiss A | title = The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways | journal = Cell | volume = 64 | issue = 5 | pages = 891–901 | date = March 1991 | pmid = 1705867 | doi = 10.1016/0092-8674(91)90314-o | s2cid = 23466990 }} This work prompted CD3ζ intracellular domains to be added to chimeric receptors with antibody-like extracellular domains, commonly single-chain fraction variable (scFv) domains, as well as proteins such as CD4, subsequently termed first generation CARs.{{cite journal | vauthors = Hege KM, Roberts MR | title = T-cell gene therapy | journal = Current Opinion in Biotechnology | volume = 7 | issue = 6 | pages = 629–634 | date = December 1996 | pmid = 8939644 | doi = 10.1016/s0958-1669(96)80074-7 }}{{cite journal | vauthors = June CH, Sadelain M | title = Chimeric Antigen Receptor Therapy | journal = The New England Journal of Medicine | volume = 379 | issue = 1 | pages = 64–73 | date = July 2018 | pmid = 29972754 | pmc = 7433347 | doi = 10.1056/NEJMra1706169 }}
A first generation CAR containing a CD4 extracellular domain and a CD3ζ intracellular domain was used in the first clinical trial of chimeric antigen receptor T cells by the biotechnology company Cell Genesys in the mid 1990s, allowing adoptively transferred T cells to target HIV infected cells, although it failed to show any clinical improvement. Similar early clinical trials of CAR T cells in solid tumors in the 1990s using first generation CARs targeting a solid tumor antigens such as MUC1 did not show long-term persistence of the transferred T cells or result in significant remissions.{{cite journal | vauthors = Braendstrup P, Levine BL, Ruella M | title = The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19 | journal = Cytotherapy | volume = 22 | issue = 2 | pages = 57–69 | date = February 2020 | pmid = 32014447 | pmc = 7036015 | doi = 10.1016/j.jcyt.2019.12.004 }}
In the early 2000s, co-stimulatory domains such as CD28 or 4-1BB were added to first generation CAR's CD3ζ intracellular domain. Termed second generation CARs, these constructs showed greater persistence and improved tumor clearance in pre-clinical models.{{cite journal | vauthors = Sadelain M, Rivière I, Brentjens R | title = Targeting tumours with genetically enhanced T lymphocytes | journal = Nature Reviews. Cancer | volume = 3 | issue = 1 | pages = 35–45 | date = January 2003 | pmid = 12509765 | doi = 10.1038/nrc971 | s2cid = 33707802 }} Clinical trials in the early 2010s using second generation CARs targeting CD19, a protein expressed by normal B cells as well as B-cell leukemias and lymphomas, by investigators at the NCI, University of Pennsylvania, and Memorial Sloan Kettering Cancer Center demonstrated the clinical efficacy of CAR T cell therapies and resulted in complete remissions in many heavily pre-treated patients. These trials ultimately led in the US to the FDA's first two approvals of CAR T cells in 2017, those for tisagenlecleucel (Kymriah), marketed by Novartis originally for B-cell precursor acute lymphoblastic leukemia (B-ALL), and axicabtagene ciloleucel (Yescarta), marketed by Kite Pharma originally for diffuse large B-cell lymphoma (DLBCL). There are now six FDA-approved CAR T therapies.{{Cite journal | author = Center for Biologics Evaluation and Research |date=2022-03-01 |title=Approved Cellular and Gene Therapy Products |url=https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products |journal=FDA |language=en}}
Production
File:CAR-Engineered T-Cell Adoptive Transfer.jpg
The first step in the production of CAR T-cells is the isolation of T cells from human blood. CAR T-cells may be manufactured either from the patient's own blood, known as an autologous treatment, or from the blood of a healthy donor, known as an allogeneic treatment. The manufacturing process is the same in both cases; only the choice of initial blood donor is different.{{citation needed|date=March 2021}}
First, leukocytes are isolated using a blood cell separator in a process known as leukocyte apheresis. Peripheral blood mononuclear cells (PBMCs) are then separated and collected.{{cite journal | vauthors = Jin C, Yu D, Hillerdal V, Wallgren A, Karlsson-Parra A, Essand M | title = Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors | journal = Molecular Therapy: Methods & Clinical Development | volume = 1 | pages = 14001 | date = 2014-03-05 | pmid = 26015949 | pmc = 4362340 | doi = 10.1038/mtm.2014.1 }}{{Cite book |last1=Li |first1=Nan |last2=Ho |first2=Mitchell |title=Single-Domain Antibodies |date=2022 |chapter=Development of Glypican-2 Targeting Single-Domain Antibody CAR T Cells for Neuroblastoma |chapter-url=https://pubmed.ncbi.nlm.nih.gov/35157288 |series=Methods in Molecular Biology |volume=2446 |pages=451–468 |doi=10.1007/978-1-0716-2075-5_23 |issn=1940-6029 |pmid=35157288|isbn=978-1-0716-2074-8 |s2cid=246813053 }} The products of leukocyte apheresis are then transferred to a cell-processing center. In the cell processing center, specific T cells are stimulated so that they will actively proliferate and expand to large numbers. To drive their expansion, T cells are typically treated with the cytokine interleukin 2 (IL-2) and anti-CD3 antibodies.{{cite journal | vauthors = Makita S, Yoshimura K, Tobinai K | title = Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma | journal = Cancer Science | volume = 108 | issue = 6 | pages = 1109–1118 | date = June 2017 | pmid = 28301076 | pmc = 5480083 | doi = 10.1111/cas.13239 }} Anti-CD3/CD28 antibodies are also used in some protocols.
The expanded T cells are purified and then transduced with a gene encoding the engineered CAR via a retroviral vector, typically either an integrating gammaretrovirus (RV) or a lentiviral (LV) vector. These vectors are very safe in modern times due to a partial deletion of the U3 region.{{cite journal | vauthors = Jin C, Fotaki G, Ramachandran M, Nilsson B, Essand M, Yu D | title = Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer | journal = EMBO Molecular Medicine | volume = 8 | issue = 7 | pages = 702–711 | date = July 2016 | pmid = 27189167 | pmc = 4931286 | doi = 10.15252/emmm.201505869 }} The new gene editing tool CRISPR/Cas9 has recently been used instead of retroviral vectors to integrate the CAR gene into specific sites in the genome.{{cite journal | vauthors = Jensen TI, Axelgaard E, Bak RO | title = Therapeutic gene editing in haematological disorders with CRISPR/Cas9 | journal = British Journal of Haematology | volume = 185 | issue = 5 | pages = 821–835 | date = June 2019 | pmid = 30864164 | doi = 10.1111/bjh.15851 | doi-access = free }}
The patient undergoes lymphodepletion chemotherapy prior to the introduction of the engineered CAR T-cells. The depletion of the number of circulating leukocytes in the patient upregulates the number of cytokines that are produced and reduces competition for resources, which helps to promote the expansion of the engineered CAR T-cells.{{cite journal | vauthors = Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP | title = Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? | journal = Nature Clinical Practice. Oncology | volume = 3 | issue = 12 | pages = 668–681 | date = December 2006 | pmid = 17139318 | pmc = 1773008 | doi = 10.1038/ncponc0666 }}
Clinical applications
As of March 2019, there were around 364 ongoing clinical trials happening globally involving CAR T cells.{{cite journal | vauthors = Xin Yu J, Hubbard-Lucey VM, Tang J | title = The global pipeline of cell therapies for cancer | journal = Nature Reviews. Drug Discovery | volume = 18 | issue = 11 | pages = 821–822 | date = October 2019 | pmid = 31673124 | doi = 10.1038/d41573-019-00090-z | s2cid = 190862546 }} The majority of those trials target blood cancers: CAR T therapies account for more than half of all trials for hematological malignancies. CD19 continues to be the most popular antigen target,Brudno and Kochenderfer. Chimeric antigen receptor T cell therapies for lymphoma. Nature Reviews Clinical Oncology. 2018. 15: 31-46. followed by BCMA (commonly expressed in multiple myeloma).Mikkilineni and Kochenderfer. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017. 130: 2594-602 In 2016, studies began to explore the viability of other antigens, such as CD20.{{cite journal | vauthors = Almåsbak H, Aarvak T, Vemuri MC | title = CAR T Cell Therapy: A Game Changer in Cancer Treatment | journal = Journal of Immunology Research | volume = 2016 | pages = 5474602 | date = 2016 | pmid = 27298832 | pmc = 4889848 | doi = 10.1155/2016/5474602 | doi-access = free }} Trials for solid tumors are less dominated by CAR T, with about half of cell therapy-based trials involving other platforms such as NK cells.
= Cancer =
T cells are genetically engineered to express chimeric antigen receptors specifically directed toward antigens on a patient's tumor cells, then infused into the patient where they attack and kill the cancer cells.{{cite journal | vauthors = Jacobson CA, Ritz J | title = Time to put the CAR-T before the horse | journal = Blood | volume = 118 | issue = 18 | pages = 4761–4762 | date = November 2011 | pmid = 22053170 | doi = 10.1182/blood-2011-09-376137 | doi-access = free }} Adoptive transfer of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target potentially any tumor associated antigen.{{Cite journal |last1=Li |first1=Nan |last2=Spetz |first2=Madeline R. |last3=Li |first3=Dan |last4=Ho |first4=Mitchell |date=July 2021 |title=Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3 |journal=Pharmacology & Therapeutics |volume=223 |pages=107892 |doi=10.1016/j.pharmthera.2021.107892 |issn=1879-016X |pmc=8202769 |pmid=33992682}}{{Cite journal |last1=Li |first1=Dan |last2=Lin |first2=Shaoli |last3=Hong |first3=Jessica |last4=Ho |first4=Mitchell |date=2022 |title=Immunotherapy for hepatobiliary cancers: Emerging targets and translational advances |url=https://pubmed.ncbi.nlm.nih.gov/35961708 |journal=Advances in Cancer Research |volume=156 |pages=415–449 |doi=10.1016/bs.acr.2022.01.013 |issn=2162-5557 |pmid=35961708|isbn=9780323983921 |s2cid=246978004 }}
Early CAR T cell research has focused on blood cancers. The first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).{{cite journal | vauthors = Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA | display-authors = 6 | title = Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19 | journal = Blood | volume = 116 | issue = 20 | pages = 4099–4102 | date = November 2010 | pmid = 20668228 | pmc = 2993617 | doi = 10.1182/blood-2010-04-281931 | doi-access = free }}{{cite journal | vauthors = Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA | display-authors = 6 | title = 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 = Journal of Clinical Oncology | volume = 33 | issue = 6 | pages = 540–549 | date = February 2015 | pmid = 25154820 | pmc = 4322257 | doi = 10.1200/JCO.2014.56.2025 }} There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin's lymphoma; CD33, CD123, and FLT3 in acute myeloid leukemia (AML); and BCMA in multiple myeloma.{{cite journal | vauthors = Schultz L, Mackall C | title = Driving CAR T cell translation forward | journal = Science Translational Medicine | volume = 11 | issue = 481 | pages = eaaw2127 | date = February 2019 | pmid = 30814337 | doi = 10.1126/scitranslmed.aaw2127 | doi-access = free }} Aside from CD19, CARs targeting the multiple myeloma antigen B-cell maturation antigen (BCMA) have achieved the most clinical success so far.{{cite web |last1=Mikkilineni |first1=Lekha |title=CAR T cell therapies for patients with multiple myeloma |url=https://pubmed.ncbi.nlm.nih.gov/32978608/ |website=PubMed |publisher=National Library of Medicine}} CARs targeting BCMA were initially reported by Robert Carpenter and James Kochenderfer et al.{{cite journal |last1=Carpenter |first1=Robert |last2=Evbuomwan |first2=Moses |last3=Pittaluga |first3=Stefania |last4=Rose |first4=Jeremy |last5=Raffeld |first5=Mark |last6=Yang |first6=Shicheng |last7=Gress |first7=Ronald |last8=Hakim |first8=Frances |last9=Kochenderfer |first9=James |title=B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma |journal=Clinical Cancer Research |date=15 April 2013 |volume=19 |issue=8 |page=2048-2060 |doi=10.1158/1078-0432.CCR-12-2422 |pmid=23344265 |url=https://aacrjournals.org/clincancerres/article/19/8/2048/208469/B-cell-Maturation-Antigen-Is-a-Promising-Target|pmc=3630268 }}{{cite journal |last1=Ali |first1=Syed Abbas |last2=Shi |first2=Victoria |last3=Maric |first3=Irina |last4=Wang |first4=Michael |last5=Stroncek |first5=David |last6=Rose |first6=Jeremy |last7=Brudno |first7=Jennifer |last8=Stetler-Stevenson |first8=Maryalice |last9=Feldman |first9=Steven |last10=Hansen |first10=Brenna |last11=Fellowes |first11=Vicki |last12=Hakim |first12=Frances |last13=Gress |first13=Ronald |last14=Kochenderfer |first14=James |title=T cells expressing an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma |journal=Blood |date=29 September 2016 |volume=128 |issue=13 |page=1688-1700 |doi=10.1182/blood-2016-04-711903 |pmid=27412889 |url=https://ashpublications.org/blood/article/128/13/1688/35387/T-cells-expressing-an-anti-B-cell-maturation|pmc=5043125 }} Anti-BCMA CAR T cells have now been tested in many clinical trials, and anti-BCMA CAR T-cell products have been approved by the U.S. Food and Drug Administration.{{cite journal |last1=Raje |first1=Noopur |last2=Berdeja |first2=Jesus |last3=Siegel |first3=David |last4=Jagannath |first4=Sundar |last5=Madduri |first5=Deepu |last6=Liedtke |first6=Michaela |last7=Rosenblatt |first7=Jacalyn |last8=Maus |first8=Marcela |last9=Turka |first9=Ashley |last10=Lam |first10=Lyh-Ping |last11=Morgan |first11=Richard |last12=Friedman |first12=Kevin |last13=Massaro |first13=Monica |last14=Wang |first14=Julie |last15=Russotti |first15=Greg |last16=Yang |first16=Zhihong |last17=Campbell |first17=Timothy |last18=Hege |first18=Kristen |last19=Petrocca |first19=Fabio |last20=M Travis |first20=Quigley |last21=Munshi |first21=Nikhil |last22=Kochenderfer |first22=James |title=Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma |journal=The New England Journal of Medicine |date=1 May 2019 |volume=380 |issue=18 |page=1726-1737 |doi=10.1056/NEJMoa1817226 |pmid=31042825 |url=https://www.nejm.org/doi/full/10.1056/NEJMoa1817226|pmc=8202968 }}{{cite journal |last1=Berdeja |first1=Jesus |title=Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study |journal=The Lancet |date=24 July 2021 |volume=398 |issue=10297 |page=314-324 |doi=10.1016/S0140-6736(21)00933-8 |pmid=34175021}}{{cite web |title=FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-multiple-myeloma |publisher=U.S. FDA}}
CAR T cells have also been found to be effective in treating glioblastoma. A single infusion is enough to show rapid tumor regression in a matter of days. {{Cite journal |last=Choi |first=Bryan D. |last2=Gerstner |first2=Elizabeth R. |last3=Frigault |first3=Matthew J. |last4=Leick |first4=Mark B. |last5=Mount |first5=Christopher W. |last6=Balaj |first6=Leonora |last7=Nikiforow |first7=Sarah |last8=Carter |first8=Bob S. |last9=Curry |first9=William T. |last10=Gallagher |first10=Kathleen |last11=Maus |first11=Marcela V. |date=2024-04-11 |title=Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma |url=http://www.nejm.org/doi/10.1056/NEJMoa2314390 |journal=New England Journal of Medicine |language=en |volume=390 |issue=14 |pages=1290–1298 |doi=10.1056/NEJMoa2314390 |issn=0028-4793 |pmc=11162836 |pmid=38477966}}
Solid tumors have presented a more difficult target.{{cite journal | vauthors = Lim WA, June CH | title = The Principles of Engineering Immune Cells to Treat Cancer | journal = Cell | volume = 168 | issue = 4 | pages = 724–740 | date = February 2017 | pmid = 28187291 | pmc = 5553442 | doi = 10.1016/j.cell.2017.01.016 }} Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues.{{Cite journal |last1=Li |first1=Nan |last2=Fu |first2=Haiying |last3=Hewitt |first3=Stephen M. |last4=Dimitrov |first4=Dimiter S. |last5=Ho |first5=Mitchell |date=2017-08-08 |title=Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=114 |issue=32 |pages=E6623–E6631 |doi=10.1073/pnas.1706055114 |issn=1091-6490 |pmc=5559039 |pmid=28739923|bibcode=2017PNAS..114E6623L |doi-access=free }}{{Cite journal |last1=Li |first1=Nan |last2=Torres |first2=Madeline B. |last3=Spetz |first3=Madeline R. |last4=Wang |first4=Ruixue |last5=Peng |first5=Luyi |last6=Tian |first6=Meijie |last7=Dower |first7=Christopher M. |last8=Nguyen |first8=Rosa |last9=Sun |first9=Ming |last10=Tai |first10=Chin-Hsien |last11=de Val |first11=Natalia |last12=Cachau |first12=Raul |last13=Wu |first13=Xiaolin |last14=Hewitt |first14=Stephen M. |last15=Kaplan |first15=Rosandra N. |date=2021-06-15 |title=CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice|journal=Cell Reports. Medicine |volume=2 |issue=6 |pages=100297 |doi=10.1016/j.xcrm.2021.100297 |issn=2666-3791 |pmc=8233664 |pmid=34195677}} CAR T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumor microenvironment suppresses T cell activity.
= Autoimmune disease =
While most CAR T cell studies focus on creating a CAR T cell that can eradicate a certain cell population (for instance, CAR T cells that target lymphoma cells), there are other potential uses for this technology. T cells can also mediate tolerance to antigens.{{cite journal | vauthors = Sakaguchi S, Yamaguchi T, Nomura T, Ono M | title = Regulatory T cells and immune tolerance | journal = Cell | volume = 133 | issue = 5 | pages = 775–787 | date = May 2008 | pmid = 18510923 | doi = 10.1016/j.cell.2008.05.009 | s2cid = 2315895 | doi-access = free }} A regulatory T cell outfitted with a CAR could have the potential to confer tolerance to a specific antigen, something that could be utilized in organ transplantation or rheumatologic diseases like lupus.{{cite journal | vauthors = Zhang Q, Lu W, Liang CL, Chen Y, Liu H, Qiu F, Dai Z | title = Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance | journal = Frontiers in Immunology | volume = 9 | pages = 2359 | year = 2018 | pmid = 30369931 | pmc = 6194362 | doi = 10.3389/fimmu.2018.02359 | doi-access = free }}{{cite journal | vauthors = Mougiakakos D, Krönke G, Völkl S, Kretschmann S, Aigner M, Kharboutli S, Böltz S, Manger B, Mackensen A, Schett G | display-authors = 6 | title = CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus | journal = The New England Journal of Medicine | volume = 385 | issue = 6 | pages = 567–569 | date = August 2021 | pmid = 34347960 | doi = 10.1056/NEJMc2107725 | s2cid = 236927691 | doi-access = free }}{{cite journal |last1=Chung |first1=James |last2=Brudno |first2=Jennifer |last3=Borie |first3=Dominic |last4=Kochenderfer |first4=James |title=Chimeric antigen receptor T cell therapy for autoimmune disease |journal=Nature Reviews Immunology |date=3 June 2024 |page=830-845 |url=https://www.nature.com/articles/s41577-024-01035-3}}
Approved therapies
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Safety
There are serious side effects that result from CAR T-cells being introduced into the body, including cytokine release syndrome and neurotoxicity.{{cite journal |last1=Brudno |first1=Jennifer |last2=Kochenderfer |first2=James |title=Current understanding and management of CAR T cell-associated toxicities |journal=Nature Reviews Clinical Oncology |date=20 May 2024 |page=501-521 |url=https://www.nature.com/articles/s41571-024-00903-0}} Because it is a relatively new treatment, there are few data about the long-term effects of CAR T-cell therapy. There are still concerns about long-term patient survival, as well as pregnancy complications in female patients treated with CAR T-cells.{{cite journal | vauthors = Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ | title = Toxicity and management in CAR T-cell therapy | journal = Molecular Therapy: Oncolytics | volume = 3 | pages = 16011 | date = 2016 | pmid = 27626062 | pmc = 5008265 | doi = 10.1038/mto.2016.11 }} Anaphylaxis may be a side effect, as the CAR is made with a foreign monoclonal antibody, and as a result provokes an immune response.{{Cite journal |last=Wagner |first=Dimitrios L. |last2=Fritsche |first2=Enrico |last3=Pulsipher |first3=Michael A. |last4=Ahmed |first4=Nabil |last5=Hamieh |first5=Mohamad |last6=Hegde |first6=Meenakshi |last7=Ruella |first7=Marco |last8=Savoldo |first8=Barbara |last9=Shah |first9=Nirali N. |last10=Turtle |first10=Cameron J. |last11=Wayne |first11=Alan S. |last12=Abou-el-Enein |first12=Mohamed |date=25 February 2021 |title=Immunogenicity of CAR T cells in cancer therapy |url=https://www.nature.com/articles/s41571-021-00476-2 |journal=Nature Reviews Clinical Oncology |language=en |volume=18 |issue=6 |pages=379–393 |doi=10.1038/s41571-021-00476-2 |issn=1759-4782|pmc=8923136 }}
On-target/off-tumor recognition occurs when the CAR T-cell recognizes the correct antigen, but the antigen is expressed on healthy, non-pathogenic tissue. This results in the CAR T-cells attacking non-tumor tissue, such as healthy B cells that express CD19 causing B-cell aplasia. The severity of this adverse effect can vary but the combination of prior immunosuppression, lymphodepleting chemotherapy and on-target effects causing hypogammaglobulinaemia and prolonged cytopenias places patients at increased risk of serious infections.{{cite journal | vauthors = Bupha-Intr O, Haeusler G, Chee L, Thursky K, Slavin M, Teh B | title = CAR-T cell therapy and infection: a review | journal = Expert Review of Anti-Infective Therapy | volume = 19 | issue = 6 | pages = 749–758 | date = June 2021 | pmid = 33249873 | doi = 10.1080/14787210.2021.1855143 | s2cid = 227235627 }}
There is also the unlikely possibility that the engineered CAR T-cells will themselves become transformed into cancerous cells through insertional mutagenesis, due to the viral vector inserting the CAR gene into a tumor suppressor or oncogene in the host T cell's genome. Some retroviral (RV) vectors carry a lower risk than lentiviral (LV) vectors. However, both have the potential to be oncogenic. Genomic sequencing analysis of CAR insertion sites in T cells has been established for better understanding of CAR T-cell function and persistence in vivo.
= Cytokine release syndrome =
{{Main|Cytokine release syndrome}}
The most common issue after treatment with CAR T-cells is cytokine release syndrome (CRS), a condition in which the immune system is activated and releases an increased number of inflammatory cytokines. The clinical manifestation of this syndrome resembles sepsis with high fever, fatigue, myalgia, nausea, capillary leakages, tachycardia and other cardiac dysfunction, liver failure, and kidney impairment.{{cite journal | vauthors = Breslin S | title = Cytokine-release syndrome: overview and nursing implications | journal = Clinical Journal of Oncology Nursing | volume = 11 | issue = 1 Suppl | pages = 37–42 | date = February 2007 | pmid = 17471824 | doi = 10.1188/07.CJON.S1.37-42 | s2cid = 35773028 }} CRS occurs in almost all patients treated with CAR T-cell therapy; in fact, the presence of CRS is a diagnostic marker that indicates the CAR T-cells are working as intended to kill the cancer cells. The severity of CRS does not correlate with an increased response to the treatment, but rather higher disease burden. Severe cytokine release syndrome can be managed with immunosuppressants such as corticosteroids, and with tocilizumab, an anti-IL-6 monoclonal antibody.{{cite journal | vauthors = Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL | display-authors = 6 | title = Current concepts in the diagnosis and management of cytokine release syndrome | journal = Blood | volume = 124 | issue = 2 | pages = 188–195 | date = July 2014 | pmid = 24876563 | pmc = 4093680 | doi = 10.1182/blood-2014-05-552729 }} Early intervention using tocilizumab was shown to reduce the frequency of severe CRS in multiple studies{{Cite journal | vauthors = Berg P, Schönefeld S, Ruppert-Seipp G, Funk MB |date=2022-11-29 |title=Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment |journal=Transfusion Medicine and Hemotherapy |volume=50 |issue=3 |language=english |pages=218–225 |doi=10.1159/000526786 |pmid=37435000 |pmc=10331154 |issn=1660-3796|doi-access=free }}{{cite journal | vauthors = Gardner RA, Ceppi F, Rivers J, Annesley C, Summers C, Taraseviciute A, Gust J, Leger KJ, Tarlock K, Cooper TM, Finney OC, Brakke H, Li DH, Park JR, Jensen MC | display-authors = 6 | title = Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy | journal = Blood | volume = 134 | issue = 24 | pages = 2149–2158 | date = December 2019 | pmid = 31697826 | pmc = 6908832 | doi = 10.1182/blood.2019001463 }} without affecting the therapeutic effect of the treatment. A novel strategy aimed to ameliorate CRS is based on the simultaneous expression of an artificial non-signaling IL-6 receptor on the surface of CAR T-cells. {{cite journal | vauthors = Tan AH, Vinanica N, Campana D | title = Chimeric antigen receptor-T cells with cytokine neutralizing capacity | journal = Blood advances | volume = 4 | issue = 7 | pages = 1419–1431 | date = April 2020 | pmid = 32271901 | pmc = 7160280 | doi = 10.1182/bloodadvances.2019001287 }} This construct neutralizes macrophage-derived IL-6 through sequestration, thus decreasing the severity of CRS without interfering with the antitumor capability of the CAR T-cell itself.
= Immune effector cell-associated neurotoxicity =
Neurological toxicity is also often associated with CAR T-cell treatment.{{cite journal | vauthors = Brudno JN, Kochenderfer JN | title = Toxicities of chimeric antigen receptor T cells: recognition and management | journal = Blood | volume = 127 | issue = 26 | pages = 3321–3330 | date = June 2016 | pmid = 27207799 | pmc = 4929924 | doi = 10.1182/blood-2016-04-703751 }} The underlying mechanism is poorly understood, and may or may not be related to CRS. Clinical manifestations include delirium, the partial loss of the ability to speak coherently while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures. During some clinical trials, deaths caused by neurotoxicity have occurred. The main cause of death from neurotoxicity is cerebral edema. In a study carried out by Juno Therapeutics, Inc., five patients enrolled in the trial died as a result of cerebral edema. Two of the patients were treated with cyclophosphamide alone and the remaining three were treated with a combination of cyclophosphamide and fludarabine.{{Cite news|title=Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL)|work=ClinicalTrials.gov|url=https://clinicaltrials.gov/ct2/show/NCT02535364|access-date=2018-02-21}} In another clinical trial sponsored by the Fred Hutchinson Cancer Research Center, there was one reported case of irreversible and fatal neurological toxicity 122 days after the administration of CAR T-cells.{{cite journal | vauthors = Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG | display-authors = 6 | title = CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients | journal = The Journal of Clinical Investigation | volume = 126 | issue = 6 | pages = 2123–2138 | date = June 2016 | pmid = 27111235 | pmc = 4887159 | doi = 10.1172/JCI85309 }}
Hypokinetic movement disorder (parkinsonism, or movement and neurocognitive treatment emergent adverse events) has been observed with BCMA-chimeric antigen receptor (CAR) T-cell treatment for multiple myeloma.{{Cite journal |last=Gust |first=Juliane |date=October 5, 2023 |title=BCMA-CAR T-cell treatment–associated parkinsonism |url=https://ashpublications.org/blood/article/142/14/1181/498140/BCMA-CAR-T-cell-treatment-associated-parkinsonism |access-date=April 4, 2024 |journal=Blood |volume=142 |issue=14 |pages=1181–1183 |doi=10.1182/blood.2023021860|pmid=37796518 }}
Chimeric antigen receptor structure
Chimeric antigen receptors combine many facets of normal T cell activation into a single protein. They link an extracellular antigen recognition domain to an intracellular signalling domain, which activates the T cell when an antigen is bound. CARs are composed of four regions: an antigen recognition domain, an extracellular hinge region, a transmembrane domain, and an intracellular T cell signaling domain.{{cite journal | vauthors = Chandran SS, Klebanoff CA | title = T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance | journal = Immunological Reviews | volume = 290 | issue = 1 | pages = 127–147 | date = July 2019 | pmid = 31355495 | pmc = 7027847 | doi = 10.1111/imr.12772 | doi-access = free }} 50px Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].{{cite journal | vauthors = Dotti G, Gottschalk S, Savoldo B, Brenner MK | title = Design and development of therapies using chimeric antigen receptor-expressing T cells | journal = Immunological Reviews | volume = 257 | issue = 1 | pages = 107–126 | date = January 2014 | pmid = 24329793 | pmc = 3874724 | doi = 10.1111/imr.12131 }}
= Antigen recognition domain =
The antigen recognition domain is exposed to the outside of the cell, in the ectodomain portion of the receptor. It interacts with potential target molecules and is responsible for targeting the CAR T cell to any cell expressing a matching molecule.{{citation needed|date=March 2021}}
The antigen recognition domain is typically derived from the variable regions of a monoclonal antibody linked together as a single-chain variable fragment (scFv). An scFv is a chimeric protein made up of the light (VL) and heavy (VH) chains of immunoglobins, connected with a short linker peptide.{{cite journal | vauthors = Zhang C, Liu J, Zhong JF, Zhang X | title = Engineering CAR-T cells | journal = Biomarker Research | volume = 5 | pages = 22 | date = 2017-06-24 | pmid = 28652918 | pmc = 5482931 | doi = 10.1186/s40364-017-0102-y | doi-access = free }} These VL and VH regions are selected in advance for their binding ability to the target antigen (such as CD19). The linker between the two chains consists of hydrophilic residues with stretches of glycine and serine in it for flexibility as well as stretches of glutamate and lysine for added solubility.{{cite journal | vauthors = Baldo BA | title = Chimeric fusion proteins used for therapy: indications, mechanisms, and safety | journal = Drug Safety | volume = 38 | issue = 5 | pages = 455–479 | date = May 2015 | pmid = 25832756 | doi = 10.1007/s40264-015-0285-9 | s2cid = 23852865 }} Single domain antibodies (e.g. VH, VHH, VNAR) have been engineered and developed as antigen recognition domains in the CAR format due to their high transduction efficiency in T cells.{{cite journal | vauthors = Li N, Fu H, Hewitt SM, Dimitrov DS, Ho M | title = Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 32 | pages = E6623–E6631 | date = August 2017 | pmid = 28739923 | pmc = 5559039 | doi = 10.1073/pnas.1706055114 | bibcode = 2017PNAS..114E6623L | doi-access = free }}{{cite journal | vauthors = Li D, Li N, Zhang YF, Fu H, Feng M, Schneider D, Su L, Wu X, Zhou J, Mackay S, Kramer J, Duan Z, Yang H, Kolluri A, Hummer AM, Torres MB, Zhu H, Hall MD, Luo X, Chen J, Wang Q, Abate-Daga D, Dropulic B, Hewitt SM, Orentas RJ, Greten TF, Ho M | display-authors = 6 | title = Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice | journal = Gastroenterology | volume = 158 | issue = 8 | pages = 2250–2265.e20 | date = June 2020 | pmid = 32060001 | pmc = 7282931 | doi = 10.1053/j.gastro.2020.02.011 }}{{Cite journal |last1=Li |first1=Nan |last2=Quan |first2=Alex |last3=Li |first3=Dan |last4=Pan |first4=Jiajia |last5=Ren |first5=Hua |last6=Hoeltzel |first6=Gerard |last7=de Val |first7=Natalia |last8=Ashworth |first8=Dana |last9=Ni |first9=Weiming |last10=Zhou |first10=Jing |last11=Mackay |first11=Sean |last12=Hewitt |first12=Stephen M. |last13=Cachau |first13=Raul |last14=Ho |first14=Mitchell |date=2023-04-08 |title=The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer |journal=Nature Communications |language=en |volume=14 |issue=1 |pages=1986 |doi=10.1038/s41467-023-37616-4 |issn=2041-1723 |pmc=10082787 |pmid=37031249|bibcode=2023NatCo..14.1986L }}{{Cite journal |last1=Kolluri |first1=Aarti |last2=Li |first2=Dan |last3=Li |first3=Nan |last4=Duan |first4=Zhijian |last5=Roberts |first5=Lewis R. |last6=Ho |first6=Mitchell |date=2023-02-01 |title=Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC |journal=Hepatology Communications |volume=7 |issue=2 |pages=e0022 |doi=10.1097/HC9.0000000000000022 |issn=2471-254X |pmc=9851680 |pmid=36691969}}{{Cite journal |last1=Li |first1=Dan |last2=English |first2=Hejiao |last3=Hong |first3=Jessica |last4=Liang |first4=Tianyuzhou |last5=Merlino |first5=Glenn |last6=Day |first6=Chi-Ping |last7=Ho |first7=Mitchell |date=2022-03-17 |title=A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |journal=Molecular Therapy: Oncolytics |volume=24 |pages=849–863 |doi=10.1016/j.omto.2022.02.015 |issn=2372-7705 |pmc=8917269 |pmid=35317524}}
In addition to antibody fragments, non-antibody-based approaches have also been used to direct CAR specificity, usually taking advantage of ligand/receptor pairs that normally bind to each other. Cytokines, innate immune receptors, TNF receptors, growth factors, and structural proteins have all been successfully used as CAR antigen recognition domains.
= Hinge region =
The hinge, also called a spacer, is a small structural domain that sits between the antigen recognition region and the cell's outer membrane. An ideal hinge enhances the flexibility of the scFv receptor head, reducing the spatial constraints between the CAR and its target antigen. This promotes antigen binding and synapse formation between the CAR T cells and target cells.{{cite journal | vauthors = Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, Jensen MC, Riddell SR | display-authors = 6 | title = The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity | journal = Cancer Immunology Research | volume = 3 | issue = 2 | pages = 125–135 | date = February 2015 | pmid = 25212991 | pmc = 4692801 | doi = 10.1158/2326-6066.CIR-14-0127 }} Hinge sequences are often based on membrane-proximal regions from other immune molecules including IgG, CD8, and CD28.{{cite journal | vauthors = Qin L, Lai Y, Zhao R, Wei X, Weng J, Lai P, Li B, Lin S, Wang S, Wu Q, Liang Q, Li Y, Zhang X, Wu Y, Liu P, Yao Y, Pei D, Du X, Li P | display-authors = 6 | title = Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 68 | date = March 2017 | pmid = 28288656 | pmc = 5347831 | doi = 10.1186/s13045-017-0437-8 | doi-access = free }}
= Transmembrane domain =
The transmembrane domain is a structural component, consisting of a hydrophobic alpha helix that spans the cell membrane. It anchors the CAR to the plasma membrane, bridging the extracellular hinge and antigen recognition domains with the intracellular signaling region. This domain is essential for the stability of the receptor as a whole. Generally, the transmembrane domain from the most membrane-proximal component of the endodomain is used, but different transmembrane domains result in different receptor stability. The CD28 transmembrane domain is known to result in a highly expressed, stable receptor.
Using the CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial TCR into the native TCR.{{cite journal | vauthors = Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE | title = The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex | journal = Journal of Immunology | volume = 184 | issue = 12 | pages = 6938–6949 | date = June 2010 | pmid = 20483753 | doi = 10.4049/jimmunol.0901766 | doi-access = free }}
= Intracellular T cell signaling domain =
File:Depiction of 3 generations of CARs.jpgThe intracellular T cell signaling domain lies in the receptor's endodomain, inside the cell. After an antigen is bound to the external antigen recognition domain, CAR receptors cluster together and transmit an activation signal. Then the internal cytoplasmic end of the receptor perpetuates signaling inside the T cell.
Normal T cell activation relies on the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain of CD3-zeta. To mimic this process, CD3-zeta's cytoplasmic domain is commonly used as the main CAR endodomain component. Other ITAM-containing domains have also been tried, but are not as effective.
T cells also require co-stimulatory molecules in addition to CD3 signaling in order to persist after activation. For this reason, the endodomains of CAR receptors typically also include one or more chimeric domains from co-stimulatory proteins.{{cite journal | vauthors = Sadelain M, Brentjens R, Rivière I | title = The basic principles of chimeric antigen receptor design | journal = Cancer Discovery | volume = 3 | issue = 4 | pages = 388–398 | date = April 2013 | pmid = 23550147 | pmc = 3667586 | doi = 10.1158/2159-8290.CD-12-0548 }} Signaling domains from a wide variety of co-stimulatory molecules have been successfully tested, including CD28, CD27, CD134 (OX40), and CD137 (4-1BB).
The intracellular signaling domain used defines the generation of a CAR T cell. First generation CARs include only a CD3-zeta cytoplasmic domain. Second generation CARs add a co-stimulatory domain, like CD28 or 4-1BB. The involvement of these intracellular signaling domains improve T cell proliferation, cytokine secretion, resistance to apoptosis, and in vivo persistence. Third generation CARs combine multiple co-stimulatory domains, such as CD28-41BB or CD28-OX40, to augment T cell activity. Preclinical data show the third-generation CARs exhibit improved effector functions and better in vivo persistence as compared to second-generation CARs.
Research directions
= Antigen recognition =
Although the initial clinical remission rates after CAR T cell therapy in all patients are as high as 90%,{{cite press release|title=A Cure for Cancer? How CAR-T Therapy is Revolutionizing Oncology.|publisher=labiotech|date=March 8, 2018|url=https://labiotech.eu/car-t-therapy-cancer-review/|access-date=April 19, 2018}} long-term survival rates are much lower. The cause is typically the emergence of leukemia cells that do not express CD19 and so evade recognition by the CD19–CAR T cells, a phenomenon known as antigen escape. Preclinical studies developing CAR T cells with dual targeting of CD19 plus CD22 or CD19 plus CD20 have demonstrated promise, and trials studying bispecific targeting to circumvent CD19 down-regulation are ongoing.
In 2018, a version of CAR was developed that is referred to as SUPRA CAR, or split, universal, and programmable.{{cite journal| vauthors = Choe JH, Williams JZ, Lim WA |year=2020|title=Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology|journal=Annual Review of Cancer Biology|volume=4|pages=121–139|doi=10.1146/annurev-cancerbio-030419-033657|doi-access=free}} Multiple mechanisms can be deployed to finely regulate the activity of SUPRA CAR, which limits overactivation. In contrast to the traditional CAR design, SUPRA CAR allows targeting of multiple antigens without further genetic modification of a person's immune cells.{{cite journal | vauthors = Cho JH, Collins JJ, Wong WW | title = Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses | journal = Cell | volume = 173 | issue = 6 | pages = 1426–1438.e11 | date = May 2018 | pmid = 29706540 | pmc = 5984158 | doi = 10.1016/j.cell.2018.03.038 }}
Treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors.[http://endocyte.com/technology/smdc/ SMDC technology]. {{Webarchive|url=https://web.archive.org/web/20160327012636/http://endocyte.com/technology/smdc/|date=2016-03-27}} ENDOCYTE{{cite press release|title=Endocyte announces promising preclinical data for application of SMDC technology in CAR T cell therapy in late-breaking abstract at American Association for Cancer Research (AACR) annual meeting 2016|publisher=Endocyte|date=April 19, 2016|url=http://investor.endocyte.com/releasedetail.cfm?releaseid=965753|access-date=December 20, 2017|archive-url=https://web.archive.org/web/20170730115500/http://investor.endocyte.com/releasedetail.cfm?ReleaseID=965753|archive-date=July 30, 2017}}
= CAR T function =
Fourth generation CARs (also known as TRUCKs or armored CARs) further add factors that enhance T cell expansion, persistence, and anti-tumoral activity. This can include cytokines, such is IL-2, IL-5, IL-12 and co-stimulatory ligands.{{cite journal | vauthors = Kueberuwa G, Kalaitsidou M, Cheadle E, Hawkins RE, Gilham DE | title = CD19 CAR T Cells Expressing IL-12 Eradicate Lymphoma in Fully Lymphoreplete Mice through Induction of Host Immunity | journal = Molecular Therapy: Oncolytics | volume = 8 | pages = 41–51 | date = March 2018 | pmid = 29367945 | pmc = 5772011 | doi = 10.1016/j.omto.2017.12.003 }}{{cite journal | vauthors = Chmielewski M, Abken H | title = TRUCKs: the fourth generation of CARs | journal = Expert Opinion on Biological Therapy | volume = 15 | issue = 8 | pages = 1145–1154 | date = 2015 | pmid = 25985798 | doi = 10.1517/14712598.2015.1046430 | s2cid = 42535203 }}
= Control mechanisms =
Adding a synthetic control mechanism to engineered T cells allows doctors to precisely control the persistence or activity of the T cells in the patient's body, with the goal of reducing toxic side effects.{{cite journal | vauthors = Zhang E, Xu H | title = A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 1 | date = January 2017 | pmid = 28049484 | pmc = 5210295 | doi = 10.1186/s13045-016-0379-6 | doi-access = free }} The major control techniques trigger T cell death or limit T cell activation, and often regulate the T cells via a separate drug that can be introduced or withheld as needed.{{citation needed|date=March 2021}}
Suicide genes: Genetically modified T cells are engineered to include one or more genes that can induce apoptosis when activated by an extracellular molecule. Herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase 9 (iCasp9) are two types of suicide genes that have been integrated into CAR T cells.{{cite journal | vauthors = Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C | display-authors = 6 | title = HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia | journal = Science | volume = 276 | issue = 5319 | pages = 1719–1724 | date = June 1997 | pmid = 9180086 | doi = 10.1126/science.276.5319.1719 }}{{cite journal | vauthors = Quintarelli C, Vera JF, Savoldo B, Giordano Attianese GM, Pule M, Foster AE, Heslop HE, Rooney CM, Brenner MK, Dotti G | display-authors = 6 | title = Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes | journal = Blood | volume = 110 | issue = 8 | pages = 2793–2802 | date = October 2007 | pmid = 17638856 | pmc = 2018664 | doi = 10.1182/blood-2007-02-072843 }} In the iCasp9 system, the suicide gene complex has two elements: a mutated FK506-binding protein with high specificity to the small molecule rimiducid/AP1903, and a gene encoding a pro-domain-deleted human caspase 9. Dosing the patient with rimiducid activates the suicide system, leading to rapid apoptosis of the genetically modified T cells. Although both the HSV-TK and iCasp9 systems demonstrate a noticeable function as a safety switch in clinical trials, some defects limit their application. HSV-TK is virus-derived and may be immunogenic to humans.{{cite journal | vauthors = Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, Lupton SD, Overell RW, Reynolds TC, Corey L, Greenberg PD | display-authors = 6 | title = T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients | journal = Nature Medicine | volume = 2 | issue = 2 | pages = 216–223 | date = February 1996 | pmid = 8574968 | doi = 10.1038/nm0296-216 | s2cid = 35503876 }} It is also currently unclear whether the suicide gene strategies will act quickly enough in all situations to halt dangerous off-tumor cytotoxicity.{{citation needed|date=March 2021}}
Dual-antigen receptor: CAR T cells are engineered to express two tumor-associated antigen receptors at the same time, reducing the likelihood that the T cells will attack non-tumor cells. Dual-antigen receptor CAR T cells have been reported to have less intense side effects.{{cite journal | vauthors = Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M | title = Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor | journal = Nature Biotechnology | volume = 20 | issue = 1 | pages = 70–75 | date = January 2002 | pmid = 11753365 | doi = 10.1038/nbt0102-70 | s2cid = 20302096 | title-link = T-cell receptor }} An in vivo study in mice shows that dual-receptor CAR T cells effectively eradicated prostate cancer and achieved complete long-term survival.{{cite journal | vauthors = Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, Burbridge SE, Box C, Eccles SA, Maher J | display-authors = 6 | title = Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling | journal = Journal of Clinical Immunology | volume = 32 | issue = 5 | pages = 1059–1070 | date = October 2012 | pmid = 22526592 | doi = 10.1007/s10875-012-9689-9 | s2cid = 17660404 }}
ON-switch and OFF-switch: In this system, CAR T cells can only function in the presence of both tumor antigen and a benign exogenous molecule. To achieve this, the CAR T cell's engineered chimeric antigen receptor is split into two separate proteins that must come together in order to function. The first receptor protein typically contains the extracellular antigen binding domain, while the second protein contains the downstream signaling elements and co-stimulatory molecules (such as CD3ζ and 4-1BB). In the presence of an exogenous molecule (such as a rapamycin analog), the binding and signaling proteins dimerize together, allowing the CAR T cells to attack the tumor.{{cite journal | vauthors = Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA | title = Remote control of therapeutic T cells through a small molecule-gated chimeric receptor | journal = Science | volume = 350 | issue = 6258 | pages = aab4077 | date = October 2015 | pmid = 26405231 | pmc = 4721629 | doi = 10.1126/science.aab4077 | bibcode = 2015Sci...350.4077W }} Human EGFR truncated form (hEGFRt) has been used as an OFF-switch for CAR T cells using cetuximab.
Bispecific molecules as switches: Bispecific molecules target both a tumor-associated antigen and the CD3 molecule on the surface of T cells. This ensures that the T cells cannot become activated unless they are in close physical proximity to a tumor cell.{{cite journal | vauthors = Frankel SR, Baeuerle PA | title = Targeting T cells to tumor cells using bispecific antibodies | journal = Current Opinion in Chemical Biology | volume = 17 | issue = 3 | pages = 385–392 | date = June 2013 | pmid = 23623807 | doi = 10.1016/j.cbpa.2013.03.029 }} The anti-CD20/CD3 bispecific molecule shows high specificity to both malignant B cells and cancer cells in mice.{{cite journal | vauthors = Sun LL, Ellerman D, Mathieu M, Hristopoulos M, Chen X, Li Y, Yan X, Clark R, Reyes A, Stefanich E, Mai E, Young J, Johnson C, Huseni M, Wang X, Chen Y, Wang P, Wang H, Dybdal N, Chu YW, Chiorazzi N, Scheer JM, Junttila T, Totpal K, Dennis MS, Ebens AJ | display-authors = 6 | title = Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies | journal = Science Translational Medicine | volume = 7 | issue = 287 | pages = 287ra70 | date = May 2015 | pmid = 25972002 | doi = 10.1126/scitranslmed.aaa4802 | s2cid = 24939667 }} FITC is another bifunctional molecule used in this strategy. FITC can redirect and regulate the activity of the FITC-specific CAR T cells toward tumor cells with folate receptors.{{cite journal | vauthors = Kim CH, Axup JY, Lawson BR, Yun H, Tardif V, Choi SH, Zhou Q, Dubrovska A, Biroc SL, Marsden R, Pinstaff J, Smider VV, Schultz PG | display-authors = 6 | title = Bispecific small molecule-antibody conjugate targeting prostate cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 44 | pages = 17796–17801 | date = October 2013 | pmid = 24127589 | pmc = 3816437 | doi = 10.1073/pnas.1316026110 | bibcode = 2013PNAS..11017796K | doi-access = free }}
= Advances in CAR T cell manufacturing. =
Due to the high costs of CAR T cell therapy, a number of alternative efforts are being investigated to improve CAR T cell manufacturing and reduce costs. In vivo CAR T cell manufacturing strategies{{Cite journal |last1=Smith |first1=Tyrel T. |last2=Stephan |first2=Sirkka B. |last3=Moffett |first3=Howell F. |last4=McKnight |first4=Laura E. |last5=Ji |first5=Weihang |last6=Reiman |first6=Diana |last7=Bonagofski |first7=Emmy |last8=Wohlfahrt |first8=Martin E. |last9=Pillai |first9=Smitha P. S. |last10=Stephan |first10=Matthias T. |date=2017-04-17 |title=In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers |url=http://dx.doi.org/10.1038/nnano.2017.57 |journal=Nature Nanotechnology |volume=12 |issue=8 |pages=813–820 |doi=10.1038/nnano.2017.57 |pmid=28416815 |pmc=5646367 |issn=1748-3387}}{{Cite journal |last1=Agarwal |first1=Shiwani |last2=Weidner |first2=Tatjana |last3=Thalheimer |first3=Frederic B. |last4=Buchholz |first4=Christian J. |date=2019-10-10 |title=In vivo generated human CAR T cells eradicate tumor cells |url=http://dx.doi.org/10.1080/2162402x.2019.1671761 |journal=OncoImmunology |volume=8 |issue=12 |pages=e1671761 |doi=10.1080/2162402x.2019.1671761 |pmid=31741773 |pmc=6844313 |issn=2162-402X}} are being tested. In addition, bioinstructive materials have been developed for CAR T cell generation.{{Cite journal |last1=Agarwalla |first1=Pritha |last2=Ogunnaike |first2=Edikan A. |last3=Ahn |first3=Sarah |last4=Froehlich |first4=Kristen A. |last5=Jansson |first5=Anton |last6=Ligler |first6=Frances S. |last7=Dotti |first7=Gianpietro |last8=Brudno |first8=Yevgeny |date=2022-03-24 |title=Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells |url=http://dx.doi.org/10.1038/s41587-022-01245-x |journal=Nature Biotechnology |volume=40 |issue=8 |pages=1250–1258 |doi=10.1038/s41587-022-01245-x |pmid=35332339 |pmc=9376243 |issn=1087-0156}} Rapid CAR T cell generation is also possible through shortening or eliminating the activation and expansion steps.{{Cite journal |last1=Ghassemi |first1=Saba |last2=Durgin |first2=Joseph S. |last3=Nunez-Cruz |first3=Selene |last4=Patel |first4=Jai |last5=Leferovich |first5=John |last6=Pinzone |first6=Marilia |last7=Shen |first7=Feng |last8=Cummins |first8=Katherine D. |last9=Plesa |first9=Gabriela |last10=Cantu |first10=Vito Adrian |last11=Reddy |first11=Shantan |last12=Bushman |first12=Frederic D. |last13=Gill |first13=Saar I. |last14=O'Doherty |first14=Una |last15=O'Connor |first15=Roddy S. |date=February 2022 |title=Rapid manufacturing of non-activated potent CAR T cells |journal=Nature Biomedical Engineering |language=en |volume=6 |issue=2 |pages=118–128 |doi=10.1038/s41551-021-00842-6 |pmid=35190680 |pmc=8860360 |issn=2157-846X}}
= In situ modification =
Another approach is to modify T cells and/or B cells still in the body using viral vectors.{{Cite journal |last=Ledford |first=Heidi |date=2023-12-20 |title=Cancer-fighting CAR-T cells could be made inside body with viral injection |url=https://www.nature.com/articles/d41586-023-03969-5 |journal=Nature |volume=625 |issue=7994 |pages=225–226 |language=en |doi=10.1038/d41586-023-03969-5|pmid=38129613 |url-access=subscription }}
= Alternative Activating Domains =
Recent advancements in CAR T-cell therapy have focused on alternative activating domains to enhance efficacy and overcome resistance in solid tumors. For instance, Toll-like receptor 4{{Cite journal |last1=Chakraborty |first1=Samik |last2=Ye |first2=Juan |last3=Wang |first3=Herui |last4=Sun |first4=Mitchell |last5=Zhang |first5=Yaping |last6=Sang |first6=Xueyu |last7=Zhuang |first7=Zhengping |date=2023-10-23 |title=Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy |journal=Frontiers in Immunology |language=English |volume=14 |doi=10.3389/fimmu.2023.1227833 |doi-access=free |pmid=37936697 |issn=1664-3224|pmc=10626551 }}{{Cite journal |last1=Mikolič |first1=Veronika |last2=Pantović-Žalig |first2=Jelica |last3=Malenšek |first3=Špela |last4=Sever |first4=Matjaž |last5=Lainšček |first5=Duško |last6=Jerala |first6=Roman |date=June 2024 |title=Toll-like receptor 4 signaling activation domains promote CAR T cell function against solid tumors |url=https://doi.org/10.1016/j.omton.2024.200815 |journal=Molecular Therapy: Oncology |volume=32 |issue=2 |pages=200815 |doi=10.1016/j.omton.2024.200815 |pmid=38840781 |issn=2950-3299|pmc=11152746 }}{{Cite journal |last1=Chen |first1=Xue |last2=Zhang |first2=Yunxiao |last3=Fu |first3=Yao |date=2022-06-01 |title=The critical role of Toll-like receptor-mediated signaling in cancer immunotherapy |journal=Medicine in Drug Discovery |volume=14 |pages=100122 |doi=10.1016/j.medidd.2022.100122 |issn=2590-0986|doi-access=free }} (TLR4) signaling components can be incorporated into CAR constructs to modulate cytokine production and boost T-cell activation and proliferation, leading to enhanced CAR T-cell expansion and persistence. Similarly, the FYN kinase,{{Cite journal |last1=Wu |first1=Ling |last2=Brzostek |first2=Joanna |last3=Sakthi Vale |first3=Previtha Dawn |last4=Wei |first4=Qianru |last5=Koh |first5=Clara K. T. |last6=Ong |first6=June Xu Hui |last7=Wu |first7=Liang-Zhe |last8=Tan |first8=Jia Chi |last9=Chua |first9=Yen Leong |last10=Yap |first10=Jiawei |last11=Song |first11=Yuan |last12=Tan |first12=Vivian Jia Yi |last13=Tan |first13=Triscilla Y. Y. |last14=Lai |first14=Junyun |last15=MacAry |first15=Paul A. |date=2023-02-21 |title=CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance |journal=Cell Reports. Medicine |volume=4 |issue=2 |pages=100917 |doi=10.1016/j.xcrm.2023.100917 |issn=2666-3791 |pmc=9975250 |pmid=36696897}} a member of the Src family kinases involved in T-cell receptor signaling, can be integrated to improve the signaling cascade within CAR T-cells, resulting in better targeting and elimination of cancer cells. Additionally, KIR-based CARs{{Cite journal |last1=Wang |first1=Enxiu |last2=Wang |first2=Liang-Chuan |last3=Tsai |first3=Ching-Yi |last4=Bhoj |first4=Vijay |last5=Gershenson |first5=Zack |last6=Moon |first6=Edmund |last7=Newick |first7=Kheng |last8=Sun |first8=Jing |last9=Lo |first9=Albert |last10=Baradet |first10=Timothy |last11=Feldman |first11=Michael D. |last12=Barrett |first12=David |last13=Puré |first13=Ellen |last14=Albelda |first14=Steven |last15=Milone |first15=Michael C. |date=July 2015 |title=Generation of Potent T-cell Immunotherapy for Cancer using DAP12-based, Multichain, Chimeric Immunoreceptors |journal=Cancer Immunology Research |volume=3 |issue=7 |pages=815–826 |doi=10.1158/2326-6066.CIR-15-0054 |issn=2326-6066 |pmc=4490943 |pmid=25941351}}{{Cite web |date=2022-09-25 |title=First-in-Human Trial to Assess KIR-CAR T-Cell Therapy in MSLN+ Solid Tumors |url=https://www.cgtlive.com/view/first-in-human-trial-kir-car-t-cell-therapy-msln-solid-tumors |access-date=2024-06-05 |website=CGTlive™ |language=en}}{{Cite journal |date=May 2014 |title=152. A Chimeric Antigen Receptor (CARs) Based Upon a Killer Immunoglobulin-Like Receptor (KIR) Triggers Robust Cytotoxic Activity in Solid Tumors |journal=Molecular Therapy |volume=22 |pages=S57 |doi=10.1016/s1525-0016(16)35165-6 |issn=1525-0016|doi-access=free }}{{Cite journal |last1=Xu |first1=Jun |last2=Nunez-Cruz |first2=Selene |last3=Leferovich |first3=John M. |last4=Gulendran |first4=Gayathri |last5=Zhang |first5=Chune |last6=Yucel |first6=Nora D. |last7=Blair |first7=Megan C. |last8=Stanley |first8=William S. |last9=Johnson |first9=Laura A. |last10=Siegel |first10=Don L. |last11=Milone |first11=Michael C. |date=2024-03-22 |title=Abstract 6332: Evaluating the relationship of affinity, functional avidity, and in vivo potency in KIR-CAR T cells |url=https://aacrjournals.org/cancerres/article/84/6_Supplement/6332/735622/Abstract-6332-Evaluating-the-relationship-of |journal=Cancer Research |language=en |volume=84 |issue=6_Supplement |pages=6332 |doi=10.1158/1538-7445.AM2024-6332 |issn=1538-7445|url-access=subscription }} (KIR-CAR), which use the transmembrane and intracellular domains of the activating receptor KIR2DS2 combined with the DAP-12 signaling adaptor, have shown improved T-cell proliferation and antitumor activity. These strategies, including the use of nonconventional costimulatory molecules like MyD88/CD40,{{Cite journal |last1=Prinzing |first1=Brooke |last2=Schreiner |first2=Patrick |last3=Bell |first3=Matthew |last4=Fan |first4=Yiping |last5=Krenciute |first5=Giedre |last6=Gottschalk |first6=Stephen |date=2020-11-05 |title=MyD88/CD40 signaling retains CAR T cells in a less differentiated state |journal=JCI Insight |volume=5 |issue=21 |pages=e136093, 136093 |doi=10.1172/jci.insight.136093 |issn=2379-3708 |pmc=7710311 |pmid=33148882}}{{Cite journal |last1=Collinson-Pautz |first1=Matthew R. |last2=Chang |first2=Wei-Chun |last3=Lu |first3=An |last4=Khalil |first4=Mariam |last5=Crisostomo |first5=Jeannette W. |last6=Lin |first6=Pei-Yi |last7=Mahendravada |first7=Aruna |last8=Shinners |first8=Nicholas P. |last9=Brandt |first9=Mary E. |last10=Zhang |first10=Ming |last11=Duong |first11=MyLinh |last12=Bayle |first12=J. Henri |last13=Slawin |first13=Kevin M. |last14=Spencer |first14=David M. |last15=Foster |first15=Aaron E. |date=September 2019 |title=Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies |journal=Leukemia |language=en |volume=33 |issue=9 |pages=2195–2207 |doi=10.1038/s41375-019-0417-9 |pmid=30816327 |issn=1476-5551|pmc=6756044 }} highlight the innovative approaches being taken to optimize CAR T-cell therapies for more effective cancer treatments.
Economics
The cost of CAR T cell therapies has been criticized, with the initial costs of tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) being $375,000 and $475,000 respectively.{{cite journal | vauthors = Lyman GH, Nguyen A, Snyder S, Gitlin M, Chung KC | title = Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma | journal = JAMA Network Open | volume = 3 | issue = 4 | pages = e202072 | date = April 2020 | pmid = 32250433 | pmc = 7136832 | doi = 10.1001/jamanetworkopen.2020.2072 }} The high cost of CAR T therapies is due to complex cellular manufacturing in specialized good manufacturing practice (GMP) facilities as well as the high level of hospital care necessary 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 Medicare and by many but not all private insurers.{{Cite web|title=Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)|url=https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=291|access-date=2021-03-22|website=www.cms.gov|language=en-US}}{{Cite web|title=CAR T-cell Therapy: An Update on Coverage and Reimbursement - Hematology.org|url=https://www.hematology.org/advocacy/policy-news/2019/car-t-cell-therapy-an-update-on-coverage-and-reimbursement|access-date=2021-03-22|website=www.hematology.org|language=en|archive-date=2022-01-24|archive-url=https://web.archive.org/web/20220124001132/https://www.hematology.org/advocacy/policy-news/2019/car-t-cell-therapy-an-update-on-coverage-and-reimbursement|url-status=dead}} Manufacturers of CAR T cells have developed alternative payment programs due to the high cost of CAR T therapy, such as by requiring payment only if the CAR T therapy induces a complete remission by a certain time point after treatment.{{cite journal | vauthors = Fiorenza S, Ritchie DS, Ramsey SD, Turtle CJ, Roth JA | title = Value and affordability of CAR T-cell therapy in the United States | journal = Bone Marrow Transplantation | volume = 55 | issue = 9 | pages = 1706–1715 | date = September 2020 | pmid = 32474570 | doi = 10.1038/s41409-020-0956-8 | s2cid = 218987876 }}
Additionally, CAR T cell therapies are not available worldwide yet. CAR T cell therapies have been approved in China, Australia, Singapore, the United Kingdom, and some European countries.{{cite web | vauthors = Eder M |title=Which countries is CAR T-cell therapy available in? {{!}} SingleUseSupport |url=https://www.susupport.com/which-countries-car-t-cell-therapy-available/ |access-date=13 May 2022 |date=25 November 2021}} In February 2022 Brazil approved tisagenlecleucel (Kymriah) treatment.{{Cite web |date=2022-02-23 |title=Anvisa aprova produto de terapia avançada para tratamento de câncer |url=https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2022/anvisa-aprova-produto-de-terapia-avancada-para-tratamento-de-cancer |access-date=2022-06-07 |website=Agência Nacional de Vigilância Sanitária - Anvisa |language=pt-br}}
See also
References
{{reflist}}
External links
- [https://www.cancer.gov/about-cancer/treatment/research/car-t-cells CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers]. National Cancer Institute, July 2019