CAR T cell - Knowledge

1335:(iCasp9) are two types of suicide genes that have been integrated into CAR T cells. 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. It is also currently unclear whether the suicide gene strategies will act quickly enough in all situations to halt dangerous off-tumor cytotoxicity. 1347:: 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. Human EGFR truncated form (hEGFRt) has been used as an OFF-switch for CAR T cells using 306: 1218: 498: 31: 1341:: 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. An in vivo study in mice shows that dual-receptor CAR T cells effectively eradicated prostate cancer and achieved complete long-term survival. 1261:

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.

4506: 3827: 1357:: 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. The anti-CD20/CD3 bispecific molecule shows high specificity to both malignant B cells and cancer cells in mice. 1089: 336:(PBMCs) are then separated and collected. 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 1225:

The 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

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monoclonal antibody. Early intervention using tocilizumab was shown to reduce the frequency of severe CRS in multiple studies 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

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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. Clinical trials in the early 2010s using second generation CARs targeting CD19, a protein expressed by normal

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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

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Although the initial clinical remission rates after CAR T cell therapy in all patients are as high as 90%, 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

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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

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As of March 2019, there were around 364 ongoing clinical trials happening globally involving CAR T cells. 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,

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CARs (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

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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. Signaling domains from a wide variety of co-stimulatory molecules have been successfully

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and other cardiac dysfunction, liver failure, and kidney impairment. 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

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In 2018, a version of CAR was developed that is referred to as SUPRA CAR, or split, universal, and programmable. 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

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Neurological toxicity is also often associated with CAR T-cell treatment. 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

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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

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Solid tumors have presented a more difficult target. 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. CAR T cells are also not trafficked efficiently into the center of solid tumor

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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. The major control techniques trigger T cell death or limit T cell activation, and often

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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

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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

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Collinson-Pautz, Matthew R.; Chang, Wei-Chun; Lu, An; Khalil, Mariam; Crisostomo, Jeannette W.; Lin, Pei-Yi; Mahendravada, Aruna; Shinners, Nicholas P.; Brandt, Mary E.; Zhang, Ming; Duong, MyLinh; Bayle, J. Henri; Slawin, Kevin M.; Spencer, David M.; Foster, Aaron E. (September 2019).

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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.

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Ghassemi, Saba; Durgin, Joseph S.; Nunez-Cruz, Selene; Patel, Jai; Leferovich, John; Pinzone, Marilia; Shen, Feng; Cummins, Katherine D.; Plesa, Gabriela; Cantu, Vito Adrian; Reddy, Shantan; Bushman, Frederic D.; Gill, Saar I.; O'Doherty, Una; O'Connor, Roddy S. (February 2022).

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and by many but not all private insurers. 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.

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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. The high cost of CAR T therapies is due to complex cellular manufacturing in specialized

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and neurological toxicity. 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.

119:. 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 95:

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.

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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

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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

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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. A

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Wu, Ling; Brzostek, Joanna; Sakthi Vale, Previtha Dawn; Wei, Qianru; Koh, Clara K. T.; Ong, June Xu Hui; Wu, Liang-Zhe; Tan, Jia Chi; Chua, Yen Leong; Yap, Jiawei; Song, Yuan; Tan, Vivian Jia Yi; Tan, Triscilla Y. Y.; Lai, Junyun; MacAry, Paul A. (2023-02-21).

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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

970:. 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. 1000:

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

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Li, Nan; Torres, Madeline B.; Spetz, Madeline R.; Wang, Ruixue; Peng, Luyi; Tian, Meijie; Dower, Christopher M.; Nguyen, Rosa; Sun, Ming; Tai, Chin-Hsien; de Val, Natalia; Cachau, Raul; Wu, Xiaolin; Hewitt, Stephen M.; Kaplan, Rosandra N. (2021-06-15).

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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.

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Wang, Enxiu; Wang, Liang-Chuan; Tsai, Ching-Yi; Bhoj, Vijay; Gershenson, Zack; Moon, Edmund; Newick, Kheng; Sun, Jing; Lo, Albert; Baradet, Timothy; Feldman, Michael D.; Barrett, David; Puré, Ellen; Albelda, Steven; Milone, Michael C. (July 2015).

1397:(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, a member of the 3670: 5586:

Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, et al. (October 2012). "Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling".

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receptor on the surface of CAR T-cells. 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.

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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. In February 2022 Brazil approved

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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.

1279:. 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. 391:). In 2016, studies began to explore the viability of other antigens, such as CD20. Trials for solid tumors are less dominated by CAR T, with about half of cell therapy-based trials involving other platforms such as 111:). 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. 403:

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.

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Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, et al. (December 1987). "Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions".

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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

1427:(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 1067:

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.

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Xu, Jun; Nunez-Cruz, Selene; Leferovich, John M.; Gulendran, Gayathri; Zhang, Chune; Yucel, Nora D.; Blair, Megan C.; Stanley, William S.; Johnson, Laura A.; Siegel, Don L.; Milone, Michael C. (2024-03-22).

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Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, et al. (February 1996). "T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients".

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Li, Nan; Quan, Alex; Li, Dan; Pan, Jiajia; Ren, Hua; Hoeltzel, Gerard; de Val, Natalia; Ashworth, Dana; Ni, Weiming; Zhou, Jing; Mackay, Sean; Hewitt, Stephen M.; Cachau, Raul; Ho, Mitchell (2023-04-08).

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Smith, Tyrel T.; Stephan, Sirkka B.; Moffett, Howell F.; McKnight, Laura E.; Ji, Weihang; Reiman, Diana; Bonagofski, Emmy; Wohlfahrt, Martin E.; Pillai, Smitha P. S.; Stephan, Matthias T. (2017-04-17).

5238:"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" 216:

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

3554: 3477: 3760:"U.S. Food and Drug Administration Approves Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel), a New CAR T Cell Therapy for Adults with Relapsed or Refractory Large B-cell Lymphoma" 6668: 5411:

Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, et al. (June 1997). "HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia".

2885:"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" 1294:

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

1237:. 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. 5025:"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" 3366:"Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah(TM) (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice" 1401:

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,

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Depiction of first, second, and third generation chimeric antigen receptors with the scFv segments in green and the various intracellular TCR signaling components in red, blue and yellow

3524:"Yescarta® (Axicabtagene Ciloleucel) Receives European Marketing Authorization for the Treatment of Relapsed or Refractory DLBCL and PMBCL, After Two or More Lines of Systemic Therapy" 142:. 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 5722:

Sun LL, Ellerman D, Mathieu M, Hristopoulos M, Chen X, Li Y, et al. (May 2015). "Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies".

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antigen binding and synapse formation between the CAR T cells and target cells. Hinge sequences are often based on membrane-proximal regions from other immune molecules including

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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

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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

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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.

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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

3388: 3623:"Kite's CAR T-cell Therapy Yescarta® First in Europe to Receive Positive CHMP Opinion for Use in Second-line Diffuse Large B-cell Lymphoma and High-grade B-cell Lymphoma" 1987:

Irving BA, Weiss A (March 1991). "The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways".

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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

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Recent advancements in CAR T-cell therapy have focused on alternative activating domains to enhance efficacy and overcome resistance in solid tumors. For instance,

1052:. 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 1377:

have been developed for CAR T cell generation. Rapid CAR T cell generation is also possible through shortening or eliminating the activation and expansion steps.

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Agarwalla, Pritha; Ogunnaike, Edikan A.; Ahn, Sarah; Froehlich, Kristen A.; Jansson, Anton; Ligler, Frances S.; Dotti, Gianpietro; Brudno, Yevgeny (2022-03-24).

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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

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Gross G, Gorochov G, Waks T, Eshhar Z (February 1989). "Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity".

6589:"Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies" 2215: 6491: 2235:"Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors" 1402: 689: 162:

was described in 1987 by Yoshihisa Kuwana et al. at Fujita Health University and Kyowa Hakko Kogyo, Co. Ltd. in Japan, and independently in 1989 by

6450:"152. A Chimeric Antigen Receptor (CARs) Based Upon a Killer Immunoglobulin-Like Receptor (KIR) Triggers Robust Cytotoxic Activity in Solid Tumors" 6676: 5831:"Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma" 1944:

Eshhar Z, Bach N, Fitzer-Attas CJ, Gross G, Lustgarten J, Waks T, Schindler DG (1996). "The T-body approach: potential for cancer immunotherapy".

765: 635: 202: 4404: 3741: 2834:"Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19" 4741:"The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer" 3604: 1490: 1061: 609: 262: 6697:

Fiorenza S, Ritchie DS, Ramsey SD, Turtle CJ, Roth JA (September 2020). "Value and affordability of CAR T-cell therapy in the United States".

3671:"Kite's CAR T-cell Therapy Yescarta® Granted European Marketing Authorization for the Treatment of Relapsed or Refractory Follicular Lymphoma" 1129:

regions are selected in advance for their binding ability to the target antigen (such as CD19). The linker between the two chains consists of

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correlate with an increased response to the treatment, but rather higher disease burden. Severe cytokine release syndrome can be managed with

5237: 2308: 1161:) have been engineered and developed as antigen recognition domains in the CAR format due to their high transduction efficiency in T cells. 408:

of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target potentially any

3038:"Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice" 1048:), and seizures. During some clinical trials, deaths caused by neurotoxicity have occurred. The main cause of death from neurotoxicity is 1286:

Treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors.

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There is also the unlikely possibility that the engineered CAR T-cells will themselves become transformed into cancerous cells through

3828:"FDA D.I.S.C.O. Burst Edition: FDA approval of Breyanzi (lisocabtagene maraleucel) for second-line treatment of large B-cell lymphoma" 935: 830: 778: 726: 659: 205:. This work prompted CD3ζ intracellular domains to be added to chimeric receptors with antibody-like extracellular domains, commonly 4676:"Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma" 3087:"Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma" 2792: 884: 538: 333: 108: 1064:, there was one reported case of irreversible and fatal neurological toxicity 122 days after the administration of CAR T-cells. 3478:"Novartis Kymriah® receives EC approval as first CAR-T cell therapy for adults with relapsed or refractory follicular lymphoma" 366:(LV) vector. These vectors are very safe in modern times due to a partial deletion of the U3 region. The new gene editing tool 6424: 621: 206: 3787: 6805: 6644: 5448:"Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes" 640: 424: 294: 3719: 1414:, highlight the innovative approaches being taken to optimize CAR T-cell therapies for more effective cancer treatments. 3989:

Bupha-Intr O, Haeusler G, Chee L, Thursky K, Slavin M, Teh B (June 2021). "CAR-T cell therapy and infection: a review".

3647:"U.S. FDA Approves Yescarta® for Relapsed or Refractory Follicular Lymphoma After Two or More Lines of Systemic Therapy" 1879:"Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity" 282: 270: 6529:

Prinzing, Brooke; Schreiner, Patrick; Bell, Matthew; Fan, Yiping; Krenciute, Giedre; Gottschalk, Stephen (2020-11-05).

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Mikolič, Veronika; Pantović-Žalig, Jelica; Malenšek, Špela; Sever, Matjaž; Lainšček, Duško; Jerala, Roman (June 2024).

4925:"The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity" 4868:"A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer" 174:

in Israel. Originally termed "T-bodies", these early approaches combined an antibody's ability to specifically bind to

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Chakraborty, Samik; Ye, Juan; Wang, Herui; Sun, Mitchell; Zhang, Yaping; Sang, Xueyu; Zhuang, Zhengping (2023-10-23).

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Li, Dan; English, Hejiao; Hong, Jessica; Liang, Tianyuzhou; Merlino, Glenn; Day, Chi-Ping; Ho, Mitchell (2022-03-17).

3454:"FDA approves Novartis Kymriah® CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma" 2883:

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. (February 2015).

1424: 5265:"CD19 CAR T Cells Expressing IL-12 Eradicate Lymphoma in Fully Lymphoreplete Mice through Induction of Host Immunity" 4811:"Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC" 321:

treatment. The manufacturing process is the same in both cases; only the choice of initial blood donor is different.

6492:"Abstract 6332: Evaluating the relationship of affinity, functional avidity, and in vivo potency in KIR-CAR T cells" 3809:"CAR T Cell Therapy Breyanzi® Approved as Relapsed or Refractory Large B-cell Lymphoma Second-Line Therapy in Japan" 1358: 258: 5220: 370:

has recently been used instead of retroviral vectors to integrate the CAR gene into specific sites in the genome.

4185:"Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy" 1109:

linked together as a single-chain variable fragment (scFv). An scFv is a chimeric protein made up of the light (V

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Sadelain M, Rivière I, Brentjens R (January 2003). "Targeting tumours with genetically enhanced T lymphocytes".

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Using the CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial

427:(DLBCL). There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including 2832:

Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. (November 2010).

1624:"Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts" 1428: 786: 409: 266: 198: 6369:"Generation of Potent T-cell Immunotherapy for Cancer using DAP12-based, Multichain, Chimeric Immunoreceptors" 305: 3849: 2402:"Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer" 2353:"Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma" 1374: 974: 900: 667: 351: 286: 73: 6791:

CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. National Cancer Institute July 2019

3417: 6815: 6741: 6311:"CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance" 4331:"Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL)" 1015: 838: 464: 448: 405: 5446:

Quintarelli C, Vera JF, Savoldo B, Giordano Attianese GM, Pule M, Foster AE, et al. (October 2007).

6810: 5541:"Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor" 2124:"The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19" 1673:"Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy" 4631:

Baldo BA (May 2015). "Chimeric fusion proteins used for therapy: indications, mechanisms, and safety".

3389:"Novartis receives European Commission approval of its CAR-T cell therapy, Kymriah® (tisagenlecleucel)" 2546:

Xin Yu J, Hubbard-Lucey VM, Tang J (October 2019). "The global pipeline of cell therapies for cancer".

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There are serious side effects that result from CAR T-cells being introduced into the body, including

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Frankel SR, Baeuerle PA (June 2013). "Targeting T cells to tumor cells using bispecific antibodies".

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Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, et al. (February 2015).

4752: 4687: 3098: 1890: 1454: 1394: 1082: 904: 850: 798: 760: 6212:"Toll-like receptor 4 signaling activation domains promote CAR T cell function against solid tumors" 4183:

Gardner RA, Ceppi F, Rivers J, Annesley C, Summers C, Taraseviciute A, et al. (December 2019).

3586:"Yescarta® Now Approved in Japan for Initial Treatment of Relapsed/Refractory Large B-Cell Lymphoma" 3313:

Mougiakakos D, Krönke G, Völkl S, Kretschmann S, Aigner M, Kharboutli S, et al. (August 2021).

6153:"Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy" 5066:"Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes" 1106: 959: 646: 392: 329: 318: 314: 229:

did not show long-term persistence of the transferred T cells or result in significant remissions.

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Agarwal, Shiwani; Weidner, Tatjana; Thalheimer, Frederic B.; Buchholz, Christian J. (2019-10-10).

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in that they combine both antigen-binding and T cell activating functions into a single receptor.

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The transmembrane domain is a structural component, consisting of a

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Chimeric antigen receptors combine many facets of normal

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Chimeric antigen receptor T cell production and infusion:

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may be a side effect, as the CAR is made with a foreign

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Primary mediastinal large B-cell lymphoma (Third Line)

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The first chimeric receptors containing portions of an

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5. Engineered T cells are infused back into the patient

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Different components of a chimeric antigen receptor

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These V 1085:, and an intracellular T cell signaling domain. 577:Indication (Targeted disease / Line of Therapy) 4457: 4455: 4453: 4451: 4449: 4447: 4445: 3942:"Toxicity and management in CAR T-cell therapy" 3909: 3907: 3887: 3885: 3803: 3801: 3781: 3779: 3735: 3733: 3580: 3578: 3576: 3574: 3518: 3516: 1231:immunoreceptor tyrosine-based activation motifs 962:, and as a result provokes an immune response. 3713: 3711: 3709: 3412: 3410: 3408: 3360: 3358: 2934: 2932: 2930: 2928: 2351:Makita S, Yoshimura K, Tobinai K (June 2017). 1617: 1615: 1613: 1611: 1609: 1607: 1605: 1555: 1553: 1141:in it for flexibility as well as stretches of 926:Multiple myeloma (Fourth Line), (Second Line) 711:Diffuse large B-cell lymphoma (Second Line) 354:with a gene encoding the engineered CAR via a 36:1. T cells are isolated from a patient's blood 3865: 3863: 3843: 3841: 2216:"Approved Cellular and Gene Therapy Products" 1233:(ITAMs) present in the cytoplasmic domain of 1060:. In another clinical trial sponsored by the 1035:Immune effector cell-associated neurotoxicity 821:Diffuse large B-cell lymphoma (Second Line) 553:CAR T Cell Therapies with Regulatory Approval 505:The examples and perspective in this section 213:, subsequently termed first generation CARs. 8: 4523: 4521: 4519: 4232:Tan AH, Vinanica N, Campana D (April 2020). 3383: 3381: 3379: 2449:Jensen TI, Axelgaard E, Bak RO (June 2019). 209:(scFv) domains, as well as proteins such as 1877:Gross G, Waks T, Eshhar Z (December 1989). 350:The expanded T cells are purified and then 197:were shown to activate T cell signaling by 76:proteins that have been engineered to give 1720:Zhang H, Zhao P, Huang H (December 2020). 1510:"Engineering CAR-T cells: Design concepts" 550: 523:, or create a new section, as appropriate. 6620: 6562: 6465: 6400: 6342: 6284: 6243: 6186: 6168: 6088: 6030: 5973: 5912: 5854: 5800: 5790: 5663: 5471: 5387: 5377: 5288: 5193: 5152: 5116:(Press release). labiotech. March 8, 2018 5089: 5040: 4999: 4989: 4948: 4899: 4842: 4780: 4709: 4699: 4607: 4597: 4553: 4489: 4479: 4379: 4306: 4257: 4208: 4159: 4141: 4100: 3965: 3330: 3289: 3279: 3230: 3215:"Regulatory T cells and immune tolerance" 3189: 3128: 3110: 3061: 3005: 2956: 2908: 2859: 2849: 2740: 2683: 2642: 2632: 2541: 2539: 2537: 2535: 2515: 2466: 2425: 2376: 2258: 2147: 2093: 1920: 1902: 1747: 1737: 1696: 1647: 1585: 1533: 539:Learn how and when to remove this message 415:Early CAR T cell research has focused on 103:from T cells in a patient's own blood or 5355: 5353: 5351: 5168:Cho JH, Collins JJ, Wong WW (May 2018). 4281:Brudno JN, Kochenderfer JN (June 2016). 3914:European Medicines Agency (2023-07-27). 3870:European Medicines Agency (2023-07-27). 3786:European Medicines Agency (2023-11-10). 3718:European Medicines Agency (2023-01-30). 2941:"Driving CAR T cell translation forward" 2668:"Time to put the CAR-T before the horse" 2615:Almåsbak H, Aarvak T, Vemuri MC (2016). 1508:Srivastava S, Riddell SR (August 2015). 387:followed by BCMA (commonly expressed in 29: 5154:10.1146/annurev-cancerbio-030419-033657 4462:Chandran SS, Klebanoff CA (July 2019). 3991:Expert Review of Anti-Infective Therapy 1481: 203:University of California, San Francisco 5824: 5822: 5820: 4804: 4802: 4800: 3742:"TECARTUS (brexucabtagene autoleucel)" 3720:"TECARTUS (brexucabtagene autoleucel)" 3696:"TECARTUS (brexucabtagene autoleucel)" 3150: 3148: 2939:Schultz L, Mackall C (February 2019). 1726:Experimental Hematology & Oncology 1062:Fred Hutchinson Cancer Research Center 373:The patient undergoes lymphodepletion 263:Memorial Sloan Kettering Cancer Center 6769:(in Brazilian Portuguese). 2022-02-23 5135:Choe JH, Williams JZ, Lim WA (2020). 4733: 4731: 4729: 4575: 4573: 4360:The Journal of Clinical Investigation 3935: 3933: 3931: 3929: 3031: 3029: 3027: 3025: 2666:Jacobson CA, Ritz J (November 2011). 2346: 2344: 2282: 2280: 2278: 2117: 2115: 2113: 2028: 2026: 1365:Advances in CAR T cell manufacturing. 1213:Intracellular T cell signaling domain 80:the new ability to target a specific 7: 5366:Journal of Hematology & Oncology 5314:Expert Opinion on Biological Therapy 4978:Journal of Hematology & Oncology 4130:Transfusion Medicine and Hemotherapy 4034:Clinical Journal of Oncology Nursing 3605:"YESCARTA (axicabtagene ciloleucel)" 1946:Springer Seminars in Immunopathology 5689:Current Opinion in Chemical Biology 3319:The New England Journal of Medicine 2074:The New England Journal of Medicine 2070:"Chimeric Antigen Receptor Therapy" 1836:The New England Journal of Medicine 1072:Chimeric antigen receptor structure 2496:Nature Clinical Practice. Oncology 580:Agency Product Number, Drug Label 358:, typically either an integrating 334:Peripheral blood mononuclear cells 99:CAR T cells can be derived either 25: 5847:10.1001/jamanetworkopen.2020.2072 4403:Gust, Juliane (October 5, 2023). 3850:"ABECMA (idecabtagene vicleucel)" 2980:Lim WA, June CH (February 2017). 2068:June CH, Sadelain M (July 2018). 713:Follicular lymphoma (Third Line) 178:with the constant domains of the 109:Lentiviral vector in gene therapy 4504: 4250:10.1182/bloodadvances.2019001287 2725:10.1016/j.pharmthera.2021.107892 2590:Nature Reviews Clinical Oncology 2035:Current Opinion in Biotechnology 1355:Bispecific molecules as switches 496: 281:originally for B-cell precursor 5141:Annual Review of Cancer Biology 3440:US Food and Drug Administration 2713:Pharmacology & Therapeutics 574:Intracellular signaling domain 5724:Science Translational Medicine 5589:Journal of Clinical Immunology 5360:Zhang E, Xu H (January 2017). 5064:Casucci M, Bondanza A (2011). 2945:Science Translational Medicine 2621:Journal of Immunology Research 2548:Nature Reviews. Drug Discovery 2455:British Journal of Haematology 2287:Li, Nan; Ho, Mitchell (2022). 1389:Alternative Activating Domains 1009:, nausea, capillary leakages, 465:hostile tumor microenvironment 207:single-chain fraction variable 1: 6508:10.1158/1538-7445.AM2024-6332 6467:10.1016/s1525-0016(16)35165-6 6385:10.1158/2326-6066.CIR-15-0054 6112:Ledford, Heidi (2023-12-20). 6061:Nature Biomedical Engineering 5958:10.1080/2162402x.2019.1671761 5425:10.1126/science.276.5319.1719 5326:10.1517/14712598.2015.1046430 5269:Molecular Therapy: Oncolytics 4941:10.1158/2326-6066.CIR-14-0127 4872:Molecular Therapy: Oncolytics 4003:10.1080/14787210.2021.1855143 3946:Molecular Therapy: Oncolytics 2047:10.1016/s0958-1669(96)80074-7 641:Diffuse large B-cell lymphoma 425:diffuse large B-cell lymphoma 295:diffuse large B-cell lymphoma 27:Genetically engineered T cell 6286:10.1016/j.medidd.2022.100122 5736:10.1126/scitranslmed.aaa4802 5464:10.1182/blood-2007-02-072843 4827:10.1097/HC9.0000000000000022 4299:10.1182/blood-2016-04-703751 4093:10.1182/blood-2014-05-552729 3436:"KYMRIAH (tisagenlecleucel)" 3054:10.1053/j.gastro.2020.02.011 2958:10.1126/scitranslmed.aaw2127 2889:Journal of Clinical Oncology 2851:10.1182/blood-2010-04-281931 2685:10.1182/blood-2011-09-376137 2301:10.1007/978-1-0716-2075-5_23 2001:10.1016/0092-8674(91)90314-o 1786:10.1016/0006-291x(87)90502-x 1578:10.1158/2159-8290.CD-12-0548 1306:and co-stimulatory ligands. 875:(Fourth Line), (Third Line) 467:suppresses T cell activity. 283:acute lymphoblastic leukemia 6740:Eder M (25 November 2021). 6699:Bone Marrow Transplantation 6228:10.1016/j.omton.2024.200815 6216:Molecular Therapy: Oncology 2773:Advances in Cancer Research 1809:Transplantation Proceedings 1425:good manufacturing practice 1133:residues with stretches of 571:Antigen recognition domain 519:, discuss the issue on the 70:artificial T cell receptors 6847: 6547:10.1172/jci.insight.136093 6373:Cancer Immunology Research 6327:10.1016/j.xcrm.2023.100917 6273:Medicine in Drug Discovery 6170:10.3389/fimmu.2023.1227833 6130:10.1038/d41586-023-03969-5 6073:10.1038/s41551-021-00842-6 6015:10.1038/s41587-022-01245-x 5701:10.1016/j.cbpa.2013.03.029 5281:10.1016/j.omto.2017.12.003 5186:10.1016/j.cell.2018.03.038 4929:Cancer Immunology Research 4884:10.1016/j.omto.2022.02.015 4765:10.1038/s41467-023-37616-4 3232:10.1016/j.cell.2008.05.009 3174:10.1016/j.xcrm.2021.100297 2998:10.1016/j.cell.2017.01.016 2785:10.1016/bs.acr.2022.01.013 2560:10.1038/d41573-019-00090-z 2140:10.1016/j.jcyt.2019.12.004 1739:10.1186/s40164-020-00190-2 1097:Antigen recognition domain 1005:with high fever, fatigue, 993: 259:University of Pennsylvania 253:, by investigators at the 54:chimeric antigen receptors 6711:10.1038/s41409-020-0956-8 6605:10.1038/s41375-019-0417-9 5601:10.1007/s10875-012-9689-9 5379:10.1186/s13045-016-0379-6 4991:10.1186/s13045-017-0437-8 4815:Hepatology Communications 4645:10.1007/s40264-015-0285-9 4599:10.1186/s40364-017-0102-y 4582:"Engineering CAR-T cells" 996:Cytokine release syndrome 990:Cytokine release syndrome 951:cytokine release syndrome 893:ciltacabtagene autoleucel 735:brexucabtagene autoleucel 66:chimeric T cell receptors 18:Chimeric antigen receptor 5042:10.4049/jimmunol.0901766 4421:10.1182/blood.2023021860 4201:10.1182/blood.2019001463 4046:10.1188/07.CJON.S1.37-42 3281:10.3389/fimmu.2018.02359 2901:10.1200/JCO.2014.56.2025 2293:Single-Domain Antibodies 1904:10.1073/pnas.86.24.10024 1689:10.18632/oncotarget.6175 1526:10.1016/j.it.2015.06.004 1375:bioinstructive materials 1345:ON-switch and OFF-switch 1245:tested, including CD28, 787:lisocabtagene maraleucel 559:CAR T cell (Brand name) 410:tumor associated antigen 289:(Yescarta), marketed by 62:chimeric immunoreceptors 6541:(21): e136093, 136093. 6157:Frontiers in Immunology 5792:10.1073/pnas.1316026110 5656:10.1126/science.aab4077 4701:10.1073/pnas.1706055114 3268:Frontiers in Immunology 3112:10.1073/pnas.1706055114 2418:10.15252/emmm.201505869 2406:EMBO Molecular Medicine 1640:10.15252/emmm.201607485 1628:EMBO Molecular Medicine 1489:Fox M (July 12, 2017). 1331:(HSV-TK) and inducible 975:insertional mutagenesis 668:axicabtagene ciloleucel 287:axicabtagene ciloleucel 277:(Kymriah), marketed by 6502:(6_Supplement): 6332. 6315:Cell Reports. Medicine 3162:Cell Reports. Medicine 2173:Nature Reviews. Cancer 1222: 1093: 1044:), lowered alertness ( 839:idecabtagene vicleucel 565:Approval Agency: Date 449:acute myeloid leukemia 310: 45: 5897:10.1038/nnano.2017.57 5885:Nature Nanotechnology 5029:Journal of Immunology 4745:Nature Communications 4534:Immunological Reviews 4468:Immunological Reviews 2605:. 2017. 130: 2594-602 2086:10.1056/NEJMra1706169 1440:(Kymriah) treatment. 1339:Dual-antigen receptor 1240:T cells also require 1220: 1209:into the native TCR. 1091: 986:persistence in vivo. 742:Kite Pharma / Gilead 382:Clinical applications 308: 33: 6806:Cancer immunotherapy 6003:Nature Biotechnology 5545:Nature Biotechnology 5180:(6): 1426–1438.e11. 3332:10.1056/NEJMc2107725 3048:(8): 2250–2265.e20. 2634:10.1155/2016/5474602 1848:10.1056/NEJMp1711886 1514:Trends in Immunology 1455:Checkpoint inhibitor 1395:Toll-like receptor 4 1381:In situ modification 1190:Transmembrane domain 1083:transmembrane domain 766:B-cell precursor ALL 761:Mantle cell lymphoma 636:B-cell precursor ALL 517:improve this section 507:may not represent a 127:and growth factors. 84:. The receptors are 5783:2013PNAS..11017796K 5777:(44): 17796–17801. 5648:2015Sci...350.4077W 5419:(5319): 1719–1724. 4757:2023NatCo..14.1986L 4692:2017PNAS..114E6623L 4686:(32): E6623–E6631. 3958:10.1038/mto.2016.11 3103:2017PNAS..114E6623L 3097:(32): E6623–E6631. 1895:1989PNAS...8610024G 1889:(24): 10024–10028. 1815:(1 Pt 1): 127–130. 1683:(42): 44179–44190. 1270:Antigen recognition 1265:Research directions 1226:inside the T cell. 1107:monoclonal antibody 960:monoclonal antibody 647:Follicular Lymphoma 555: 330:leukocyte apheresis 146:antitumor effects. 6673:www.hematology.org 5557:10.1038/nbt0102-70 5510:10.1038/nm0296-216 5223:2016-03-27 at the 4586:Biomarker Research 4335:ClinicalTrials.gov 4040:(1 Suppl): 37–42. 2592:. 2018. 15: 31-46. 2508:10.1038/ncponc0666 2251:10.1038/mtm.2014.1 1958:10.1007/BF00820666 1399:Src family kinases 1310:Control mechanisms 1223: 1094: 1042:expressive aphasia 1016:immunosuppressants 808:MHLW: 12/20/2022 695:MHLW: 12/22/2022 551: 488:Approved therapies 471:Autoimmune disease 433:Hodgkin's lymphoma 311: 191:chimeric receptors 172:Weizmann Institute 46: 6460:: S57. May 2014. 6454:Molecular Therapy 6124:(7994): 225–226. 5835:JAMA Network Open 5642:(6258): aab4077. 5082:10.7150/jca.2.378 5070:Journal of Cancer 5035:(12): 6938–6949. 4546:10.1111/imr.12131 4481:10.1111/imr.12772 4415:(14): 1181–1183. 4293:(26): 3321–3330. 4195:(24): 2149–2158. 4143:10.1159/000526786 2951:(481): eaaw2127. 2844:(20): 4099–4102. 2678:(18): 4761–4762. 2468:10.1111/bjh.15851 2369:10.1111/cas.13239 2310:978-1-0716-2074-8 1842:(14): 1313–1315. 1470:Immune checkpoint 1078:T cell activation 942: 941: 911:EMA: 05/25/2022 909:FDA: 02/28/2022 857:EMA: 08/18/2021 855:FDA: 03/26/2021 805:EMA: 04/04/2022 795:Juno Therapeutics 747:EMA: 12/14/2020 745:FDA: 07/24/2020 686:EMA: 08/27/2018 684:FDA: 10/18/2017 549: 548: 541: 478:regulatory T cell 406:Adoptive transfer 356:retroviral vector 16:(Redirected from 6838: 6778: 6777: 6775: 6774: 6759: 6753: 6752: 6750: 6748: 6737: 6731: 6730: 6705:(9): 1706–1715. 6694: 6688: 6687: 6685: 6684: 6675:. Archived from 6665: 6659: 6658: 6656: 6655: 6641: 6635: 6634: 6624: 6599:(9): 2195–2207. 6583: 6577: 6576: 6566: 6526: 6520: 6519: 6486: 6480: 6479: 6469: 6446: 6440: 6439: 6437: 6436: 6421: 6415: 6414: 6404: 6363: 6357: 6356: 6346: 6305: 6299: 6298: 6288: 6264: 6258: 6257: 6247: 6207: 6201: 6200: 6190: 6172: 6148: 6142: 6141: 6109: 6103: 6102: 6092: 6051: 6045: 6044: 6034: 6009:(8): 1250–1258. 5994: 5988: 5987: 5977: 5952:(12): e1671761. 5933: 5927: 5926: 5916: 5875: 5869: 5868: 5858: 5826: 5815: 5814: 5804: 5794: 5762: 5756: 5755: 5730:(287): 287ra70. 5719: 5713: 5712: 5684: 5678: 5677: 5667: 5627: 5621: 5620: 5595:(5): 1059–1070. 5583: 5577: 5576: 5536: 5530: 5529: 5492: 5486: 5485: 5475: 5458:(8): 2793–2802. 5443: 5437: 5436: 5408: 5402: 5401: 5391: 5381: 5357: 5346: 5345: 5320:(8): 1145–1154. 5309: 5303: 5302: 5292: 5260: 5254: 5253: 5251: 5249: 5244:on July 30, 2017 5234: 5228: 5214: 5208: 5207: 5197: 5165: 5159: 5158: 5156: 5132: 5126: 5125: 5123: 5121: 5110: 5104: 5103: 5093: 5061: 5055: 5054: 5044: 5020: 5014: 5013: 5003: 4993: 4969: 4963: 4962: 4952: 4920: 4914: 4913: 4903: 4863: 4857: 4856: 4846: 4806: 4795: 4794: 4784: 4735: 4724: 4723: 4713: 4703: 4671: 4665: 4664: 4628: 4622: 4621: 4611: 4601: 4577: 4568: 4567: 4557: 4525: 4514: 4508: 4503: 4493: 4483: 4459: 4440: 4439: 4437: 4435: 4400: 4394: 4393: 4383: 4372:10.1172/JCI85309 4366:(6): 2123–2138. 4351: 4345: 4344: 4342: 4341: 4327: 4321: 4320: 4310: 4278: 4272: 4271: 4261: 4244:(7): 1419–1431. 4229: 4223: 4222: 4212: 4180: 4174: 4173: 4163: 4145: 4121: 4115: 4114: 4104: 4072: 4066: 4065: 4029: 4023: 4022: 3986: 3980: 3979: 3969: 3937: 3924: 3923: 3911: 3902: 3901: 3889: 3880: 3879: 3867: 3858: 3857: 3845: 3836: 3835: 3823: 3817: 3816: 3805: 3796: 3795: 3783: 3774: 3773: 3771: 3770: 3756: 3750: 3749: 3737: 3728: 3727: 3715: 3704: 3703: 3691: 3685: 3684: 3682: 3681: 3667: 3661: 3660: 3658: 3657: 3643: 3637: 3636: 3634: 3633: 3619: 3613: 3612: 3600: 3594: 3593: 3582: 3569: 3568: 3566: 3565: 3551: 3538: 3537: 3535: 3534: 3520: 3511: 3510: 3498: 3492: 3491: 3489: 3488: 3482:www.novartis.com 3474: 3468: 3467: 3465: 3464: 3450: 3444: 3443: 3432: 3426: 3425: 3414: 3403: 3402: 3400: 3399: 3393:www.novartis.com 3385: 3374: 3373: 3370:www.novartis.com 3362: 3353: 3352: 3334: 3310: 3304: 3303: 3293: 3283: 3259: 3253: 3252: 3234: 3210: 3204: 3203: 3193: 3152: 3143: 3142: 3132: 3114: 3082: 3076: 3075: 3065: 3042:Gastroenterology 3033: 3020: 3019: 3009: 2977: 2971: 2970: 2960: 2936: 2923: 2922: 2912: 2880: 2874: 2873: 2863: 2853: 2829: 2823: 2822: 2764: 2755: 2754: 2744: 2704: 2698: 2697: 2687: 2663: 2657: 2656: 2646: 2636: 2612: 2606: 2599: 2593: 2586: 2580: 2579: 2543: 2530: 2529: 2519: 2487: 2481: 2480: 2470: 2446: 2440: 2439: 2429: 2397: 2391: 2390: 2380: 2363:(6): 1109–1118. 2348: 2339: 2338: 2284: 2273: 2272: 2262: 2230: 2224: 2223: 2211: 2205: 2204: 2168: 2162: 2161: 2151: 2119: 2108: 2107: 2097: 2065: 2059: 2058: 2030: 2021: 2020: 1984: 1978: 1977: 1941: 1935: 1934: 1924: 1906: 1874: 1868: 1867: 1831: 1825: 1824: 1804: 1798: 1797: 1768: 1762: 1761: 1751: 1741: 1717: 1711: 1710: 1700: 1668: 1662: 1661: 1651: 1634:(9): 1183–1197. 1619: 1600: 1599: 1589: 1566:Cancer Discovery 1557: 1548: 1547: 1537: 1505: 1499: 1498: 1486: 1438:tisagenlecleucel 1329:thymidine kinase 1054:cyclophosphamide 979:tumor suppressor 873:Multiple myeloma 803:FDA: 02/05/2021 586:tisagenlecleucel 556: 544: 537: 533: 530: 524: 500: 499: 492: 463:masses, and the 457:multiple myeloma 389:multiple myeloma 343:(IL-2) and anti- 275:tisagenlecleucel 247:B-cell leukemias 60:)—also known as 21: 6846: 6845: 6841: 6840: 6839: 6837: 6836: 6835: 6796: 6795: 6787: 6782: 6781: 6772: 6770: 6761: 6760: 6756: 6746: 6744: 6739: 6738: 6734: 6696: 6695: 6691: 6682: 6680: 6667: 6666: 6662: 6653: 6651: 6643: 6642: 6638: 6585: 6584: 6580: 6528: 6527: 6523: 6496:Cancer Research 6488: 6487: 6483: 6448: 6447: 6443: 6434: 6432: 6423: 6422: 6418: 6365: 6364: 6360: 6307: 6306: 6302: 6266: 6265: 6261: 6209: 6208: 6204: 6150: 6149: 6145: 6111: 6110: 6106: 6053: 6052: 6048: 5996: 5995: 5991: 5935: 5934: 5930: 5877: 5876: 5872: 5828: 5827: 5818: 5764: 5763: 5759: 5721: 5720: 5716: 5686: 5685: 5681: 5629: 5628: 5624: 5585: 5584: 5580: 5538: 5537: 5533: 5498:Nature Medicine 5494: 5493: 5489: 5445: 5444: 5440: 5410: 5409: 5405: 5359: 5358: 5349: 5311: 5310: 5306: 5262: 5261: 5257: 5247: 5245: 5236: 5235: 5231: 5225:Wayback Machine 5217:SMDC technology 5215: 5211: 5167: 5166: 5162: 5134: 5133: 5129: 5119: 5117: 5112: 5111: 5107: 5063: 5062: 5058: 5022: 5021: 5017: 4971: 4970: 4966: 4922: 4921: 4917: 4865: 4864: 4860: 4808: 4807: 4798: 4737: 4736: 4727: 4673: 4672: 4668: 4630: 4629: 4625: 4579: 4578: 4571: 4527: 4526: 4517: 4461: 4460: 4443: 4433: 4431: 4402: 4401: 4397: 4353: 4352: 4348: 4339: 4337: 4329: 4328: 4324: 4280: 4279: 4275: 4231: 4230: 4226: 4182: 4181: 4177: 4123: 4122: 4118: 4074: 4073: 4069: 4031: 4030: 4026: 3988: 3987: 3983: 3939: 3938: 3927: 3913: 3912: 3905: 3891: 3890: 3883: 3869: 3868: 3861: 3847: 3846: 3839: 3825: 3824: 3820: 3807: 3806: 3799: 3785: 3784: 3777: 3768: 3766: 3758: 3757: 3753: 3739: 3738: 3731: 3717: 3716: 3707: 3693: 3692: 3688: 3679: 3677: 3669: 3668: 3664: 3655: 3653: 3645: 3644: 3640: 3631: 3629: 3621: 3620: 3616: 3602: 3601: 3597: 3584: 3583: 3572: 3563: 3561: 3553: 3552: 3541: 3532: 3530: 3522: 3521: 3514: 3500: 3499: 3495: 3486: 3484: 3476: 3475: 3471: 3462: 3460: 3452: 3451: 3447: 3434: 3433: 3429: 3422:www.reuters.com 3416: 3415: 3406: 3397: 3395: 3387: 3386: 3377: 3364: 3363: 3356: 3312: 3311: 3307: 3261: 3260: 3256: 3212: 3211: 3207: 3154: 3153: 3146: 3084: 3083: 3079: 3035: 3034: 3023: 2979: 2978: 2974: 2938: 2937: 2926: 2882: 2881: 2877: 2831: 2830: 2826: 2795: 2766: 2765: 2758: 2706: 2705: 2701: 2665: 2664: 2660: 2614: 2613: 2609: 2600: 2596: 2587: 2583: 2554:(11): 821–822. 2545: 2544: 2533: 2502:(12): 668–681. 2489: 2488: 2484: 2448: 2447: 2443: 2399: 2398: 2394: 2350: 2349: 2342: 2311: 2286: 2285: 2276: 2232: 2231: 2227: 2213: 2212: 2208: 2170: 2169: 2165: 2121: 2120: 2111: 2067: 2066: 2062: 2032: 2031: 2024: 1986: 1985: 1981: 1943: 1942: 1938: 1876: 1875: 1871: 1833: 1832: 1828: 1806: 1805: 1801: 1770: 1769: 1765: 1719: 1718: 1714: 1670: 1669: 1665: 1621: 1620: 1603: 1559: 1558: 1551: 1507: 1506: 1502: 1488: 1487: 1483: 1478: 1446: 1420: 1391: 1383: 1367: 1312: 1292: 1272: 1267: 1215: 1192: 1171: 1160: 1156: 1152: 1128: 1124: 1116: 1112: 1099: 1074: 1037: 1020:corticosteroids 998: 992: 947: 545: 534: 528: 525: 514: 501: 497: 490: 473: 401: 384: 360:gammaretrovirus 303: 293:originally for 176:diverse targets 160:T cell receptor 152: 43: 41: 39: 37: 35: 28: 23: 22: 15: 12: 11: 5: 6844: 6842: 6834: 6833: 6828: 6823: 6818: 6813: 6808: 6798: 6797: 6794: 6793: 6786: 6785:External links 6783: 6780: 6779: 6754: 6732: 6689: 6660: 6636: 6578: 6521: 6481: 6441: 6416: 6379:(7): 815–826. 6358: 6300: 6259: 6202: 6143: 6104: 6067:(2): 118–128. 6046: 5989: 5946:OncoImmunology 5928: 5891:(8): 813–820. 5870: 5841:(4): e202072. 5816: 5757: 5714: 5695:(3): 385–392. 5679: 5622: 5578: 5531: 5504:(2): 216–223. 5487: 5438: 5403: 5347: 5304: 5255: 5229: 5209: 5160: 5127: 5105: 5056: 5015: 4964: 4935:(2): 125–135. 4915: 4858: 4796: 4725: 4666: 4639:(5): 455–479. 4623: 4569: 4540:(1): 107–126. 4515: 4474:(1): 127–147. 4441: 4395: 4346: 4322: 4273: 4238:Blood advances 4224: 4175: 4136:(3): 218–225. 4116: 4087:(2): 188–195. 4067: 4024: 3997:(6): 749–758. 3981: 3925: 3903: 3881: 3859: 3837: 3818: 3797: 3775: 3751: 3729: 3705: 3686: 3675:www.gilead.com 3662: 3651:www.gilead.com 3638: 3627:www.gilead.com 3614: 3595: 3590:www.gilead.com 3570: 3559:www.gilead.com 3539: 3528:www.gilead.com 3512: 3493: 3469: 3445: 3427: 3404: 3375: 3354: 3325:(6): 567–569. 3305: 3254: 3225:(5): 775–787. 3205: 3144: 3077: 3021: 2992:(4): 724–740. 2972: 2924: 2895:(6): 540–549. 2875: 2824: 2793: 2756: 2699: 2658: 2607: 2594: 2581: 2531: 2482: 2461:(5): 821–835. 2441: 2412:(7): 702–711. 2392: 2357:Cancer Science 2340: 2309: 2274: 2225: 2206: 2185:10.1038/nrc971 2163: 2109: 2060: 2041:(6): 629–634. 2022: 1995:(5): 891–901. 1979: 1952:(2): 199–209. 1936: 1869: 1826: 1799: 1780:(3): 960–968. 1763: 1712: 1663: 1601: 1572:(4): 388–398. 1549: 1520:(8): 494–502. 1500: 1480: 1479: 1477: 1474: 1473: 1472: 1467: 1462: 1457: 1452: 1445: 1442: 1419: 1416: 1390: 1387: 1382: 1379: 1366: 1363: 1311: 1308: 1291: 1290:CAR T function 1288: 1277:antigen escape 1271: 1268: 1266: 1263: 1242:co-stimulatory 1214: 1211: 1191: 1188: 1170: 1167: 1158: 1154: 1150: 1126: 1122: 1114: 1113:) and heavy (V 1110: 1098: 1095: 1073: 1070: 1050:cerebral edema 1036: 1033: 994:Main article: 991: 988: 946: 943: 940: 939: 927: 924: 921: 916: 913: 907: 898: 889: 888: 876: 870: 867: 864: 859: 853: 844: 835: 834: 822: 819: 816: 813: 810: 801: 792: 783: 782: 770: 768:(Third Line) 763:(Third Line) 758: 755: 752: 749: 743: 740: 731: 730: 718: 709: 703: 700: 697: 692:: 06/23/2021 682: 673: 664: 663: 651: 633: 624: 619: 614: 612:: 05/15/2019 606:: 08/22/2018 601:: 08/30/2017 596: 591: 582: 581: 578: 575: 572: 569: 566: 563: 560: 547: 546: 511:of the subject 509:worldwide view 504: 502: 495: 489: 486: 472: 469: 431:in refractory 400: 397: 383: 380: 302: 299: 151: 148: 105:allogeneically 26: 24: 14: 13: 10: 9: 6: 4: 3: 2: 6843: 6832: 6829: 6827: 6824: 6822: 6819: 6817: 6816:Immune system 6814: 6812: 6809: 6807: 6804: 6803: 6801: 6792: 6789: 6788: 6784: 6768: 6764: 6758: 6755: 6743: 6736: 6733: 6728: 6724: 6720: 6716: 6712: 6708: 6704: 6700: 6693: 6690: 6679:on 2022-01-24 6678: 6674: 6670: 6664: 6661: 6650: 6646: 6640: 6637: 6632: 6628: 6623: 6618: 6614: 6610: 6606: 6602: 6598: 6594: 6590: 6582: 6579: 6574: 6570: 6565: 6560: 6556: 6552: 6548: 6544: 6540: 6536: 6532: 6525: 6522: 6517: 6513: 6509: 6505: 6501: 6497: 6493: 6485: 6482: 6477: 6473: 6468: 6463: 6459: 6455: 6451: 6445: 6442: 6430: 6426: 6420: 6417: 6412: 6408: 6403: 6398: 6394: 6390: 6386: 6382: 6378: 6374: 6370: 6362: 6359: 6354: 6350: 6345: 6340: 6336: 6332: 6328: 6324: 6321:(2): 100917. 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3394: 3390: 3384: 3382: 3380: 3376: 3372:. 2017-08-30. 3371: 3367: 3361: 3359: 3355: 3350: 3346: 3342: 3338: 3333: 3328: 3324: 3320: 3316: 3309: 3306: 3301: 3297: 3292: 3287: 3282: 3277: 3273: 3269: 3265: 3258: 3255: 3250: 3246: 3242: 3238: 3233: 3228: 3224: 3220: 3216: 3209: 3206: 3201: 3197: 3192: 3187: 3183: 3179: 3175: 3171: 3168:(6): 100297. 3167: 3163: 3159: 3151: 3149: 3145: 3140: 3136: 3131: 3126: 3122: 3118: 3113: 3108: 3104: 3100: 3096: 3092: 3088: 3081: 3078: 3073: 3069: 3064: 3059: 3055: 3051: 3047: 3043: 3039: 3032: 3030: 3028: 3026: 3022: 3017: 3013: 3008: 3003: 2999: 2995: 2991: 2987: 2983: 2976: 2973: 2968: 2964: 2959: 2954: 2950: 2946: 2942: 2935: 2933: 2931: 2929: 2925: 2920: 2916: 2911: 2906: 2902: 2898: 2894: 2890: 2886: 2879: 2876: 2871: 2867: 2862: 2857: 2852: 2847: 2843: 2839: 2835: 2828: 2825: 2820: 2816: 2812: 2808: 2804: 2800: 2796: 2794:9780323983921 2790: 2786: 2782: 2778: 2774: 2770: 2763: 2761: 2757: 2752: 2748: 2743: 2738: 2734: 2730: 2726: 2722: 2718: 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1320:Suicide genes 1316: 1309: 1307: 1305: 1301: 1297: 1289: 1287: 1284: 1280: 1278: 1269: 1264: 1262: 1258: 1256: 1255:CD137 (4-1BB) 1252: 1248: 1243: 1238: 1236: 1232: 1227: 1219: 1212: 1210: 1208: 1203: 1200: 1197: 1189: 1187: 1185: 1181: 1177: 1168: 1166: 1162: 1148: 1144: 1140: 1136: 1132: 1120: 1119:immunoglobins 1108: 1103: 1096: 1090: 1086: 1084: 1079: 1071: 1069: 1065: 1063: 1059: 1055: 1051: 1047: 1043: 1034: 1032: 1029: 1025: 1021: 1017: 1012: 1008: 1004: 997: 989: 987: 984: 980: 976: 971: 969: 963: 961: 957: 952: 944: 938: 937: 932: 928: 925: 922: 920: 917: 914: 912: 908: 906: 902: 899: 897: 894: 891: 890: 887: 886: 881: 877: 874: 871: 868: 865: 863: 860: 858: 854: 852: 848: 845: 843: 840: 837: 836: 833: 832: 827: 823: 820: 817: 814: 811: 809: 806: 802: 800: 796: 793: 791: 788: 785: 784: 781: 780: 775: 771: 769: 767: 762: 759: 756: 753: 750: 748: 744: 741: 739: 736: 733: 732: 729: 728: 723: 719: 717: 714: 710: 707: 704: 701: 698: 696: 693: 691: 687: 683: 681: 677: 674: 672: 669: 666: 665: 662: 661: 656: 652: 650: 649:(Third Line) 648: 644: 643:(Third Line) 642: 638:(Third Line) 637: 634: 632: 628: 625: 623: 620: 618: 615: 613: 611: 607: 605: 600: 597: 595: 592: 590: 587: 584: 583: 579: 576: 573: 570: 567: 564: 561: 558: 557: 554: 543: 540: 532: 529:November 2023 522: 518: 512: 510: 503: 494: 493: 487: 485: 483: 479: 470: 468: 466: 460: 458: 454: 450: 446: 442: 438: 434: 430: 426: 422: 418: 417:blood cancers 413: 411: 407: 398: 396: 394: 390: 381: 379: 376: 371: 369: 365: 361: 357: 353: 348: 346: 342: 341:interleukin 2 339: 335: 331: 327: 322: 320: 316: 307: 300: 298: 296: 292: 288: 285:(B-ALL), and 284: 280: 276: 272: 268: 264: 260: 256: 252: 248: 244: 239: 235: 230: 228: 223: 219: 214: 212: 208: 204: 200: 196: 192: 187: 185: 181: 177: 173: 169: 165: 161: 157: 149: 147: 145: 141: 137: 133: 128: 126: 122: 118: 112: 110: 106: 102: 97: 94: 89: 87: 83: 79: 75: 71: 67: 63: 59: 55: 51: 32: 19: 6811:Gene therapy 6771:. Retrieved 6766: 6757: 6745:. Retrieved 6735: 6702: 6698: 6692: 6681:. Retrieved 6677:the original 6672: 6663: 6652:. Retrieved 6648: 6639: 6596: 6592: 6581: 6538: 6534: 6524: 6499: 6495: 6484: 6457: 6453: 6444: 6433:. Retrieved 6431:. 2022-09-25 6428: 6419: 6376: 6372: 6361: 6318: 6314: 6303: 6276: 6272: 6262: 6219: 6215: 6205: 6160: 6156: 6146: 6121: 6117: 6107: 6064: 6060: 6049: 6006: 6002: 5992: 5949: 5945: 5939: 5931: 5888: 5884: 5873: 5838: 5834: 5774: 5770: 5760: 5727: 5723: 5717: 5692: 5688: 5682: 5639: 5635: 5625: 5592: 5588: 5581: 5551:(1): 70–75. 5548: 5544: 5534: 5501: 5497: 5490: 5455: 5451: 5441: 5416: 5412: 5406: 5369: 5365: 5317: 5313: 5307: 5272: 5268: 5258: 5248:December 20, 5246:. Retrieved 5242:the original 5232: 5212: 5177: 5173: 5163: 5144: 5140: 5130: 5118:. Retrieved 5108: 5073: 5069: 5059: 5032: 5028: 5018: 4981: 4977: 4967: 4932: 4928: 4918: 4875: 4871: 4861: 4821:(2): e0022. 4818: 4814: 4748: 4744: 4683: 4679: 4669: 4636: 4632: 4626: 4589: 4585: 4537: 4533: 4471: 4467: 4432:. Retrieved 4412: 4408: 4398: 4363: 4359: 4349: 4338:. Retrieved 4334: 4325: 4290: 4286: 4276: 4241: 4237: 4227: 4192: 4188: 4178: 4133: 4129: 4119: 4084: 4080: 4070: 4037: 4033: 4027: 3994: 3990: 3984: 3949: 3945: 3919: 3897: 3875: 3853: 3831: 3821: 3812: 3791: 3767:. Retrieved 3764:news.bms.com 3763: 3754: 3745: 3723: 3699: 3689: 3678:. Retrieved 3674: 3665: 3654:. Retrieved 3650: 3641: 3630:. Retrieved 3626: 3617: 3608: 3598: 3589: 3562:. Retrieved 3558: 3531:. Retrieved 3527: 3506: 3496: 3485:. Retrieved 3481: 3472: 3461:. Retrieved 3457: 3448: 3439: 3430: 3421: 3396:. 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