CAR T cell therapy

from Wikipedia, the free encyclopedia

In the CAR-T cell therapy - CAR represents C himeric A ntigen R preceptor - is a novel cancer immunotherapy , in which genetically altered T cells (so-called CAR-T cells ) with the synthetic antigen-specific receptors are used .

method

In CAR-T-cell therapy, T-cells are first obtained from the patient's blood, which are then genetically modified in the laboratory so that they form chimeric antigen receptors (CAR) on their surface that are directed against cancer-specific surface proteins. The immune cells are thus artificially trained on the cancer. The CAR-T cells modified in this way are reinfused into the patient, where they ideally multiply and lead to a violent and long-lasting immune reaction against the cancer.

In principle, various T cell and other receptors can be changed chimerically. The CD19 receptor was chosen as the first target, as it is very common in B-cell leukemia and B-cell lymphoma and is expressed much more strongly and more frequently than other receptors such as the CD20 receptor or CD22 receptor. Since the B-lymphocyte antigen CD19 occurs exclusively on B-cells, the only possible undesirable "on-target" effect is B-cell aplasia , which can be treated with immunoglobulin therapy.

Receptors

If a leukocyte finds a foreign antigen (for example a bacterial or virus particle), it presents this antigen on its cell surface, bound to an HLA allele. This is recognized by a T-cell receptor (on a T-cell , a special lymphocyte ) and then triggers an activation in the T-cell, which triggers an adaptive immune response against the antigen. The T-cell receptor consists of the two antigen-specific heterodimeric α- and β-chains, which are firmly connected via a disulfide bridge and on the cell surface close to CD3 receptors and their ε-, γ-, β- and ζ chains are associated, which play an important role as co- stimulators .

The first generation of CAR-T receptors was developed in the 1990s by placing specific receptors on the immune-activating proteins on the T-cell surface ("chimeric"). A light and a heavy protein chain derived from immunoglobulin for specific antigen recognition was placed on a transmembrane domain that had an activation domain in its intracellular section, usually a ζ chain of the CD3 receptor. This enabled HLA-independent activation, but due to the low signal capacity, this did not lead to permanent activation.

This was then achieved with the second generation of CAR T cell receptors, which, like "normal" T cell receptors, showed double signal activation ( dual signaling CAR ). For this purpose, chimeric costimulators were used, which promote T-cell proliferation with repeated antigen contact and have an anti-apoptotic effect, thus paving the way for CAR-T-cell therapy.

Side effects

Like most cancer therapies, CAR-T cell therapy can cause serious side effects. One of the most common side effects is the cytokine release syndrome (Engl. Cytokine release syndrome (CRS)). There are sometimes life-threatening side effects such as fever , chills , breathing difficulties and skin rashes . The symptoms are probably caused by the massive breakdown of the cancer cells, which releases a large number of cytokines . In August 2017, the US was part of Administration FDA tocilizumab (: tradename Actemra / RoActemra ; Manufacturer Roche ) for the treatment of CRS approved .

First representative

  • Tisagenlecleucel (CTL019) (trade name: Kymriah ; manufacturer Novartis ) is the first active ingredient to be approved by the FDA in the USA for this adoptive immunotherapy, specifically for the treatment of a specific form of acute lymphoblastic leukemia (ALL). Because it is the first representative of a completely new therapeutic approach, it is called first in class . It is the first gene therapy to be approved in the United States. In June 2018, the has CHMP of the EMA recommended approval for Europe. As a result, the EU Commission voted for approval in the EU, which Novartis announced on August 27, 2018.
  • In October 2017, Axicabtagen-Ciloleucel , (KTE-C19, Axi-cel) (trade name: Yescarta ; manufacturer Gilead Sciences or - through the acquisition - originally from Kite Pharma ) against various forms of leukemia was approved in the USA . In June 2018, the CHMP recommended EMA approval for Europe. The corresponding European approval was granted in August 2018. In March 2020, the pharmaceutical company Bristol-Myers Squibb (as legal successor to Juno Therapeutics ) was awarded a claim for damages of 1.2 billion US dollars due to patent infringements . Gilead announced that it would object to this.

costs

The cost of CAR T cell therapy is exceptionally high. In the United States, Yescarta treatment costs $ 373,000 per patient. In Kymriah even 475,000 US dollars will be required. However, these costs will only be billed if the therapy is successful. The success of the therapy is defined by the effect of the treatment after one month. In Germany, treatment of ALL and non-Hodgkin lymphomas with Kymriah costs € 380,000. The high therapy costs are justified by the high manufacturing costs, which are said to be around 50,000 US dollars per patient.

More candidates

Other companies are also working on further representatives of CAR T cell therapy, e.g. B.

  • Celgene - now BMS due to a merger - develops z. B. in cooperation with bluebird bio : Idecabtagene Vicleucel (ide-cel; bb2121). In November 2017, the joint candidate bb2121 for the treatment of multiple myeloma received the so-called Breakthrough Therapy Designation from the FDA, which enables an accelerated approval process. In May 2020, the two companies BMS and bluebird bio received a "Refusal to File" letter from the Food and Drug Administration (FDA). H. a preliminary denial of the March 2020 Biologics License Application (BLA) for Idecabtagene Vicleucel.
  • In January 2018, Celgene - now BMS - announced it would acquire Juno Therapeutics , Inc. ( NASDAQ : JUNO) for $ 9 billion. Juno is a pioneer in the development of CART therapeutics with a broad portfolio exploring multiple targets and cancer indications.
  • The German company gemoab has developed three proprietary next-generation immunotherapy platforms - UniCAR, RevCAR and ATAC - that promise advantages over existing immunotherapies.

Centers

CAR-T cell therapy is currently only available at selected centers that have sufficient clinical experience with cell therapies. In accordance with the quality requirements of the approval authorities, individual centers are trained by the manufacturers for the use of CAR T cell therapy. Around 15 German university hospitals are currently qualified for treatment with Kymriah and / or Yescarta . An official list of already certified centers does not yet exist. The contact person is the treating oncologist or the manufacturer of the relevant CAR-T-cell product.

literature

  • A. Ronson, A. Tvito, JM Rowe: Treatment of Relapsed / Refractory Acute Lymphoblastic Leukemia in Adults. In: Current Oncology Reports . Volume 18, No. 6, June 2016, p. 39, doi: 10.1007 / s11912-016-0519-8 , PMID 27207612 (Review).
  • Leukemia & Lymphoma Society: " Acute Lymphoblastic Leukemia. "
  • Bettina Reismüller, Christina Peters, Michael N. Dworzak, Ulrike Pötschger, Christian Urban: Outcome of Children and Adolescents With a Second or Third Relapse of Acute Lymphoblastic Leukemia (ALL) . In: Journal of Pediatric Hematology / Oncology . tape 35 , no. 5 , 2013, p. e200 – e204 , doi : 10.1097 / mph.0b013e318290c3d6 .
  • Nicola Siegmund-Schultze: CAR T cells. Hope and hype. and New Strategy in Oncology. CAR-T cells are reaching clinical practice. In: Deutsches Ärzteblatt. Volume 116, Issue 49, (December) 2019, pp. B 1887 and p. B 1888-1891.
  • Vijay Ramaswamy: CAR T cells for childhood diffuse midline gliomas. (See www.nature.com ).

See also

Web links

Individual evidence

  1. ^ A b Carl H. June, Michel Sadelain: Chimeric Antigen Receptor Therapy New England Journal of Medicine 2018, Volume 379, Issue 1 of July 5, 2018, pages 64-73, DOI: 10.1056 / NEJMra1706169
  2. ^ CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers , Cancer.gov, accessed September 9, 2017
  3. ↑ FDA approves Roche's Actemra / RoActemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome , Roche PM, August 30, 2017, accessed September 9, 2017
  4. ↑ KYMRIAH , FDA status, accessed September 9, 2017
  5. ↑ 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 , PM Novartis of August 30, 2017 , accessed September 9, 2017
  6. ↑ a b First two CAR-T cell medicines recommended for approval in the European Union , PM EMA dated June 29, 2018, accessed on June 30, 2018
  7. ↑ Kymriah - Opinion , PM EMA, June 28, 2018, accessed June 30, 2018
  8. ↑ a b Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) June 25-28, 2018 , PM EMA of June 29, 2018, accessed on June 29, 2018
  9. ↑ Novartis gene therapy for blood cancer approved in the EU , Reuters of August 27, 2018
  10. ↑ Novartis receives European Commission approval of its CAR-T cell therapy, Kymriah® (tisagenlecleucel) , Novartis from August 27, 2018
  11. ↑ Gilead Sciences Completes Acquisition of Kite Pharma, Inc. , Gilead PM, October 3, 2017, accessed October 15, 2017
  12. ↑ Kite's Yescarta ™ (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy , PM Gilead, October 18, 2017 on November 22, 2017
  13. ↑ Dominik Feldges: Novartis trumps with a new cancer drug. In: nzz.ch. August 31, 2017. Retrieved November 26, 2017 .
  14. ↑ Kite Announces New Worldwide Facilities and Expanded Collaboration With National Cancer Institute to Support Cell Therapy Pipeline , PM Gilead Sciences, May 15, 2018, accessed May 20, 2018
  15. ↑ Yescarta - Opinion , PM EMA June 28, 2018, accessed June 30, 2018
  16. ↑ Yescarta® (Axicabtagene Ciloleucel) Receives European Marketing Authorization , PM Gilead, August 27, 2018, accessed February 18, 2020
  17. ↑ Yescarta Axicabtagene Ciloleucel , EPAR of the EMA, accessed on February 18, 2020
  18. ↑ Bristol-Myers Patent Win Over Gilead Grows to $ 1.2 Billion Bloomberg dated April 10, 2020, accessed April 13, 2020
  19. ↑ Bristol-Myers' win in US patent case against Gilead boosted to $ 1.2 billion , Reuters April 10, 2020, accessed April 13, 2020
  20. ↑ EMA: CAR-T cell therapy soon also in Europe. In: aerzteblatt.de . June 29, 2018. Retrieved May 25, 2019 .
  21. ↑ sda / awp: First gene therapy is approved in the USA. In: nzz.ch. August 30, 2017. Retrieved November 26, 2017 .
  22. ↑ Kymriah: CAR-T cells fight leukemia and lymphoma. In: wissensschau.de. August 27, 2018, accessed May 25, 2019 .
  23. ↑ Celgene Corporation and bluebird bio Complete Enrollment of Pivotal KarMMa Study of anti-BCMA Car T Cell Therapy bb2121 in Patients with Relapsed and Refractory Multiple Myeloma , Celgene PM November 27, 2018, accessed March 7, 2019
  24. ↑ Celgene Corporation and bluebird bio Announce bb2121 Anti-BCMA CAR-T Cell Therapy Has Been Granted Breakthrough Therapy Designation from FDA and Prime Eligibility from EMA for Relapsed and Refractory Multiple Myeloma , PM Celgene, November 16, 2017, accessed November 22, 2017
  25. ↑ Bristol Myers Squibb and bluebird bio Provide Regulatory Update on Idecabtagene Vicleucel (ide-cel, bb2121) for the Treatment of Patients with Multiple Myeloma , PM BMS, May 13, 2020, accessed May 14, 2020
  26. ↑ Celgene Corporation to Acquire Juno Therapeutics, Inc., Advancing Global Leadership in Cellular Immunotherapy , Celgene PM, January 22, 2018, accessed May 14, 2020
  27. ↑ Our Science , website GEMoaB, accessed February 17, 2020
  28. ↑ Update CAR-T-Cell Therapy , Cancer Information Service, accessed on April 29, 2020
  29. ↑ University Hospital Halle (Saale) will offer CAR-T cell therapy against lymph gland cancer from mid-2020 , PM University Hospital Halle (Saale) from April 28, 2020, accessed on April 29, 2020