nach oben

Cancer Immunology, Immunotherapy

Erschienen in:

09.09.2016 | Review

The growing world of CAR T cell trials: a systematic review

verfasst von: Astrid Holzinger, Markus Barden, Hinrich Abken

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 12/2016

Einloggen, um Zugang zu erhalten

Abstract

In recent years, cancer treatment involving adoptive cell therapy with chimeric antigen receptor (CAR)-modified patient’s immune cells has attracted growing interest. Using gene transfer techniques, the patient’s T cells are modified ex vivo with a CAR which redirects the T cells toward the cancer cells through an antibody-derived binding domain. The T cells are activated by the CAR primary signaling and costimulatory domains. Such “second generation” CAR T cells induced complete remission of B cell malignancies in the long-term. In this fast-moving field with a growing number of engineered T cell products, we list about 100 currently ongoing trials here that involve CAR T cells targeting hematopoietic malignancies and solid cancer. Major challenges in the further development of the therapy are briefly discussed.

Eshhar Z (2008) The T-body approach: redirecting T cells with antibody specificity. Handb Exp Pharmacol 181:329–342. doi:10.1007/978-3-540-73259-4_14 CrossRef

Finney HM, Lawson AD, Bebbington CR, Weir AN (1998) Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 161:2791–2797PubMed

Hombach A, Wieczarkowiecz A, Marquardt T et al (2001) Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J Immunol 167:6123–6131CrossRefPubMed

Chmielewski M, Kopecky C, Hombach AA, Abken H (2011) IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res 71:5697–5706CrossRefPubMed

Maude SL, Frey N, Shaw PA et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507–1517. doi:10.1056/NEJMoa1407222 CrossRefPubMedPubMedCentral

Singh N, Frey NV, Grupp SA, Maude SL (2016) CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia. Curr Treat Options Oncol 17:28. doi:10.1007/s11864-016-0406-4 CrossRefPubMed

Savoldo B, Ramos CA, Liu E et al (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Investig 121:1822–1826. doi:10.1172/JCI46110 CrossRefPubMedPubMedCentral

Cruz CRY, Micklethwaite KP, Savoldo B et al (2013) Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122:2965–2973. doi:10.1182/blood-2013-06-506741 CrossRefPubMedPubMedCentral

Xu X-J, Zhao H-Z, Tang Y-M (2013) Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials. Leuk Lymphoma 54:255–260. doi:10.3109/10428194.2012.715350 CrossRefPubMed

10.

Zhang T, Cao L, Xie J et al (2015) Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget 6:33961–33971. doi:10.18632/oncotarget.5582 PubMedPubMedCentral

11.

Kalos M, Levine BL, Porter DL et al (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73. doi:10.1126/scitranslmed.3002842 CrossRefPubMedPubMedCentral

12.

Porter DL, Levine BL, Kalos M et al (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733. doi:10.1056/NEJMoa1103849 CrossRefPubMedPubMedCentral

13.

Porter DL, Hwang W-T, Frey NV et al (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139. doi:10.1126/scitranslmed.aac5415 CrossRefPubMed

14.

Brentjens RJ, Rivière I, Park JH et al (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817–4828. doi:10.1182/blood-2011-04-348540 CrossRefPubMedPubMedCentral

15.

Kochenderfer JN, Dudley ME, Feldman SA et al (2012) B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:2709–2720. doi:10.1182/blood-2011-10-384388 CrossRefPubMedPubMedCentral

16.

Davila ML, Bouhassira DCG, Park JH et al (2014) Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol 99:361–371. doi:10.1007/s12185-013-1479-5 CrossRefPubMed

17.

Lee DW, Kochenderfer JN, Stetler-Stevenson M et al (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517–528. doi:10.1016/S0140-6736(14)61403-3 CrossRefPubMed

18.

Morgan RA, Yang JC, Kitano M et al (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851. doi:10.1038/mt.2010.24 CrossRefPubMedPubMedCentral

19.

Ahmed N, Brawley VS, Hegde M et al (2015) Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696. doi:10.1200/JCO.2014.58.0225 CrossRefPubMedPubMedCentral

20.

Gross G, Eshhar Z (2016) Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol 56:59–83. doi:10.1146/annurev-pharmtox-010814-124844 CrossRefPubMed

21.

Fedorov VD, Themeli M, Sadelain M (2013) PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med 5:215ra172. doi:10.1126/scitranslmed.3006597 CrossRefPubMedPubMedCentral

22.

Kloss CC, Condomines M, Cartellieri M et al (2012) Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 31:71–75. doi:10.1038/nbt.2459 CrossRefPubMed

23.

Beatty GL, Haas AR, Maus MV et al (2014) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2:112–120. doi:10.1158/2326-6066.CIR-13-0170 CrossRefPubMed

24.

Brentjens R, Yeh R, Bernal Y et al (2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 18:666–668. doi:10.1038/mt.2010.31 CrossRefPubMedPubMedCentral

25.

Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518. doi:10.1056/NEJMoa1215134 CrossRefPubMedPubMedCentral

26.

Chen F, Teachey DT, Pequignot E et al (2016) Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods 434:1–8. doi:10.1016/j.jim.2016.03.005 CrossRefPubMed

27.

Davila ML, Riviere I, Wang X et al (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25. doi:10.1126/scitranslmed.3008226 CrossRefPubMedPubMedCentral

28.

Maude SL, Barrett D, Teachey DT, Grupp SA (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20:119–122. doi:10.1097/PPO.0000000000000035 CrossRefPubMedPubMedCentral

29.

Teachey DT, Lacey SF, Shaw PA et al (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 6:664–679. doi:10.1158/2159-8290.CD-16-0040 CrossRefPubMed

30.

Katz SC, Burga RA, McCormack E et al (2015) Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified t-cell therapy for CEA + Liver Metastases. Clin Cancer Res 21:3149–3159. doi:10.1158/1078-0432.CCR-14-1421 CrossRefPubMedPubMedCentral

31.

Xu Y, Zhang M, Ramos CA et al (2014) Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123:3750–3759. doi:10.1182/blood-2014-01-552174 CrossRefPubMedPubMedCentral

32.

Abken H (2015) Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors. Immunotherapy 7:535–544. doi:10.2217/imt.15.15 CrossRefPubMed

33.

Kobold S, Grassmann S, Chaloupka M et al (2015) Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J Natl Cancer Inst. doi:10.1093/jnci/djv146 PubMedCentral

34.

Kawalekar OU, O’Connor RS, Fraietta JA et al (2016) Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44:380–390. doi:10.1016/j.immuni.2016.01.021 CrossRefPubMed

35.

Kochenderfer JN, Wilson WH, Janik JE et al (2010) Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116:4099–4102. doi:10.1182/blood-2010-04-281931 CrossRefPubMedPubMedCentral

36.

Kochenderfer JN, Dudley ME, Kassim SH et al (2015) 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. J Clin Oncol 33:540–549. doi:10.1200/JCO.2014.56.2025 CrossRefPubMed

37.

Kochenderfer JN, Dudley ME, Carpenter RO et al (2013) Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129–4139. doi:10.1182/blood-2013-08-519413 CrossRefPubMedPubMedCentral

38.

Brentjens RJ, Davila ML, Riviere I et al (2013) CD19-targeted t cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38. doi:10.1126/scitranslmed.3005930 CrossRefPubMedPubMedCentral

39.

Garfall AL, Maus MV, Hwang W-T et al (2015) Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med 373:1040–1047. doi:10.1056/NEJMoa1504542 CrossRefPubMedPubMedCentral

40.

Till BG, Jensen MC, Wang J et al (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119:3940–3950. doi:10.1182/blood-2011-10-387969 CrossRefPubMedPubMedCentral

41.

Wang Q, Wang Y, Lv H et al (2015) Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 23:184–191. doi:10.1038/mt.2014.164 PubMed

42.

Ritchie DS, Neeson PJ, Khot A et al (2013) Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 21:2122–2129. doi:10.1038/mt.2013.154 CrossRefPubMedPubMedCentral

43.

van Schalkwyk MCI, Papa SE, Jeannon J-P et al (2013) Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer. Hum Gene Ther Clin Dev 24:134–142. doi:10.1089/humc.2013.144 CrossRefPubMed

44.

Morgan RA, Johnson LA, Davis JL et al (2012) Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 23:1043–1053. doi:10.1089/hum.2012.041 CrossRefPubMedPubMedCentral

45.

Maus MV, Haas AR, Beatty GL et al (2013) T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 1:26–31. doi:10.1158/2326-6066.CIR-13-0006 CrossRefPubMedCentral

46.

You F, Jiang L, Zhang B et al (2016) Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci. 59:386–397. doi:10.1007/s11427-016-5024-7 CrossRefPubMed

Titel: The growing world of CAR T cell trials: a systematic review
verfasst von: Astrid Holzinger
Markus Barden
Hinrich Abken
Publikationsdatum: 09.09.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 12/2016
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1895-5

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

The growing world of CAR T cell trials: a systematic review

Abstract

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2016

Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer

Anti-GITR therapy promotes immunity against malignant glioma in a murine model

Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model

Macrophage migration inhibitory factor (MIF) is induced by cytotoxic drugs and is involved in immune escape and migration in childhood rhabdomyosarcoma

Surface biotinylation of cytotoxic T lymphocytes for in vivo tracking of tumor immunotherapy in murine models

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie