CART.docx

1、CART1. Nat Rev Clin Oncol. 2014 Nov 11. doi: 10.1038/nrclinonc.2014.190. Epub ahead of printImmunotherapy: Treatment of aggressive lymphomas with anti-CD19 CAR T cells.Klebanoff CA, Yamamoto TN, Restifo NP.Author information: Center for Cancer Research, Surgery Branch, Immunotherapy Section, 10 Cent

2、erDrive, Building 10/CRC, Room 3 West-5816, Bethesda, MA 20892, USA.PMID: 25384948 PubMed - as supplied by publisher2. Sci Transl Med. 2014 Nov 5;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-depen

3、dent tumor immunity.Adusumilli PS(1), Cherkassky L(2), Villena-Vargas J(2), Colovos C(2), ServaisE(2), Plotkin J(3), Jones DR(4), Sadelain M(5).Author information: (1)Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA. Thoracic Service, Department of Surgery,

4、 Memorial Sloan KetteringCancer Center, New York, NY 10065, USA. adusumipmskcc.org sadelaimmskcc.org.(2)Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan KetteringCancer Center, New York, NY 10065, USA

5、.(3)Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA.(4)Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.(5)Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA.

6、Immunology Program, Sloan Kettering Institute, New York, NY 10065,USA. adusumipmskcc.org sadelaimmskcc.org.Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcomingseveral obstacles, including inefficie

7、nt T cell tumor infiltration andinsufficient functional persistence. Taking advantage of an orthotopic model thatfaithfully mimics human pleural malignancy, we evaluated two routes ofadministration of mesothelin-targeted T cells using the M28z CAR. We found thatintrapleurally administered CAR T cell

8、s vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term completeremissions. After intrapleural T cell administration, prompt in vivoantigen-induced T cell activation allowed robust CAR T cell expansion andeffector differentiation, resulting in enh

9、anced antitumor efficacy and functionalT cell persistence for 200 days. Regional T cell administration also promotedefficient elimination of extrathoracic tumor sites. This therapeutic efficacy wasdependent on early CD4(+) T cell activation associated with a higher intratumoralCD4/CD8 cell ratios an

10、d CD28-dependent CD4(+) T cell-mediated cytotoxicity. Incontrast, intravenously delivered CAR T cells, even when accumulated atequivalent numbers in the pleural tumor, did not achieve comparable activation,tumor eradication, or persistence. The ability of intrapleurally administered Tcells to circul

11、ate and persist supports the concept of delivering optimal CAR Tcell therapy through regional distribution centers. On the basis of theseresults, we are opening a phase 1 clinical trial to evaluate the safety ofintrapleural administration of mesothelin-targeted CAR T cells in patients withprimary or

12、 secondary pleural malignancies.Copyright 2014, American Association for the Advancement of Science.PMID: 25378643 PubMed - in process3. Cancer Res. 2014 Oct 8. pii: canres.0079.2014. Epub ahead of printEfficacy of CAR T cell therapy in large tumors relies upon stromal targeting byIFNTextor A(1), Li

13、stopad J(2), Whrmann LL(3), Perez C(1), Kruschinski A(1),Chmielewski M(4), Abken H(5), Blankenstein T(3), Charo J(6).Author information: (1)Molecular Immunology and Gene Therapy, MDC.(2)Immunology, Max-Delbrck-Center for Molecular Medicine and Institute forImmunology, Charite.(3)Robert-Roessle-Str 1

14、0, Max-Delbrueck-Centrum.(4)Center for Molecular Medicine Cologne, University of Cologne.(5)Tumorgenetics, Clinic I for Internal Medicine and Centre for Molecular MedicineCologne (CMMC), University of Cologne.(6)Oncology Institute, Loyola University Chicago jehcha.Adoptive T cell therapy using chime

15、ric antigen receptor-modified T cells (CAR-Ttherapy) has shown dramatic efficacy in patients with circulating lymphoma.However, eradication of solid tumors with CAR-T therapy has not been reported yetto be efficacious. In solid tumors, stroma destruction, due to MHC-restrictedcross-presentation of t

16、umor antigens to T cells, may be essential. However,CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but notstroma cells. In this report, we show how CAR-Ts can be engineered to eradicatelarge established tumors with provision of a suitable CD28 costimulatory signal. In a HER-2-dependent tumor mode