Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System

被引：269

作者：

Avanzi, Mauro P. ^{[1
]}

Yeku, Oladapo ^{[1
]}

Li, Xinghuo ^{[3
]}

Wijewarnasuriya, Dinali P. ^{[3
]}

van Leeuwen, Dayenne G. ^{[1
]}

Cheung, Kenneth ^{[1
]}

Park, Hyebin ^{[1
]}

Purdon, Terence J. ^{[1
]}

Daniyan, Anthony F. ^{[1
]}

Spitzer, Matthew H. ^{[2
]}

Brentjens, Renier J. ^{[1
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[3] Weill Cornell Sch Med, New York, NY 10065 USA

来源：

CELL REPORTS | 2018年 / 23卷 / 07期

关键词：

MYELOID CELLS; ERADICATION; RESISTANCE; MICE;

D O I：

10.1016/j.celrep.2018.04.051

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.

引用

页码：2130 / 2141

页数：12

共 34 条

[21] Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts [J].

Krevvata, Maria ;

Silva, Barbara C. ;

Manavalan, John S. ;

Galan-Diez, Marta ;

Kode, Aruna ;

Matthews, Brya Grace ;

Park, David ;

Zhang, Chiyuan A. ;

Galili, Naomi ;

Nickolas, Thomas L. ;

Dempster, David W. ;

Dougall, William ;

Teruya-Feldstein, Julie ;

Economides, Aris N. ;

Kalajzic, Ivo ;

Raza, Azra ;

Berman, Ellin ;

Mukherjee, Siddhartha ;

Bhagat, Govind ;

Kousteni, Stavroula .

BLOOD, 2014, 124 (18) :2834-2846

[22] T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial [J].

Lee, Daniel W. ;

Kochenderfer, James N. ;

Stetler-Stevenson, Maryalice ;

Cui, Yongzhi K. ;

Delbrook, Cindy ;

Feldman, Steven A. ;

Fry, Terry J. ;

Orentas, Rimas ;

Sabatino, Marianna ;

Shah, Nirali N. ;

Steinberg, Seth M. ;

Stroncek, Dave ;

Tschemia, Nick ;

Yuan, Constance ;

Zhang, Hua ;

Zhang, Ling ;

Rosenberg, Steven A. ;

Wayne, Alan S. ;

Mackall, Crystal L. .

LANCET, 2015, 385 (9967) :517-528

[23] Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma [J].

Louis, Chrystal U. ;

Savoldo, Barbara ;

Dotti, Gianpietro ;

Pule, Martin ;

Yvon, Eric ;

Myers, G. Doug ;

Rossig, Claudia ;

Russell, Heidi V. ;

Diouf, Oumar ;

Liu, Enli ;

Liu, Hao ;

Wu, Meng-Fen ;

Gee, Adrian P. ;

Mei, Zhuyong ;

Rooney, Cliona M. ;

Heslop, Helen E. ;

Brenner, Malcolm K. .

BLOOD, 2011, 118 (23) :6050-6056

[24] Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes [J].

Mantovani, A ;

Sozzani, S ;

Locati, M ;

Allavena, P ;

Sica, A .

TRENDS IN IMMUNOLOGY, 2002, 23 (11) :549-555

[25] Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia [J].

Maude, Shannon L. ;

Frey, Noelle ;

Shaw, Pamela A. ;

Aplenc, Richard ;

Barrett, David M. ;

Bunin, Nancy J. ;

Chew, Anne ;

Gonzalez, Vanessa E. ;

Zheng, Zhaohui ;

Lacey, Simon F. ;

Mahnke, Yolanda D. ;

Melenhorst, Jan J. ;

Rheingold, Susan R. ;

Shen, Angela ;

Teachey, David T. ;

Levine, Bruce L. ;

June, Carl H. ;

Porter, David L. ;

Grupp, Stephan A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (16) :1507-1517

[26] A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma [J].

O'Rourke, Donald M. ;

Nasrallah, MacLean P. ;

Desai, Arati ;

Melenhorst, Jan J. ;

Mansfield, Keith ;

Morrissette, Jennifer J. D. ;

Martinez-Lage, Maria ;

Brem, Steven ;

Maloney, Eileen ;

Shen, Angela ;

Isaacs, Randi ;

Mohan, Suyash ;

Plesa, Gabriela ;

Lacey, Simon F. ;

Navenot, Jean-Marc ;

Zheng, Zhaohui ;

Levine, Bruce L. ;

Okada, Hideho ;

June, Carl H. ;

Brogdon, Jennifer L. ;

Maus, Marcela V. .

SCIENCE TRANSLATIONAL MEDICINE, 2017, 9 (399)

[27] IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia [J].

Pegram, H. J. ;

Purdon, T. J. ;

van Leeuwen, D. G. ;

Curran, K. J. ;

Giralt, S. A. ;

Barker, J. N. ;

Brentjens, R. J. .

LEUKEMIA, 2015, 29 (02) :415-422

[28] Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning [J].

Pegram, Hollie J. ;

Lee, James C. ;

Hayman, Erik G. ;

Imperato, Gavin H. ;

Tedder, Thomas F. ;

Sadelain, Michel ;

Brentjens, Renier J. .

BLOOD, 2012, 119 (18) :4133-4141

[29] Tumor growth impedes natural-killer-cell maturation in the bone marrow [J].

Richards, John O. ;

Chang, Xing ;

Blaser, Bradley W. ;

Caligiuri, Michael A. ;

Zheng, Pan ;

Liu, Yang .

BLOOD, 2006, 108 (01) :246-252

[30] Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy [J].

Sotillo, Elena ;

Barrett, David M. ;

Black, Kathryn L. ;

Bagashev, Asen ;

Oldridge, Derek ;

Wu, Glendon ;

Sussman, Robyn ;

Lanauze, Claudia ;

Ruella, Marco ;

Gazzara, Matthew R. ;

Martinez, Nicole M. ;

Harrington, Colleen T. ;

Chung, Elaine Y. ;

Perazzelli, Jessica ;

Hofmann, Ted J. ;

Maude, Shannon L. ;

Raman, Pichai ;

Barrera, Alejandro ;

Gill, Saar ;

Lacey, Simon F. ;

Melenhorst, Jan J. ;

Allman, David ;

Jacoby, Elad ;

Fry, Terry ;

Mackall, Crystal ;

Barash, Yoseph ;

Lynch, Kristen W. ;

Maris, John M. ;

Grupp, Stephan A. ;

Thomas-Tikhonenko, Andrei .

CANCER DISCOVERY, 2015, 5 (12) :1282-1295

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