Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells

TY - JOUR

T1 - Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells

AU - Davies, David M

AU - Foster, Julie

AU - Van Der Stegen, Sjoukje J C

AU - Parente-Pereira, Ana C

AU - Chiapero-Stanke, Laura

AU - Delinassios, George J

AU - Burbridge, Sophie E

AU - Kao, Vincent

AU - Liu, Zhe

AU - Bosshard-Carter, Leticia

AU - Van Schalkwyk, May C I

AU - Box, Carol

AU - Eccles, Suzanne A

AU - Mather, Stephen J

AU - Wilkie, Scott

AU - Maher, John

PY - 2012/4

Y1 - 2012/4

N2 - Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.

AB - Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.

U2 - 10.2119/molmed.2011.00493

DO - 10.2119/molmed.2011.00493

M3 - Article

C2 - 22354215

SN - 1076-1551

VL - 18

SP - 565

EP - 576

JO - Molecular Medicine

JF - Molecular Medicine

IS - 1

ER -