Flexible Targeting of ErbB Dimers That Drive Tumorigenesis by Using Genetically Engineered T Cells

Abstract

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 ErbBengineered 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 T1E28z + 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.

Driving CAR T-cells forward

“…For example, the TAA-recognition receptor, T1E28z, is composed of second-generation CAR signalling domains (CD28/CD3ζ) ligated to T1E, a chimeric polypeptide that binds to HER1 homodimers and to HER2/HER3 heterodimers 142 . The signalling receptor is a chimeric cytokine receptor (4αβ), in which the IL-4 receptor ectodomain is ligated to the β-chain subunit shared by IL-2 and IL-15 receptors, enabling IL-2/IL-15-like pro-inflammatory stimulating signalling triggered by IL-4 — a cytokine that has a role in the immune microenvironment in many tumour types 141 .…”

CAR T-cell Therapy: Toxicity and The Relevance of Preclinical Models

“…In contrast to the absence of toxicity observed using CAR's armed with scFv targeting Her2/neu in preclinical model systems, human T cells armed with the T1E28z second-generation CAR, which binds ErbB-1 homodimers and also ErbB2/3 heterodimers, displayed toxicity in mice [47]. This CAR transgene was co-expressed with a chimeric protein consisting of the IL-4α chain fused to the IL-2/IL-15 β chain permitting IL-4-driven selection of gene-modified T cells [47].…”

“…This CAR transgene was co-expressed with a chimeric protein consisting of the IL-4α chain fused to the IL-2/IL-15 β chain permitting IL-4-driven selection of gene-modified T cells [47]. Interestingly, the route of administration of T1E28z CAR T cells strongly influenced toxicity and antitumor efficacy in the SCID/Beige mouse.…”

Adoptive T-Cell Therapy for Solid Tumors

“…55 In addition, targeting individual ErbB receptors often results in acquired resistance because of enhanced activity of nontargeted receptors. In light of this, Davies et al 56 developed a second-generation CAR that incorporates a chimeric polypeptide, TIE, designed to achieve broad specificity for the ErbB network. ErbB-specific CAR T cells recognized and lysed several ErbB-positive tumor cell lines in vitro.…”