Abstract 1932: Targeting the extended erbb receptor family using chimeric antigen receptor (CAR)-grafted t-cells as a treatment for head and neck cancer

Abstract

Abstract Over-expression of the epidermal growth factor receptor (ErbB1) is found in the majority of squamous cell carcinomas of the head and neck (SCCHN), making it an attractive therapeutic target. However, tumors often become refractory to ErbB1-specific therapies by upregulating other ErbB receptors. In keeping with this, increased expression of additional ErbB kinases is associated with poorer prognosis in SCCHN. Consequently, we hypothesized that simultaneous targeting of multiple ErbB receptors would represent a more robust therapeutic strategy. This hypothesis has been tested using adoptive T-cell therapy, in which primary human T-cells have been genetically manipulated to express a chimeric antigen receptor (CAR) named T28z. The broadened ErbB-targeting capacity of T28z is mediated by a chimeric peptide derived from transforming growth factor-α and EGF, known as T1E. Signaling is provided by a fused CD28+CD3ζ endodomain, ensuring full T-cell activation. To characterize the ErbB dimers recognized by T28z+ T-cells, co-cultivation experiments were performed with a panel of transfected 32D hematopoietic cells that express all ErbB receptors, alone or in pairs. We observed that a wide range of ErbB dimers are targeted, including those containing ErbB1 and the profoundly mitogenic ErbB2/ErbB3 heterodimer. T28z-grafted T-cells underwent activation on all of 13 SCCHN monolayers (displaying a range of ErbB expression profiles), when compared to T-cells expressing a control CAR with a truncated endodomain (T1NA). Importantly, T-cell activation was accompanied by tumor cell destruction, cytokine release and proliferation. Minimal T-cell activation was seen on control monolayers that express low ErbB levels. To study the in-vivo efficacy and toxicity of T28z-expressing T-cells, SCID/Beige mice were inoculated intraperitoneally (ip) with the SCCHN cell line, HN3, engineered to express firefly luciferase. Mice with established tumor were treated ip after 13 days with PBS or with 2×107 human T-cells that express T28z or T1NA. Tumor status was evaluated weekly using bioluminescent imaging (BLI). Compared to control groups, mice treated with T28z+ T-cells showed markedly delayed tumor growth and remain alive with minimal BLI signal >100 days post treatment. No toxicity was observed despite the capacity of human ErbB ligands (contained within T1E) to engage murine ErbB receptors. These data show that simultaneous targeting of the extended ErbB family may be achieved using a single T-cell population and that these cells are capable of inducing tumor regression in-vivo without untoward toxicity. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1932.