Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors

Abstract

NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157–165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1157–165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1157–165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-012-1384-4) contains supplementary material, which is available to authorized users.

Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma

“…Killing assays were carried out with the IncuCyte FLR-Platform (Essen BioScience), as described previously (53,54). Adherent A375 cells were plated at 2 × 10 4 cells per well and incubated overnight at 37°C/5% CO 2 in RPMI-1640 medium supplemented with 10% heat-inactivated FBS and GlutaMAX (Life Technologies) in a 96-well flat-bottom plate.…”

Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma

“…For instance, McCormack et al (2012) recently reported promising preclinical data investigating the novel immunotherapeutic agent ImmTAC-NYE (Immune-mobilizing monoclonal T-cell receptors Against Cancer-NY-ESO-1). 42 ImmTAC-NYE is a bi-specific fusion protein comprised of a monoclonal T-cell receptor specific for both NY-ESO-1 and LAGE-1 fused with anti-CD3, which activates a potent antitumor T-cell response.…”

Cancer Immunotherapy Confers a Global Benefit

“…Of all cancer-testis antigens, MAGE-1 family has obtained growing interest as potential target for different cancers at variable stages [ 169 -173 ]. MAGE-A3 and NY-ESO-1, two cancer-testis antigens, have been used to develop cancer vaccines against melanoma [ 174 -176 ], lung cancer [ 177 ], ovarian carcinoma [ 178 ], and prostate cancer [ 179 ]. In addition to tumor-specifi c antigens, tumorassociated antigens with narrow distribution in tumor cells are widely used in cancer immunotherapy like tumor lysate antigens in DC-loaded vaccines [ 37 , 180 , 181 ].…”