NY-ESO-1 and LAGE1A: An emerging target for cell therapies in solid tumours

Background Cell therapies have transformed the field of hematologic cancers, but treatment of solid tumours remains challenging. Emerging evidence suggests that T cell receptor (TCR)- engineered T cells targeting NY-ESO-1 hold promise for patients with solid tumours. NY-ESO-1 (CTAG1B) and LAGE1A (CTAG2) are tumour associated antigens (TAA) that share the SLLMWITQC peptide bound to human leukocyte antigen HLA-A*02 and are expressed in various cancers. GSK3377794 are autologous T cells engineered to express an affinity enhanced NY-ESO-1c259 TCR recognizing the SLLMWITQC/HLA-A*02 complex. Cell therapy trials using NY-ESO-1c259 TCR have shown promising efficacy in patients with synovial sarcoma, metastatic melanoma and multiple myeloma. Recently, a separate study using T cells targeted to NY-ESO-1 resulted in a partial response in a patient with advanced lung adenocarcinoma. This study aims to assess: 1) the prevalence of NY-ESO-1 and LAGE1A in various malignancies 2) GSK3377794 function against various tumours and 3) means to selectively modulate TAA expression in tumours to increase potential patient benefit. Methods Gene and transcript level RNAseq data for NY-ESO-1 and LAGE1A respectively, were extracted from TCGA B38 using ArrayStudio v10. A solid tumour biobank was established. HLA-A*02 expression was confirmed by flow cytometry and NY-ESO-1/LAGE1A levels were measured via qRT-PCR. Epigenetic modifiers were applied to increase TAA expression in tumours in vitro and in vivo. GSK3377794 anti-tumour function was determined by IFN-γ secretion. Results NY-ESO-1 and LAGE1A expression varied across malignancies and disease stages. Prevalence is high in synovial sarcoma and multiple myeloma (60-70%) and lower in lung cancer (12-15%). IFN-γ production by GSK3377794 positively correlates with antigen expression. Treatment with epigenetic modifiers lead to increased NY-ESO-1/LAGE1A expression in nonimmunogenic lung tumours, enhancing specific targeting by GSK3377794. Conclusions To date this is the most comprehensive analysis, using a set of clinically relevant sample specimens, that correlates antigen expression levels with functional responses of GSK3377794 in solid tumors. Epigenetic modifiers can improve GSK3377794 anti-tumour effect in lung cancer. Legal entity responsible for the study GlaxoSmithKline. Funding GlaxoSmithKline. Disclosure I. Eleftheriadou: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. S. Brett: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. A. Domogala: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. L. Patasic: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. M.A. Kijewska: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. K. Soor: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. M. Georgouli: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. J. Dopierala: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. P. Fisher: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. J. Jing: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. J. Euesden: Full / Part-time employment: GlaxosmithKline. K.R. Auger: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. R. Roberts: Full / Part-time employment: GlaxosmithKline. S. O’Sullivan: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. L. Castelletti: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. M. Damm: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. D. Pankov: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. L.A. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. A. Shalabi: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline. C. Britten: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxosmithKline.