Abstract LB001: Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients
Authors: Wang Tianjiao , Navenot Jean-Marc , Rafail Stavros , Carroll Mark , Wang Ruoxi , McAlpine Cheryl , Biswas Swethajit , Brophy Francine , Elefant Erica , Bayer Paige , McGuigan Sandra , Williams Dennis , Blumenschein George , Butler Marcus , Clarke Jeffrey M. , Gainor Justin F. , Govindan Ramaswamy , Moreno Victor , Tu Janet , Hong David S. 
Published: June 2022

Autologous T-cells engineered with T-cell receptors (TCRs) targeting tumor antigens are promising therapies for metastatic solid cancers.1 Specific peptide enhanced affinity receptor (SPEAR) T-cell therapies are T-cells with engineered HLA-restricted TCRs that precisely target tumor cells with specific antigens, such as MAGE-A4 (a cancer testis antigen), presented on the surface by HLA molecules. In SPEAR T-cell clinical trials targeting MAGE-A4, a 2-step prescreen is done before enrolment. 1) Patients undergo HLA typing via a high-resolution (allelic, 4-digit) sequence-based assay, and those who are positive for the inclusion alleles (HLA-A*02:01P, 02:02P, 02:03P, 02:06P) and not positive for the exclusion allele A*02:05P are eligible. 2) Tumor MAGE-A4 testing is done via an immunohistochemical clinical trial assay (MAGE-A4+ cutoff: ≥30% tumor cell staining at ≥2+ intensity) in HLA-eligible patients. A screening protocol (NCT02636855) has been used in Phase 1 trials of first- and next-generation SPEAR T-cells targeting MAGE-A4 (NCT03132922, NCT04044859) with responses in multiple MAGE-A4+ tumors. As of November 19, 2021, 6,168 patients with 9 solid tumor types were screened at 32 sites across North America and Europe in this screening protocol; among which, 2,744 were HLA-eligible (eligibility rate: 45%, range per tumor type: 42%-55%). HLA-A*02:01 was the most frequent HLA-A*02 allele. Of these HLA-eligible patients, 1,549 had tumor tissues evaluable for MAGE-A4 expression; among which, 313 were MAGE-A4+ (MAGE-A4+ rate: 20%, range: 8%-54%) (Table). MAGE-A4 showed highest prevalence in synovial sarcoma and myxoid/round cell liposarcoma but was seen across all tumor types investigated. Our results will be discussed in the context of tumor histopathology, disease status, and demography. HLA and MAGE-A4 biomarker data will inform the therapeutic opportunities for SPEAR T-cells targeting MAGE-A4 in metastatic solid cancers. 1. D’Angelo et al. Cancer Discov. 2018;8:944.

HLA eligibility and MAGE-A4 prevalence in a screening protocol (NCT02636855) Indication Esophageal cancer Esophagogastric junction cancer Gastric cancer Head and neck squamous cell carcinoma Non-small cell lung cancer Melanoma Ovarian cancer Urothelial cancer Synovial sarcoma and myxoid/round cell liposarcoma HLA screened (N) 284 228 271 601 3189 668 539 270 118 HLA eligible (%) 46 45 43 42 43 50 49 43 55 MAGE-A4 evaluable (N) 104 91 73 200 457 245 225 93 61 MAGE-A4 positive (%) 22 25 8 22 14 16 24 32 54

Citation Format: Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas, Francine Brophy, Erica Elefant, Paige Bayer, Sandra McGuigan, Dennis Williams, George Blumenschein, Marcus Butler, Jeffrey M. Clarke, Justin F. Gainor, Ramaswamy Govindan, Victor Moreno, Janet Tu, David S. Hong. Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB001.