Abstract A023: Identifying new therapeutic indications for afamitresgene autoleucel (“afami-cel” [formerly ADP-A2M4]) in adult and pediatric sarcomas using MAGE-A4 immunohistochemistry
Authors: Biswas Swethajit , Laberiano Caddie , Wani Khalida , Ingram Davis , Lu Wei , Lazcano Rossana , Wang Wei-Lien , Chen Yao , Williams Dennis , McAlpine Cheryl , Lazar Alexander J. , Solis Soto Luisa M. 
Published: September 2022

Introduction: Melanoma-associated antigen A4 (MAGE-A4) is a cancer testis antigen expressed in multiple solid tumors. Afami-cel is an autologous, specific peptide enhanced affinity receptor T-cell therapy targeting MAGE-A4 in HLA-A*02+ patients, which has shown promising efficacy in heavily pretreated metastatic synovial sarcoma (SS) and myxoid liposarcoma (MLPS) with cellular features (myxoid/round cell liposarcoma, MRCLS). Assessing MAGE-A4 expression across a wider range of adult and pediatric sarcoma subtypes could identify new therapeutic indications for afami-cel. Methods: Formalin-fixed, paraffin-embedded tissue microarrays from resections of primary and metastatic sarcomas were collected from 1981 to 2015 at The University of Texas MD Anderson Cancer Center. Included sarcomas were: SS (n=70), osteosarcomas (OS; n=107), Ewing sarcomas (ES; n=125), angiosarcoma (n=101), non-uterine leiomyosarcoma (n=186), malignant peripheral nerve sheath tumor (MPNST; n=95), pleomorphic liposarcoma (n=42), MLPS (n=78), uterine leiomyosarcoma (ULMS; n=216), and undifferentiated pleomorphic sarcoma (n=82). Tumors from patients ≤21 years were considered pediatric sarcomas. MAGE-A4 expression intensity (0 to 3+) was assessed by a research-only, non-clinical-trial use, immunohistochemistry assay developed at MD Anderson using a monoclonal antibody (Origene, Rockville, MD). The staining was reported as H-score (range 0–300; [(% positive cells intensity 1) x 1] + [(% positive cells intensity 2+) x 2] + [(% positive cells intensity 3+) x 3]) and percentage of MAGE-A4 expression ≥1+ or 2+. Samples with 30% of tumor cells showing ≥2+ MAGE-A4 expression were considered positive. Results: We analyzed 1102 samples from 702 sarcoma patients. The mean (range) H-score was 26.2 (0–101.9), and 532 (59%) samples were from female patients. Patients’ ages ranged from 5 to 90 years; 124 (11.3%) samples were pediatric. Most common SS was monophasic histology (72%), and most MLPS lacked a cellular component (65%). SS had the highest percentage of MAGE-A4 positivity (47.1%, mean H-score: 101.9), followed by MLPS (16.7%, mean H-score: 36.6), pleomorphic liposarcoma (11.9%), angiosarcoma (9.9%), ULMS (7.4%), MPNST (6.3%), OS (6.5%), LMS (2.7%), and UPS (2.4%). All Ewing sarcoma samples were negative. In pediatric patients, MAGE-A4 positivity was seen only in SS, OS, and angiosarcoma (MAGE-A4 positive rate: 33.3% [5/15], 7.9% [5/62], 25% [1/4], respectively). In MLPS, MRCLS showed significantly more MAGE-A4 positive cases than uniformly myxoid tumors (30% vs 11.8%, Tukey's test, a=0.05). In ULMS, recurrent tumors had significantly more MAGE-A4 positive cases than metastatic tumors (12.1% vs 2.4%, Tukey's test, a=0.05). Conclusions: MAGE-A4 was heterogeneously expressed across 10 sarcoma subtypes. The rates of MAGE-A4 positivity were the highest in SS and MLPS and were lower in other sarcoma subtypes. MAGE-A4 testing in sarcoma subtypes other than SS and MLPS warrants evaluating afami-cel in these ultrarare subtypes of soft tissue sarcomas where treatment options are very limited.

Citation Format: Swethajit Biswas, Caddie Laberiano, Khalida Wani, Davis Ingram, Wei Lu, Rossana Lazcano, Wei-Lien Wang, Yao Chen, Dennis Williams, Cheryl McAlpine, Alexander J. Lazar, Luisa M. Solis Soto. Identifying new therapeutic indications for afamitresgene autoleucel (“afami-cel” [formerly ADP-A2M4]) in adult and pediatric sarcomas using MAGE-A4 immunohistochemistry [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A023.