Hong and Tine et al. reported the safety and efficacy of Afamitresgene autoleucel (afami-cel), a MAGE-A4-targeting engineered TCR T cell therapy, in HLA-A*02+ patients with MAGE-A4-expressing solid tumors. Prolonged cytopenia, CRS, and neurotoxicity were the most common treatment-emergent AEs. The overall ORR was 24% (9/38), which is due to high ORR in patients with synovial sarcoma 44%. Functional afami-cel persisted in blood up to 18 months post treatment, and peak serum IFNγ levels correlated with clinical activity. A lower lymphodepleting chemotherapy regime showed a favorable hematological toxicity profile and was selected for a phase 2 trial.
Contributed by Shishir Pant
ABSTRACT: Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.
Author Info: (1) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. dshong@mdanderson.org. (2)
Author Info: (1) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. dshong@mdanderson.org. (2) Section of Medical Oncology, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (3) Adaptimmune, Abingdon, Oxfordshire, UK. (4) Adaptimmune, Abingdon, Oxfordshire, UK. (5) Sarah Cannon Cancer Institute, Tennessee Oncology/One Oncology, Nashville, TN, USA. (6) Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA. (7) Duke Cancer Institute, Duke University, Durham, NC, USA. (8) Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Thoracic-Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Adaptimmue, Philadelphia, PA, USA. (12) Adaptimmune, Abingdon, Oxfordshire, UK. (13) Adaptimmune, Abingdon, Oxfordshire, UK. (14) Adaptimmune, Abingdon, Oxfordshire, UK. (15) Adaptimmue, Philadelphia, PA, USA. (16) Adaptimmue, Philadelphia, PA, USA. (17) Adaptimmue, Philadelphia, PA, USA. (18) Adaptimmue, Philadelphia, PA, USA. (19) Adaptimmue, Philadelphia, PA, USA. (20) Adaptimmune, Abingdon, Oxfordshire, UK. (21) Adaptimmue, Philadelphia, PA, USA. (22) Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. (23) Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. (24) Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. (25) Adaptimmune, Abingdon, Oxfordshire, UK. (26) Adaptimmune, Abingdon, Oxfordshire, UK. (27) Adaptimmune, Abingdon, Oxfordshire, UK. (28) Adaptimmune, Abingdon, Oxfordshire, UK. (29) Adaptimmune, Abingdon, Oxfordshire, UK. (30) Adaptimmune, Abingdon, Oxfordshire, UK. (31) Adaptimmune, Abingdon, Oxfordshire, UK. (32) Adaptimmue, Philadelphia, PA, USA. (33) Adaptimmue, Philadelphia, PA, USA. (34) Section of Medical Oncology, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (35) Section of Medical Oncology, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (36) Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (37) Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (38) Adaptimmue, Philadelphia, PA, USA. (39) Adaptimmue, Philadelphia, PA, USA. (40) Adaptimmue, Philadelphia, PA, USA. (41) Sarcoma Medical Oncology, Moffitt Cancer Center, Tampa, FL, USA. (42) Department of Internal Medicine, Division of Medical Oncology, and Department of Biomedical Informatics, Division of Computational Biology and Bioinformatics, Ohio State University, Columbus, OH, USA. (43) University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA. (44) Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.
