Background Immunotherapy in the form of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells has revolutionized the treatment of select malignancies.1–2 However, beyond CD19+ cancers, clinical responses to CAR-T have been modest in pediatric cancers, likely due to lower mutational burden. Antigen spreading, an expanded anti-tumor immune response through exposure to neoantigens, has been observed in patients following treatment with immunotherapy agents or chemotherapy for malignancies with typically higher mutational burdens.3–6]. However, this has not been observed in pediatric patients with solid tumors after standard treatment. We demonstrated the safety of autologous tumor-associated antigen-specific T lymphocytes (TAA-T) specific for WT1, PRAME, and Survivin in Phase I studies.7 We also identified antigen spreading post-infusion with increased T cells specific for non-targeted antigens MAGE-A3, MAGE-A4, SSX-2, and SOX-2, all expressed on solid tumors.8–12 We hypothesized that antigen spreading would be greater in patients who received TAA-T than in those who received standard chemotherapy or radiation therapy.
Methods Fourteen patients with pediatric solid tumors who received standard-of-care therapy were enrolled on the standard chemotherapy arm and compared to fourteen relapsed/refractory patients who received TAA-T infusion. Peripheral blood samples were taken prior to therapy, during therapy, and off therapy if available, and these were evaluated for the presence of T cells specific to MAGE-A3, MAGE-A4, SSX-2, and SOX-2 as measured by IFN-γ ELISPOT.
Results Our results demonstrate the presence of antigen spreading in newly diagnosed patients who receive standard therapy as evidenced by T cells specific for MAGE-A3 (mean: 28.2, range: 0–137 IFN-y SFC/1e5 cells (SFC)), MAGE-A4 (mean: 31.8, range: 0–270 SFC), SSX-2 (mean: 22.8, range: 0–100 SFC) and SOX-2 (mean: 7.2, range: 0–46 SFC). Similar levels of antigen spreading were also identified in relapsed/refractory patients post TAA-T infusion detecting T cells specific for MAGE-A3 (mean: 30.7, range: 0–249 SFC). MAGE-A4 (mean: 27.6, range: 0–230 SFC), SSX-2 (mean: 33.9, range: 0–200 SFC) and SOX-2 (mean: 39.5, range: 0–270 SFC).
Conclusions These results demonstrate immune activation as evidenced by antigen spreading in newly diagnosed pediatric patients with solid tumors receiving standard-of-care chemotherapy and radiation therapy, the majority of which remain in remission following treatment. Similar levels of antigen spreading were also observed in responding patients who received TAA-T for relapsed/refractory disease. This data provides further support for the role of immunotherapy in the treatment of pediatric solid tumors and the strong anti-tumor response these therapies can potentiate.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet. 2015; 385(9967): 517–528.
Davis KL, Fox E, Merchant MS, et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial. The Lancet Oncology. 2020; 21(4): 474–476.
Li AM, Hucks GE, Dinofia AM, et al. Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia. Blood. 2018; 132:556
Jackaman C, Majewski D, Fox SA, et al. Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8+ T cells in vivo. Cancer Immunol Immunother. 2012; 61(12):2343–2356.
Gulley JL, Madan RA, Pachynski R, et al. Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment. J Natl Cancer Inst. 2017; 109(4):1–9.
Brossart, P. The Role of Antigen Spreading in the Efficacy of Immunotherapies. Clin Cancer Res. 2020; 26(17):4442–4447.
Hont AB, Cruz CR, Ulrey R, et al. Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multiantigen-Associated Specific Cytotoxic T Lymphocytes: A Phase I Study. J Clin Oncol. 2019; 37(26):2349–2359.
Dalerba P, Frascella E, Macino B, et al. MAGE, BAGE and GAGE Gene Expression in Human Rhabdomyosarcomas. Int J Cancer. 2001; 93(1):85–90.
Jacobs JFM, Brasseur F, Hulsbergen-van de Kaa CA, et al. Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int J Cancer. 2006; 120(1):67–74.
References10. Naka N, Araki N, Nakanishi H, et al. Expression of SSX Genes in Human Osteosarcomas. Int J Cancer. 2002; 98(4):640–642.
11. Zayed H, Petersen I. Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors. Pathology – Research and Practice. 2018; 214(7):1000–1007.
12. Weon JL & Potts PR. The MAGE Family of Proteins and Cancer. Current Opinions in Cell Biology. 2015; 37: 1–8.
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