{ "abstract": "Background T cells with self-renewing properties are important for anti-tumor immunity. The presence of stem-like memory T cells (T SCM) and T cells expressing TCF1, critical in T cell self-renewal, within tumor-draining lymph nodes and tumors associate with improved tumor control with immune checkpoint blockade. As these tissues are not readily accessible, we investigated whether the presence of stem-like T cells in peripheral blood after immunotherapy may help identify patients more likely to respond. PDS01ADC (NHS-IL12) is a tumor-targeting IL-12 immunocytokine; the murine version of this agent (NHS-muIL12) induced significant survival benefit in poorly immunogenic murine tumor models, alone and in combination with other agents.1–7 Clinically, PDS01ADC monotherapy was safe and well tolerated in patients with advanced solid tumors, with preliminary signs of clinical activity (stable disease in 50% of evaluable patients).8 9 Here, we investigated the effects of PDS01ADC on peripheral T cell stemness in murine hosts and patients with advanced solid tumors.Methods T SCM and expression of the murine T cell stemness marker SCA1 were evaluated by flow cytometry in spleens of C57BL/6 and BALB/C mice treated with NHS-muIL12. Longitudinal PBMCs from 28 cancer patients treated with PDS01ADC in a phase I trial (NCT01417546) were assessed for circulating TSCM by flow cytometry. Expression of TCF1, PD-1, and TIGIT on TSCM and more differentiated T cell subsets was evaluated. Patients with stable disease were compared to patients with no clinical benefit.Results NHS-muIL12 treatment in mice increased SCA1+ peripheral T cells with stem-like phenotypes. In patients with advanced solid tumors, PDS01ADC increased peripheral CD8+ and CD4+ T SCM frequencies and effector memory T (TEM) cells expressing TCF1, with greater magnitude of increases associated with disease control. Orthogonal validation via dimensionality reduction and unsupervised clustering of CD8+ T cells confirmed that patients with disease control had greater increases in TSCM and TCF1+ TEM over baseline. Most peripheral TSCM remained negative for PD-1 and TIGIT throughout PDS01ADC therapy, suggesting their quiescence and self-renewal capacity. Expanded TCF1-negative CD8+ TEM expressed PD-1 with increased intensity of granzyme B, indicating an activated, cytotoxic state.Conclusions This is the first study on effects of an immunocytokine on peripheral T cell stemness in mice and humans. We show that PDS01ADC treatment in patients with advanced solid tumors boosts peripheral T cells with stem-like and activated characteristics, correlating with disease stabilization. Further studies combining PDS01ADC with other immunotherapies to synergize with this peripheral burst of T cell stemness are warranted.References Fallon J, Tighe R, Kradjian G, Guzman W, Bernhardt A, Neuteboom B, Lan Y, Sabzevari H, Schlom J, Greiner JW. The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget. 2014;5:1869–84.Morillon YM 2nd, Su Z, Schlom J, Greiner JW. Temporal changes within the (bladder) tumor microenvironment that accompany the therapeutic effects of the immunocytokine NHS-IL12. J Immunother Cancer. 2019;7:150.Minnar CM, Chariou PL, Horn LA, Hicks KC, Palena C, Schlom J, Gameiro, SR. Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies. 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Nat Commun. 2021;12:5151.Strauss J, Heery CR, Kim JW, Jochems C, Donahue RN, Montgomery AS, McMahon S, Lamping E, Marte JL, Madan RA, Bilusic M, Silver MR, Bertotti E, Schlom J, Gulley JL. First-in-human phase I trial of a tumor-targeted cytokine (NHS-IL12) in subjects with metastatic solid tumors. Clin Cancer Res. 2019;25:99-109.Gatti-Mays ME, Tschernia NP, Strauss J, Madan RA, Karzai FH, Bilusic M, Redman J, Abdul Sater H, Floudas CS, Toney NJ, Donahue RN, Jochems C, Marte JL, Francis D, McMahon S, Lamping E, Cordes L, Schlom J, Gulley JL. A phase i single-arm study of biweekly NHS-IL12 in patients with metastatic solid tumors. Oncologist. 2023;28:364-e217.Ethics Approval All subjects gave written informed consent. Study protocol ( NCT01417546) was approved by the NIH’s IRB, and conducted in accordance with institutional and federal guidelines.", "authors": [ { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Meghali Goswami" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Carolina Celades" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Christine M Minnar" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Asma S Khelifa" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Lisa K Poppe" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Dara Bracken-Clarke" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Nicole J Toney" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Megan T Lynch" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Jennifer L Marte" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Sofia R Gameiro" }, { "affiliations": [ "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "James L Gulley" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Jeffrey Schlom" }, { "affiliations": [ "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA" ], "name": "Renee N Donahue" } ], "title": "168 Increases in peripheral memory T cells with self-renewing properties in patients with advanced solid tumors treated with tumor-targeting IL-12 immunocytokine therapy", "uid": "af0e74c3-939b-5327-b454-a2789651130e" }