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2880 Effective and Safe Immune Checkpoint Blockade Induces Complete Responses in Murine PTCL Model of ALCL

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational–Non-Genetic: Poster II
Hematology Disease Topics & Pathways:
Biological therapies, Research, Lymphomas, Translational Research, T Cell lymphoma, Checkpoint Inhibitor, Diseases, Therapies, Lymphoid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Linda Gräßel, MD1*, Teresa Poggio, PhD1,2*, Geoffroy Andrieux, PhD2,3*, Irene Gonzalez-Menendez, PhD4*, Stefanie Kreutmair1,2,5*, Cornelius Miething, MD1,2*, Federico Bonofiglio, PhD6*, Ivonne Aidee Montes Mojarro, PhD4*, Marie Follo, PhD1*, Dietmar Pfeifer, PhD1*, Falko Fend, MD4*, Leticia Quintanilla-Martinez, MD4, Robert Zeiser, MD1,2, Suzanne Turner, PhD7,8*, Melanie Börries, PhD2,3*, Justus Duyster1,2* and Anna Lena Illert, MD1,2*

1Department of Hematology, Oncology, and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany
2German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
3Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
4Department of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
5Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
6Veramed GmbH, Frankfurt am Main, Germany
7CEITEC, Masaryk University, Brno, Czech Republic
8Department of Pathology, University of Cambridge, Cambridge, United Kingdom

Anaplastic large cell lymphoma (ALCL) is a rare T-cell non-Hodgkin lymphoma. In the majority of cases the disease is driven by a chromosomal translocation t(2;5)(p23;35) leading to the fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin gene (NPM), constitutively activating ALK kinase.

In the last decade immunotherapy turned out to be a real game-changer in cancer treatment, especially in the field of solid tumors. Regarding T-cell lymphomas (TCL), the significance of immune checkpoint inhibition is still highly debated. The outcomes in preclinical models as well as clinical trials are ranging from response to hyperprogression. Consequently, to provide a better understanding of the role and underlying mechanisms of targeting immune checkpoint axes, preclinical models of TCL are urgently needed to identify patients that benefit from immunotherapy as well as potential biomarkers.

To examine disease biology and therapy effects of ALCL in vivo, we use a syngeneic retroviral bone marrow transplantation mouse model of ALK+ ALCL that closely resembles the disease in humans. In order to study the effect of blocking the PD-1/PD-L1-axis in ALCL in vivo, serial transplantations of lymphoma cells from a murine thymus were performed. We further investigated both spontaneous and immunotherapy-induced immune responses and characterized the interaction of innate and adaptive immune master players with flow cytometry, cytokine analysis, histology and transcriptome analysis.

In our mouse model of ALK+ ALCL we confirmed the upregulation of PD-L1 on ALK+ lymphoma cells in vivo. Immune checkpoint inhibition of PD-L1 in vivo leads to high complete response rates, prolonged survival and significantly reduced lymphoma burden of treated animals. Flow cytometry analysis revealed that PD-L1 blockade reverses Treg-mediated immunosuppression and causes augmented circulation of CD8+ effector T-lymphocytes. Treatment with depletion antibodies of lymphocyte subpopulations unveils CD4+ T-cells and NK-cells but not CD8+ T-cells as master players of checkpoint-mediated immune response to ALK+ ALCL. Accordingly, we identified exhausted CD4+ T-cells in non-responders to checkpoint inhibition underlining the central role of CD4+ T-cells in ALCL immune surveillance and response.

These results are contributing to a broader understanding of the immune surveillance and response in ALCL, with the outmost goal of better identifying patients that benefit from immunotherapy.

Disclosures: Zeiser: Incyte Corporation: Consultancy; Magenta: Consultancy; Novartis Pharmaceuticals: Consultancy; Equilium: Consultancy; Daiichi: Consultancy; Celularity: Consultancy. Illert: AbbVie, Janssen-Cilag, Takeda, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Roche, AstraZeneca, Janssen-Cilag, Takeda: Other: Travel support and attending meetings; Roche, AstraZeneca, Ars Tempi, Takeda: Honoraria.

*signifies non-member of ASH