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552 Combination of Ibrutinib and Nivolumab Overcomes Ibrutinib Resistance in a Novel Patient-Derived Mantle Cell Lymphoma 3D Model

Program: Oral and Poster Abstracts
Type: Oral
Session: 622. Lymphomas: Translational–Non-Genetic: Translational Research in Lymphoma: Prognostic Biomarkers and Novel Therapeutic Vulnerabilities
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, Lymphomas, non-Hodgkin lymphoma, B Cell lymphoma, Combination therapy, genomics, bioinformatics, Checkpoint Inhibitor, blood banking, Diseases, immune mechanism, cell expansion, aggressive lymphoma, Therapies, Immunotherapy, immunology, Lymphoid Malignancies, Monoclonal Antibody Therapy, Biological Processes, molecular biology, Technology and Procedures, profiling, imaging
Sunday, December 11, 2022: 1:15 PM

Ferran Araujo-Ayala1,2*, Cèlia Dobaño-López, MSc1,2*, Juan G Valero, PhD1,2*, Ferran Nadeu, PhD1,2*, Fabien Gava, PhD3*, Carla Faria, PhD3*, Marine Norlund, PhD4*, Renaud Morin, PhD4*, Pascale Bernes-Lasserre4*, Neus Serrat, MD, PhD1*, Heribert Playa-Albinyana, MSc, BSc1,2,5*, Rubén Giménez, MSc1,2*, Elías Campo, PhD MD1,2,5,6, Jean Michel Lagarde, PhD4*, Armando López-Guillermo, MD, PhD1,2,5,7*, Eva Giné, MD, PhD1,2,7, Dolors Colomer, PhD1,2,5,6*, Christine Bezombes, PhD3* and Patricia Pérez-Galán, PhD1,2*

1Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
3Centre de Recherches en Cancérologie de Toulouse, INSERM, Toulouse, France
4IMACTIV-3D, Toulouse, France
5University of Barcelona, Barcelona, Spain
6Hematopathology Section, Pathology Department, Hospital Clinic, Barcelona, Spain
7Hematology Department, Hospital Clínic, Barcelona, Spain

Mantle cell lymphoma (MCL) is a rare and aggressive B cell non-Hodgkin lymphoma subtype which arises from mature B cells and mainly develops in the lymph node (LN) microenvironment, with a significant proportion of cases showing peripheral blood (PB) dissemination. However, the LN is the organ where MCL creates a protective and immunosuppressive tumor microenvironment (TME), including tumor-associated macrophages that induce tumor survival, proliferation and chemoresistance.

To capture disease heterogeneity and microenvironment cues, we have developed the first MCL Patient-derived lymphoma spheroid (MCL-PDLS) model culturing lymphoma cells from PB in 96-well ultra-low attachment plates with a cytokine cocktail that mimics LN stimuli. Remarkably, our model recapitulates MCL tumor oncogenic pathways. Moreover MCL-PDLS shows immune profile in a multiplexed system that allows easy drug screening including immunotherapies.

MCL-PDLS include tumor B cells and autologous T cells obtained from patients’ PB samples, together with healthy donors’ monocytes to complete the LN immune microenvironment. These populations self-organize in disc-shaped structures, as determined by light sheet microscopy, where B and T cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. Interestingly, RNA-seq analysis demonstrated that tumor cells in MCL-PDLS recapitulate fundamental hallmarks of MCL-LN (Saba et al, Blood 2015), such as proliferation, BCR, NF-kB, antigen presentation and DNA repair, among others.

Using public data basis we have determined by differential expression analysis (MCL-LN vs normal tonsils) a immune profile characteristic of MCL-LN. Flow cytometry analysis of MCL-PDLS determined that immune exhaustion profile is recapitulated in our model, including high expression of PD1, TIM-3 and TIGIT, and their corresponding ligands, together with the expression of other immune regulators such as CD70, CD27, CD47 and SIRPα.

Noteworthy, we have validated that MCL-PDLS reproduce in vivo responses to the first-in-class Bruton’s tyrosine kinase inhibitor ibrutinib, setting the basis for the discovery of novel combinatorial approaches. In this regard, we have demonstrated that the combination of ibrutinib with Nivolumab (anti-PD1), may be efficacious in ibrutinib-resistant cases and induces a Th1-polarized response and cytotoxic activity, as demonstrated by an increased IFNγ and granzyme B release, respectively.

In conclusion, MCL-PDLS recapitulates specific LN features and in vivo responses to ibrutinib, representing a robust tool to study the pathogenesis of MCL, its interaction with the TME, and to perform drug screening in a patient-derived system, thus advancing towards personalized therapeutic approaches.

Disclosures: López-Guillermo: Roche: Research Funding; Hospital Clinic de Barcelona: Current Employment; Roche, Kite/Gilead, Celgene, Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giné: Kite, a Gilead Company: Consultancy, Honoraria; Genmab: Honoraria; Janssen: Honoraria, Research Funding.

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