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4417 Anti-KIR Antibody Enhancement Of Anti-Lymphoma Activity Of Natural Killer Cells As Monotherapy and In Combination With Anti-CD20 Antibodies

Program: Oral and Poster Abstracts
Session: 625. Lymphoma: Pre-Clinical – Chemotherapy and Biologic Agents: Poster III
Monday, December 9, 2013, 6:00 PM-8:00 PM
Hall G (Ernest N. Morial Convention Center)

Holbrook E Kohrt, MD, PhD1, Ariane Thielens2*, Aurelien Marabelle, MD, MSc1*, Idit Sagiv Barfi1*, Caroline Sola2*, Fabien Chanuc2*, Nicolas Fuseri2*, Cécile Bonnafous2*, Debra K Czerwinski1, Amanda Rajapaksa1*, Erin Waller1*, Sophie Ugolini, PhD3*, Eric Vivier, PhD3*, Francois Romagne, PhD2, Ronald Levy, MD1, Pascale Andre, PhD2 and Mathieu Blery, PhD2*

1Division of Oncology, Stanford University School of Medicine, Stanford, CA
2Innate Pharma, Marseille, France
3Centre d'Immunologie de Marseille-Luminy, Marseille, France

Natural killer (NK) cells mediate anti-lymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of NK cell's efficacy by spontaneous cytoxicity. Using a killer cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with MHC class I antigens on lymphoma by anti-KIR antibodies prevents a tolerogenic interaction and augments NK cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in syngeneic and KIR transgenic murine lymphoma models.

Specifically targeting murine NK cells in vitro, anti-Ly49C/I F(ab')2 increased anti-CD20 mAb-mediated NK cell degranulation as measured by CD107a mobilization and interferon-γ release, as well as increased cytotoxicity as assessed by chromium release. In the syngeneic EL4-huCD20 lymphoma model, anti-Ly49C/I F(ab')2 enhanced the anti-lymphoma activity of anti-CD20 mAb in vivo (Fig 1A-1B) and was NK cell-dependent with efficacy abrogated by NK cell depletion with anti-Asialo-GM1. To validate these observations and the potential efficacy of a fully human anti-KIR mAb (IPH2101, lirilumab), we demonstrated, in vitro, dose-dependent KIR2DL3 saturation and tumor lysis following blockade of KIR2DL3/HLA-C with lirilumab. In the transgenic KIR murine model, lirilumab therapy improved survival in an NK cell-dependent manner in both a prophylactic and therapeutic HLA+ (221 HLA-Cw3) lymphoma model. In combination, lirilumab therapy synergistically enhanced rituximab's anti-lymphoma efficacy in vivo in an NK cell-dependent manner (Fig 2A-C).

These results support a therapeutic strategy of combination, rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor targeting therapy with an NK cell agonist thus stimulating the post-rituximab anti-lymphoma immune response.

Disclosures: Thielens: Innate Pharma: Employment, Equity Ownership. Sola: Innate Pharma: Employment, Equity Ownership. Chanuc: Innate Pharma: Employment, Equity Ownership. Fuseri: Innate Pharma: Employment. Bonnafous: Innate Pharma: Employment, Equity Ownership. Vivier: Innate Pharma: Membership on an entity’s Board of Directors or advisory committees. Romagne: Innate Pharma: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Andre: Innate-Pharma: Employment, Equity Ownership. Blery: Innate Pharma: Employment, Equity Ownership.

*signifies non-member of ASH