Abstract
Abstract Introduction: Follicular lymphoma (FL) is an indolent disease characterized by a dysfunctional immune compartment. The standard of care in FL is chemotherapy-based treatment (R-CHOP/R-CVP or R-Bendamustine), with a high overall response rate of >90% but low complete response (CR) rates between 25% to 31% (Flinn 2014). The majority of patients still relapse and often experience immune suppression resulting from chemo-related cytotoxicity that may ultimately impact outcomes. Lenalidomide (Len) has both potent direct antineoplastic and immunomodulatory activity. Len in combination with rituximab (Rtx) has shown enhanced antibody-dependent cellular cytotoxicity (ADCC) and direct apoptosis in B-cell lymphoma in vitro and in animal models (Wu 2008; Hernandez-Ilizaliturri 2005). Multiple phase II studies showed that R2 therapy achieves clinical synergy in treatment naive (Fowler 2014; Martin ICML 2017) and relapsed/refractory settings (Leonard 2015; Andorsky ASCO 2017). Here we provide a mechanistic rationale beyond ADCC for the activity observed in the clinical setting using patient samples. We show T and NK cell activation by Len in FL patients ex vivo and demonstrate R2activity in FL cell lines providing clear differentiation from immunochemotherapy. Methods: Peripheral blood mononuclear cells (PBMCs) from FL patients were treated with Len (1nM-10µM), analyzed for cytokine production by ELISA, T and NK-cell activation on day 3 and proliferation of T and NK-cells on day 5 by flow. Len, idelalisib, bendamustine (1nM-10µM), and ibrutinib (0.1nM-1µM) were each used in combination with Rtx in an ADCC and cell autonomous assay to measure apoptosis by Annexin V/ToPro-3 flow cytometry against FL cell lines DoHH2 and RL. For cell autonomous assay, cells were treated with therapeutic agents for 7 days followed by 24hr Rtx treatment. Synergy of Rtx in combination with each therapeutic agent was calculated using fractional product method (Chou, 1984). For ADCC assays, healthy donor (HD) or FL PBMC were treated with therapeutic agent for 3 days followed by a 4-hr incubation with Rtx-treated CFSE labeled target tumor cells. PBMC viability was measured immediately prior to co-culture by Annexin V/To-Pro. Results: In ex vivo FL PBMCs, Len significantly enhanced proliferating CD4+and CD8+ T cells by up to 3 and 7-fold respectively (p Conclusion: R2 is a novel and effective combination immunotherapy in FL. The mechanism of action of this combination results in T and NK cell activation, which leads to enhanced ADCC and addresses the known immune dysfunction in FL. This combination is clearly differentiated from chemo-immunotherapy. The R2 combination immunotherapy is currently being assessed in the FL frontline phase 3 RELEVANCE trial (NCT01476787) and in the relapsed FL setting in the AUGMENT trial (NCT01938001). Disclosures Chiu: Celgene: Employment, Equity Ownership. Hagner: Celgene: Employment, Equity Ownership. Trisal: Celgene: Employment, Equity Ownership. Waldman: Celgene: Employment, Equity Ownership, Patents & Royalties: US 9,587,281 B2. Cavanaugh: Celgene: Employment. Gandhi: Celgene Corporation: Employment, Equity Ownership.
Published Version
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