Abstract 2205: TG-1701, a novel irreversible Bruton's kinase (BTK) inhibitor, cooperates with ublituximab-driven ADCC and ADCP in in vitro and in vivo models of ibrutinib-resistant mantle cell lymphoma
Authors: Ribeiro Marcelo L. , Reyes-Garau Diana , Vinyoles Meritxell , Armengol Marc , Miskin Hari , Bosch Francesc , Menendez Pablo , Normant Emmanuel , Roue Gael 
Published: September 2020

Abstract
Mantle cell lymphoma (MCL) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma (NHL) that remains incurable with standard therapy. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has proven to be an effective agent for patients with relapsed/refractory MCL, although development of a cysteine to serine mutation at the BTK catalytic site (BTKC481S) or over-activation of the NF-kB pathway can impair MCL response to most BTK inhibitors (BTKis). TG-1701 is a novel irreversible inhibitor highly specific to BTK, with improved selectivity when compared to ibrutinib, currently being evaluated in a phase 1 clinical trial in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) patients. Here we show that, when compared to irreversible and reversible BTKis including ibrutinib, acalabrutinib, and ARQ-531, TG-1701 showed similar cytotoxic activity either in ibrutinib-sensitive or in ibrutinib-resistant MCL cells. We then evaluated the activity of TG-1701 and ibrutinib on anti-CD20 antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), as ibrutinib has previously been show to block rituximab-mediated ADCC due to off-target inhibition of ITK (Kohrt et al., Blood 2014). In sharp contrast with ibrutinib, which partially antagonized rituximab activity, we found that TG-1701 did not impair the anti-CD20-mediated ADCC and ADCP in a multicellular co-culture system that associated MCL to effector cells. In another set of cell-based assays, we showed that the treatment with TG-1701 led to a strong decrease in IL-10 expression, together with a significant increase in IL-2, IL-6 and IL1RN gene transcription, thus associating TG-1701 exposure with the promotion of an immune response within the tumor microenvironment (TME). Accordingly, TG-1701 cooperated with the novel anti-CD20 antibody ublituximab and the novel PI3Kδ-CK1ϵ dual inhibitor umbralisib in reducing the tumor growth in both ibrutinib-sensitive (REC1) and ibrutinib-resistant (UPN-1res) mouse models of MCL. In accordance with in vitro data, the antitumor activity of the drug combination was associated with increased production of IL-2, IL-6 and TNFα, and with an increased infiltration of mouse macrophages and NK cells. Altogether, these data warrant further clinical investigation of TG-1701-mediated engagement of TME-related anti-tumor effect, and clinical evaluation of the triple combination of TG-1701, ublituximab, and umbralisib, is ongoing.
Citation Format: Marcelo L. Ribeiro, Diana Reyes-Garau, Meritxell Vinyoles, Marc Armengol, Hari Miskin, Francesc Bosch, Pablo Menendez, Emmanuel Normant, Gael Roue. TG-1701, a novel irreversible Bruton's kinase (BTK) inhibitor, cooperates with ublituximab-driven ADCC and ADCP in in vitro and in vivo models of ibrutinib-resistant mantle cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2205.