Abstract 5516: Immunological effects of SYK inhibition using TAK659 in patients diagnosed with diffuse large B cell lymphoma
Authors: Crespo Marta , Nieto Juan C. , Hernández Cristina , del Carmen Carpio Cecilia , Jiménez Isabel , Palacio Carlos , Carabia Júlia , Abrisqueta Pau , Bosch Francesc 
Published: September 2020

Abstract
Targeted inhibition of the BCR signaling pathway is a therapeutic option for patients diagnosed with Diffuse Large B-cell Lymphoma (DLBCL) currently under clinical evaluation. Inhibition of the proximal BCR signaling kinase SYK has been shown to have direct cytotoxic effect on malignant B lymphocytes. Moreover, SYK protein also participates in immumomodulatory processes involving the inflammasome, Fcγ receptor and T cell responses in non-malignant settings. Herein we aimed to study the immunological effects of treatment with TAK659 in patients diagnosed with DLBCL. For that we longitudinally studied changes in immune cells subpopulations and cytokines in the peripheral blood of seven patients undergoing treatment with TAK659 (phase I, first in human clinical trial; NCT03123393). Patients received 100 mg of TAK659 orally once a day in 28-day cycles until disease progression, unacceptable toxicities, or withdrawal for other reasons (estimated median treatment duration 6 months). Peripheral blood was collected serially before and during treatment (after 1 week). The relative percentages of CD4 and CD8 T cells were not significantly modified. Interestingly, treatment with TAK659 significantly induced a reduction in regulatory T cells after 1 week. Additionally, treatment with TAK659 induced an increase in the proportion of central memory CD4 T cells after 1 week of treatment while effector memory went down, indicating a shift towards a more effector T cell profile. Regarding the expression of inhibitory receptors we observed a downregulation of PD-1 and LAG-3 in both CD4 and CD8 T cells after 1 week of treatment, as well as downregulation of CD4 and CD8 co-expressing PD-1 with LAG-3. Finally, we observed a reduction in the levels of IFN-γ in the plasma of patients after 1 week of treatment while TNF-α and IL-10 did not change. In order to assess if some of the immunological effects could be due to direct effect of TAK659 in T lymphocytes we treated PBMCs from healthy donors with increasing doses of TAK659 for 30' before 48 hours of TCR stimulation. The in vitro stimulation of T lymphocytes induced an increase in the proportion of regulatory T cells as well as induction of exhaustion markers in both CD4 and CD8 T cells that was counteracted by treatment with TAK659 that did not affect their viability. Overall, these findings provide initial evidence of the role of TAK 659 in potentiating the anti-tumoral immune response during treatment of DLBCL. Therefore, we believe that treatment with TAK659 can help to reinstall immune surveillance by exerting direct immunomodulatory effects which provides rationale for combination therapy not only in B-cell derived malignancies but also in solid tumors.
Citation Format: Marta Crespo, Juan C. Nieto, Cristina Hernández, Cecilia del Carmen Carpio, Isabel Jiménez, Carlos Palacio, Júlia Carabia, Pau Abrisqueta, Francesc Bosch. Immunological effects of SYK inhibition using TAK659 in patients diagnosed with diffuse large B 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 5516.