Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis

Abstract

Immunotherapy has evolved as a powerful tool for the treatment of B-cell malignancies and patient outcomes have improved by combining therapeutic antibodies with conventional chemotherapy. Overexpression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) is associated with a poor prognosis and increased levels have been described in patients with "double-hit" diffuse large B cell lymphoma, a subgroup of Burkitt´s lymphoma and pediatric ALL patients harboring a t(17;19) translocation. Here, we show that the addition of venetoclax (VEN), a specific Bcl-2 inhibitor, potently enhanced the efficacy of the therapeutic anti-CD20 antibody rituximab (RTX), anti-CD38 daratumumab (DARA) and anti-CD19, named CD19-DE, a proprietary version of tafasitamab. This was due to an increase in antibody-dependent cellular phagocytosis by macrophages as shown in vitro and in vivo in cell lines and patient-derived xenograft (PDX) models. Mechanistically, double-hit lymphoma cells subjected to VEN triggered phagocytosis in an apoptosis-independent manner. Our study identifies the combination of VEN and therapeutic antibodies as a promising novel strategy for the treatment of B-cell malignancies.

Possibly the Venetoclax/Bcl-2 Complex Interacts with the Antibody/Antigen Complex to Increase the Phagocytosis in Combined Venetoclax-Antibody Therapy in B-cell Malignancies

“…Also the use of Z-VAD-FMK in WILL-2 cells did not affect the level of ADCP of these cells on ABT-199/DARA treatment. Though the paper [6] clearly shows that the enhanced ADCP in DHL cells on treatment with ABT-199/Antibody combination vis-à-vis the treatment with antibody alone is apoptosis independent, one is not sure whether the apoptosis is blocked or not in the DHL cells on treatment with ABT-199/ Antibody combination. To answer this question the same experimental platform as that described in [6] can be used but the macrophages deficient in the Fc receptor must be taken to mix with the CARNAVAL and WILL-2 cells in phagocytosis assays; taking the macrophages deficient in the Fc receptor will suppress ADCP.…”

“…Two different therapies, anti-Bcl-2 therapy and monoclonal Antibody therapy, have been combined together to study their effects in and the mechanism of action in B cell malignancies; this study was mostly conducted both in-vitro and in-vivo in B-cell malignancy derived cell lines and the patient-derived Xenograft (PDX) murine models [6]. This short communication mostly centers around the results obtained from work [6], and draws fresh conclusions.…”

“…Two different therapies, anti-Bcl-2 therapy and monoclonal Antibody therapy, have been combined together to study their effects in and the mechanism of action in B cell malignancies; this study was mostly conducted both in-vitro and in-vivo in B-cell malignancy derived cell lines and the patient-derived Xenograft (PDX) murine models [6]. This short communication mostly centers around the results obtained from work [6], and draws fresh conclusions. I will discuss in this paper the results of experiments on Double-Hit Lymphoma (DHL) cell lines CARNAVAL (CD20+), WILL-2 (CD20-/CD38+), and Bcl-2 negative Oci-Ly7 (CD20+/CD38+); and I will not discuss the results of experiments on Burkitt Lymphoma-PDX (BL-PDX) mice and Acute Lymphoblastic Leukemia-PDX (ALL-PDX) mice primarily because the experiments involving the use of pan-Caspase inhibitor Z-VAD-FMK, and the Bax-deficient and Bak-deficient cells were not conducted on these disease models.…”

“…CD38 is normally expressed on a variety of immune cells including the cranked up B cells [2]. The anti-CD20 monoclonal antibody and the anti-CD38 monoclonal antibody used in the study [6] are Rituximab (RTX) and Daratumumab (DARA) respectively. The monoclonal antibodies directed against the cancer cells kill them by any one of the or any combination of the following four mechanisms: direct killing [8], Antibody-dependent Cellular Cytotoxicity (ADCC) [7], Complement-dependent Cy- [4], and Antibody-dependent Cellular Phagocytosis (ADCP) [1].…”

“…Venetoclax (ABT-199) in particular binds to the Bcl-2 protein only, and has been shown to cause apoptosis successfully in AML cell lines [3]. Bcl-2 has been found to be over expressed in Double-hit Diffuse Large B-cell Lymphoma, and hence ABT-199 is the only anti-Bcl-2 drug studied in the work [6].…”