Resistance to obinutuzumab-induced antibody-dependent cellular cytotoxicity caused by abnormal Fas signaling is overcome by combination therapies

Abstract

Background Obinutuzumab, a Type II anti-CD20 antibody, is used to treat follicular lymphoma. A major mode of action of obinutuzumab is antibody-dependent cellular cytotoxicity (ADCC). Knowledge of the mechanisms of resistance to obinutuzumab is important for the development of next-line strategies to follow obinutuzumab-containing therapy, including obinutuzumab retreatment. Unfortunately, the mechanisms by which tumor cells acquire resistance to ADCC are still poorly understood. To address this, we examined the mechanisms of resistance to obinutuzumab-induced ADCC and the combination efficacy of obinutuzumab and clinically available agents in the established resistant cells. Methods and results We established cells resistant to obinutuzumab-induced ADCC using the non-Hodgkin lymphoma cell line RL and examined their mechanisms of resistance and the combination efficacy of obinutuzumab and clinically available agents. Comprehensive analysis by RNA sequencing of resistance mechanisms revealed that abnormal Fas signaling decreased sensitivity to ADCC in resistant clones. Combination treatment with prednisolone, a component of CHOP and CVP, was found to enhance ADCC sensitivity of RL cells and resistant clones and to significantly suppress tumor growth in xenograft models. Treatment with prednisolone upregulated expression of CD20 and an apoptosis-inducing protein BIM, which might augment perforin/granzyme B-mediated cell death. Furthermore, pretreatment of the effector cells with bendamustine enhanced ADCC activity, and treatment with obinutuzumab plus bendamustine showed significant antitumor efficacy in xenograft models. It was speculated that bendamustine upregulates ADCC activity by potentiating granules-mediated cell killing. Conclusions Our study revealed a novel mechanism underlying obinutuzumab-induced ADCC resistance and indicated that ADCC resistance could be overcome by combining obinutuzumab with prednisolone or bendamustine. This study provides a scientific rationale for obinutuzumab-retreatment in combination with clinically available chemotherapeutic agents for obinutuzumab resistant follicular lymphoma.

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

“…Nevertheless, resistance to obinutuzumab-induced ADCC is a major problem for effective treatment. This is presumably caused by abnormal Fas signaling and can be overcome by combination therapies [ 9 , 10 ]. There are a large number of completed and ongoing studies of phase 1 to 3 with obinutuzumab to enable the application in further clinical indications and to increase efficacy by combining it with other anti-cancer drugs including acalabrutinib, bendamustine, chlorambucil, duvelisib, entospletinib, ibrutinib, idasanutlin, pixantrone, tirabrutinib, and venetocla [ 4 , 11 , 12 , 13 ].…”

Steroid Premedication and Monoclonal Antibody Therapy: Should We Reconsider?

“…Rituximab is a CD-20 targeting mAb whose Fc portion induces lymphoma cell lysis through ADCC [ 6 , 7 ]. Obinutuzumab, a new generation of anti-CD20 antibody, was designed in an attempt to overcome postulated mechanisms of resistance, however still retains ADCC as a major mechanism of action [ 8 ].…”

“…An interesting caveat to this discussion is the relationship between steroid premedication and CD20-targeted monoclonal antibodies for haematological malignancies. In trials investigating both rituximab and obinutuzumab, the addition of steroids improved ADCC [ 8 , 35 ]. However, this is thought to be likely due to steroid-induced upregulation of CD20, the target of the aforementioned mAbs [ 36 , 37 ].…”

Risk of Infections Secondary to the Use of Targeted Therapies in Hematological Malignancies

“…Obinutuzumab is a humanized monoclonal antibody that was approved in 2017 for the treatment of untreated CLL and untreated or R/R follicular lymphoma (FL) [ 68 , 69 ]. Obinutuzumab leads to the cytolysis of B-cells by activating complement and apoptotic pathways [ 70 ]. Marcus et al, in their randomized trial, categorized 1202 patients equally into groups of obinutuzumab-based therapy and rituximab-based therapy for follicular lymphoma [ 71 ].…”