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Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma.

ABSTRACT: Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been validated as an effective drug to treat B cell malignancies. Combined therapies comprising ibrutinib and anti-CD20 antibodies like rituximab were designed as a backbone in many clinical trials. However, the off-target inhibition of ibrutinib on interleukin-2 (IL-2)-inducible T cell kinase (ITK) may reduce rituximab's antibody-dependent cellular cytotoxicity (ADCC) efficacy. Orelabrutinib (Orel), a novel BTK inhibitor, was designed with high selectivity to BTK. In our study, we demonstrated in preclinical models that orelabrutinib in combination with rituximab could preserve NK-cell-mediated ADCC induced by rituximab and enhanced the apoptosis of tumor cells in vitro. The addition of orelabrutinib to rituximab had produced promising combined anti-tumor effects in B cell lymphomas in vivo. Collectively, combination therapy of orelabrutinib with rituximab would benefit patients with B cell lymphoma, especially those with relapsed or refractory disease.

SUBMITTER: Yu H

PROVIDER: S-EPMC8082047 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

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Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma.

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