Combination of rituximab and mammalian target of rapamycin inhibitor everolimus (RAD001) in diffuse large B-cell lymphoma

Abstract

We evaluated the efficacy of the anti-CD20 monoclonal antibody rituximab in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for treating diffuse large B-cell lymphoma (DLBCL). The combination of rituximab and everolimus was more effective for inhibiting cell growth compared with single-agent therapy. An increase in G0/G1 cell cycle arrest and an increased population of cells in apoptosis were observed in the combination treatment group. The addition of rituximab reduced the overexpression of p-AKT caused by the negative feedback loop of everolimus and had an enhanced effect on inhibition of mTOR signaling, thus providing a rationale for this synergistic effect. Furthermore, combination treatment was also more effective than treatment with either agent alone for inhibiting the growth of DLBCL xenografts. Our study provides preclinical evidence and a theoretical basis for combination therapy with rituximab and everolimus in DLBCL.

Regulation of Bim in Health and Disease

“…The mTOR inhibitors rapamycin (Sirolimus) and RAD001 (Everolimus) have long been known to increase the sensitivity of malignant hematopoietic cells to chemotherapeutic drugs such as glucocorticoids [ 519 , 533 , 534 , 597 - 599 ], rituximab [ 600 ] and IFNα [ 601 ], and solid tumors to cisplatin [ 602 ], mitoxantrone [ 603 ], carboplatin [ 604 ], vinorelbine [ 604 ] and taxoids [ 603 , 604 ]. One of the mechanisms by which rapamycin sensitizes tumor cells is through downregulation of Mcl-1 with simultaneous upregulation of Bim [ 533 , 534 ].…”

Emerging drugs for diffuse large B-cell lymphoma

“…In a Phase II trial, everolimus monotherapy induced a modest response, achieving an ORR of 30% in R/R DLBCL patients [54]. However, its antiproliferative activity appeared to increase when everolimus was combined with rituximab in DLBCL cell lines [55]. Based on these data, an open label Phase II trial was carried out to evaluate if the combination of everolimus with rituximab would also be efficacious in the clinical setting.…”

Everolimus in Diffuse Large B-Cell Lymphomas

“…A recent study evaluated the combination of rituximab and everolimus in DLBCL cell lines and xenografts [24]. The addition of rituximab reduced the phosphorylation of AKT caused by the negative feedback loop mediated by TORC2, resulting in more effective inhibition of cell growth and inductionf of apoptosis.…”

“…As Phase I and II studies demonstrated singleagent activity and safety in relapsed/refractory DLBCL, the next logical step was to explore the combination with a non-cross-resistant cytotoxic agent with proven activity in DLBCL and mild toxicity, such as rituximab. Moreover, previous in vitro studies have shown that everolimus and rituximab synergistically induce apoptosis in DLBCL cell lines [23,24]. For this purpose, a recent Phase II study investigated the efficacy and safety of the combination of everolimus and rituximab in patients with relapsed or refractory DLBCL who failed or were ineligible for ASCT [30].…”