Temsirolimus acts as additive with bendamustine in aggressive lymphoma

Abstract

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

Midostaurin potentiates rituximab antitumor activity in Burkitt’s lymphoma by inducing apoptosis

“…Some strategies have been implemented to sensitize rituximab therapy by combining with other agents to increase the pro-apoptotic effect. These additional agents include macromolecules such as the humanized monoclonal mapatumumab targeting TRAIL-R1 49 , the genetically engineered fusion proteins scFvRit:sFasL 50 , Apo2 ligand (Apo2L)/TRAIL (dulanermin) 51,52 and anti-CD20-interleukin-21 53 , and small molecules, such as the selective NEDD8 activating enzyme inhibitor pevonedistat (MLN4924) 54 , the mTOR (mammalian target of rapamycin) inhibitor temsirolimus 55 , and the proteasome inhibitor bortezomib 56 . However, the efficacy of these agents requires further confirmation or has been suggested to be insufficient based on clinical trials 52 .…”

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review

“…Since the introduction of first-generation mTOR inhibitors in the late 1990s, two molecules have gained FDA approval for renal cell carcinoma (namely everolimus and temsirolimus), while other mTOR inhibitors are still under investigation (77,78). In the setting of MCL, temsirolimus demonstrated superior results, compared to chemotherapy, either as a single-agent (79) or combined with rituximab (80), bendamustine (81), or R-B (82). In a phase-III randomized controlled trial in R/R MCL patients, temsirolimus was tested at two dosages in comparison with the medical practitioner preference.…”

The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL – Results From the Phase-II STORM Trial

“… 10 In r/r DLBCL, the response rate was 28% as single agent, 11 stimulating further development. As preclinical data have shown synergism between mTOR inhibitors and cytotoxic agents, 12 we postulated that the combination of mTOR inhibition to chemotherapy results in improved efficacy with acceptable toxicity. Consequently, in this study, we combined temsirolimus to the standard regimen R-DHAP (rituximab, dexamethasone, cytarabinoside, cisplatinum) for the treatment of r/r DLBCL.…”