Abstract
Simple SummaryBendamustine is a chemotherapeutic agent used to treat a variety of cancers. It has recently been used in the context of allogeneic hematopoietic cell transplantation (HCT), a treatment mostly used to treat blood cancers. Given before or after transplantation of donor blood or bone marrow cells, bendamustine has been shown to reduce the side effects of the transplant, including graft-versus-host disease, where the donated cells attack the recipient’s tissues, while also promoting the anti-cancer effects of the transplant. These are exciting findings and show that bendamustine may be used to influence the immune system, called immunomodulation, in a beneficial manner. We report our research and review the available literature outlining these immunomodulatory effects of bendamustine, in hopes that it will promote further investigations utilizing this agent in allogeneic transplants, ultimately improving patient outcomes.Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
Highlights
We demonstrated BEN-total body irradiation (TBI) results in overall better outcomes than CY-TBI based on improved graft-versus-host disease-free relapse-free survival (GRFS)
While investigating the effects of BEN on graft-versus-host disease (GvHD), GvL, survival, and other clinical outcomes is crucial to determining patient care, it is important to evaluate the effects of BEN on specific immune cells in an attempt to understand its specific immunomodulatory effects
These in vitro data, along with our in vivo murine data showing increased myeloid derived suppressor cells (MDSCs) numbers in tissues and the clinical data showing rapid and sustained neutrophil engraftment when BEN is utilized in the allogeneic hematopoietic cell transplantation (HCT) setting, indicate that this agent may have a distinct effect on the myeloid compartment
Summary
Few studies have investigated BEN as an anti-metabolite, it is thought that the benzimidazole ring may be able to bind to enzymes and confer biological effects in this manner [4]. While it is not clearly understood how, BEN has been reported to induce a higher frequency of and more stable double-strand breaks in DNA compared to other alkylating agents, including melphalan, cyclophosphamide, and carmustine [5,6]. We have limited knowledge of the precise mechanisms of action of BEN, its utility in the clinical setting has quickly expanded It has been used as an effective lymphodepleting agent prior to infusion of chimeric antigen receptor (CAR) T-cells [13]. HCT models, both highlighting its immunomodulatory effects and suggesting favorable immunomodulation resulting in graft-versus-host disease (GvHD) and tumor control
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