Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation
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cancers Review Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation Jessica Stokes 1, Megan S. Molina 1,2 , Emely A. Hoffman 1, Richard J. Simpson 1,2,3,4 and Emmanuel Katsanis 1,2,4,5,6,* 1 Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; [email protected] (J.S.); [email protected] (M.S.M.); [email protected] (E.A.H.); [email protected] (R.J.S.) 2 Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA 3 Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA 4 The University of Arizona Cancer Center, Tucson, AZ 85721, USA 5 Department of Medicine, University of Arizona, Tucson, AZ 85721, USA 6 Department of Pathology, University of Arizona, Tucson, AZ 85721, USA * Correspondence: [email protected]; Tel.: +1-520-626-7053 Simple Summary: Bendamustine 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 Citation: Stokes, J.; Molina, M.S.; transplants, ultimately improving patient outcomes. Hoffman, E.A.; Simpson, R.J.; Katsanis, E. Immunomodulatory Abstract: Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range Effects of Bendamustine in of hematological malignancies, although investigations have only recently started to delve into Hematopoietic Cell Transplantation. Cancers 2021, 13, 1702. https:// its immunomodulatory effects. These immunomodulatory properties of BEN in the context of doi.org/10.3390/cancers13071702 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 Academic Editor: Aline Bozec significant changes to key immunological cell populations, including T-cells, myeloid derived sup- pressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances Received: 2 March 2021 the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, Accepted: 1 April 2021 increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- Published: 3 April 2021 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 Publisher’s Note: MDPI stays neutral underway investigating new potential applications of BEN in the setting of allogeneic HCT. with regard to jurisdictional claims in published maps and institutional affil- Keywords: bendamustine; hematopoietic cell transplantation iations. 1. Introduction Copyright: © 2021 by the authors. Bendamustine (BEN) was developed in East Germany in 1963, where investigators Licensee MDPI, Basel, Switzerland. quickly discovered its utility in treating a number of leukemias and lymphomas [1]. BEN This article is an open access article distributed under the terms and was synthesized from nitrogen mustard and, therefore, contains a 2-chloroethylamine conditions of the Creative Commons alkylating group and is classified as an alkylating agent. As such, BEN is able to crosslink Attribution (CC BY) license (https:// DNA, forming repairable intra-strand lesions, as well as non-repairable inter-strand lesions. creativecommons.org/licenses/by/ The accumulation of cross-linked DNA lesions caused by BEN administration ultimately 4.0/). leads to cell death, with the most robust accumulation occurring in highly proliferative Cancers 2021, 13, 1702. https://doi.org/10.3390/cancers13071702 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 1702 2 of 17 cells, such as hematopoietic cells and cancerous cells. This feature of BEN is common to many chemotherapeutic compounds, including cyclophosphamide and melphalan, both of which are also alkylating agents. However, bendamustine (4-(5-[bis(2-chloroethyl)amino]- 1-methyl-2-benzimidazolyl) butyric acid hydrochloride) has a unique molecular structure, consisting of a benzimidazole ring connected to a nitrogen mustard moiety, and is a purine analog in addition to a cytotoxic alkylating agent [2,3]. The benzimidazole ring is meant to confer anti-metabolite properties and is a unique feature that is not found on any other cytotoxic compound. Although 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]. Further, when comparing the effects of BEN on solid tumor cell lines (HeLa cells) and lymphoma cell lines (U2932), BEN was found to induce cell cycle arrest at lower concentrations in hemato- logical malignancies, consistent with its clinical applications in the treatment of leukemias, lymphomas, and myelomas [7]. Among the few mechanistic studies performed on BEN, it has been shown that BEN regulates apoptotic and DNA repair pathways, inhibits mitotic checkpoints, and induces p53-dependent stress pathways [2]. BEN has similarly been shown to induce cell cycle disruption, causing G2 arrest via Cdc25 and p53 [6]. More recent studies have corroborated these findings, demonstrating that BEN induces S or G2 cell cycle arrest in a dose-dependent manner [7]. BEN is given intravenously and has a very high (95%) protein binding capacity, primarily binding to albumin, while the remaining unbound portion (5%) is biologically active. BEN undergoes significant first-pass metabolism in the liver, primarily via a cytochrome p450 enzyme complex [4], and is metabolized into two major metabolites: dihydroxy-bendamustine (HP2) and bendamustine ethyl ester (BM1EE) [8]. Nearly half of BEN is eliminated in urine in an unmetabolized form via renal excretion. BEN has a biphasic half-life, with T1/2 alpha = ~10 min and T1/2 beta = ~30 min in humans, although this pharmacokinetic property varies based on dose and species. Due to its high degree of metabolism in the liver, in addition to its renal excretion, BEN may be contraindicated in patients with renal dysfunction and severe liver damage [4,9,10]. The adverse effects of BEN are very similar to those of typical alkylating agents in the nitrogen mustard family and include nausea, vomiting, diarrhea, loss of appetite, weight loss, mucositis, immunosuppression, anemia, and thrombocytopenia [11]. Until 1990, BEN was only available in East Germany where it was marketed as Ribo- mustin [1]. In 2008, the United States Food and Drug Administration (FDA) approved BEN for the treatment of chronic lymphocytic leukemia (CLL) under the tradename Treanda [1]. BEN was approved for the treatment of rituximab-resistant non-Hodgkin’s lymphoma soon after [1,12]. In 2015, BEN HCl was approved in the United States under the tradename Bendeka [2]. Clinical trials are underway in the United States to assess a range of cancers that may be successfully treated with this agent [2]. Currently, BEN is indicated for CLL, multiple myeloma, breast cancer, small-cell lung cancer, and non-Hodgkin’s lymphoma [2]. Although 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 lymphodeplet- ing agent prior to infusion of chimeric antigen receptor (CAR) T-cells [13]. BEN has also been employed as a component of conditioning regimens for autologous hematopoietic cell transplantation (HCT) to treat multiple myeloma, Hodgkin’s lymphoma, mantle cell lymphoma, and other non-Hodgkin’s lymphomas [10,14–17]. More recently, BEN has been implemented in the context of clinical allogeneic HCT and has been studied in murine HCT models, both highlighting its immunomodulatory effects and suggesting favorable immunomodulation resulting in graft-versus-host disease (GvHD) and tumor control. Cancers 2021, 13, 1702 3 of 17 2. BEN as Pre-Transplant Conditioning in Murine Models Bone marrow transplantation as a clinical treatment evolved from radiation studies in mice and guinea pigs in the 1950s, which demonstrated that bone marrow cell infusion can rescue animals from lethal radiation [18]. In 1956, Ford et al. confirmed that donor bone marrow cells engraft in the recipient [19]. In the same year, Barnes et al. reported that donor bone marrow cells can exert anti-leukemic effects [20]. Subsequently, in 1957, the first report of a human bone marrow transplant was published by Thomas et al. [21]. Since its inception, bone marrow transplantation or hematopoietic cell transplantation (HCT) has become a widely implemented approach