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Immunologic Treatment Strategies in Mantle Cell Review Article Page 1 of 7 Immunologic treatment strategies in mantle cell lymphoma: checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engager (BiTE) molecules Joshua C. Pritchett1, Stephen M. Ansell2 1Department of Internal Medicine, 2Division of Hematology, Mayo Clinic, Rochester, MN, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Stephen M. Ansell, MD, PhD. Division of Hematology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA. Email: [email protected]. Abstract: Over the past 10–15 years, there has been a surge in the development and utilization of immunologic strategies aimed at harnessing the power of the cellular immune system to treat a remarkable range of human disease. As is being seen throughout the spectrum of malignant hematology, there are several emerging immunologic therapies which may ultimately revolutionize the treatment and clinical outcomes of patients with mantle cell lymphoma (MCL). Three unique immunologic approaches—checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and bispecific T-cell engager (BiTE) molecules—are currently on the forefront of clinical investigation. While preclinical studies have suggested a mechanistic role for immunomodulation via checkpoint blockade (PD-L1, PD-1) in patients with MCL, clinical data thus far suggests only modest success. CAR T-cell therapies, engineered to directly overcome deficiencies in the anti-tumor T-cell response, appear to show early promise and large trials actively enrolling MCL patients are currently in progress. BiTE molecules, which seek to engage and directly activate the cytotoxic power of T-cells upon bispecific interaction with tumor antigen, are being explored in treatment of MCL and early efficacy data seems encouraging as well. Keywords: Lymphoma; mantle cell lymphoma (MCL); non-Hodgkin lymphoma (NHL); immunotherapy; checkpoint inhibitor therapy; chimeric antigen receptor T-Cell therapy (CAR T-Cell therapy); bispecific T-cell engager molecules (BiTE molecules); bispecific Received: 29 September 2018; Accepted: 27 January 2019; Published: 27 May 2019. doi: 10.21037/aol.2019.05.01 View this article at: http://dx.doi.org/10.21037/aol.2019.05.01 Introduction persistence (1). In antigen “recognition,” the T-cell receptor (TCR) recognizes an APC-presented antigen (peptide- Basics of T-cell immunity MHC antigen), forming the T-cell-antigen-receptor There are several emerging immunological approaches complex. This T-cell-antigen-receptor complex delivers to the treatment of patients with mantle cell lymphoma an initial “activation” signal, referred to as “signal 1.” (MCL). In order to understand these unique approaches, it In response, the presenting APC expresses costimulatory is crucial to first appreciate the fundamental components of molecules which bind to costimulatory receptors present an effective T-cell mediated immune response. on T-cells, a process referred to as “signal 2.” The In general, an effective T-cell response to antigens is persistent combination of both antigen recognition and characterized by three key steps: recognition, activation, and costimulation (signal 1 + signal 2) ultimately leads to the © Annals of Lymphoma. All rights reserved. Ann Lymphoma 2019;3:6 | http://dx.doi.org/10.21037/aol.2019.05.01 Page 2 of 7 Annals of Lymphoma, 2019 robust production of “activated” T-cells. When this process as characterized a pattern of abnormal cytololytic activity occurs in a population of naïve T-cells, the result is clonal among neoantigen-specific CD4 T-cells which appears expansion and differentiation into effector T-cells. When unique to patients with MCL. occurring in already differentiated populations of effector Second, Yang et al. have demonstrated that T-cells in T-cells or memory T-cells, the result is performance of MCL patients appear to inhibit the production of anti- effector T-cell function (i.e., cytokine secretion, target cell tumor cytokine CD4 + CD25 through interaction between killing, etc). PD-1 and PD-L1 (4). Of note, as is the case with most Alternatively, it is also important to understand the subtypes of B cell NHL, several groups have reported the underlying processes which may lead to the production of overall lack of expression of both PD-1 (5-7) as well as unresponsive or inactivated T-cells. There are two primary PD-L1 (7,8) on malignant B cell populations in patients ways in which this may occur, both of which occur after the with MCL. However, Wang et al. have demonstrated initial “signal 1” process outlined above. First, in a process that, when present, the expression of B7-H1 (PD-L1) on known as “coinhibition,” rather than a costimulatory “signal MCL cells is able to effectively inhibit T-cell proliferation 2” process, coinhibitory molecules presented by APCs may induced by the tumor cells, impair the generation of bind to coinhibitory receptors present on T-cells. Of note, antigen-specific T-cell responses, and ultimately render even in the presence of an effective costimulation signal, the the tumor cells resistant to T-cell-mediated cytolysis (9). process of coinhibition may still occur if the coinhibitory Furthermore, this study demonstrated (both in vitro and signal dominates or out-competes the costimulatory signal. in vivo) that blocking or knocking down B7-H1 on In a second process, most often involving an immature or MCL cells effectively enhances T-cell responses and poorly activated APC, the coactivation “signal 2” is never restores tumor-cell sensitivity to T-cell-mediated killing. effectively established. In both cases, the end result is As will be further detailed below, with the advent of production of either unresponsive (anergic) T-cells or T-cell immunomodulatory therapies, the expression profile of apoptosis. PD-1 and/or PD-L1 of a given malignancy has growing implications with regard to immunotherapeutic targeting Inadequate T-cell response in MCL and efficacy within the clinical setting. In addition, as will be outlined further below, T cells Several mechanisms have been proposed to account for themselves are now being increasingly utilized for their the presence of an inadequate T-cell response in patients cytotoxic effect as anti-tumor therapies directed against with lymphoma. While “lymphomas” are in reality a malignancies which arise from aberrant immune cells, such vastly heterogenous group of malignancies which arise as lymphomas. As a proof-of-concept in the setting of MCL, from developing lymphocytes, broadly speaking, there are allogeneic SCT has been shown to be an effective treatment three chief categories into which these mechanisms are modality in these patients (10), further underlying the generally characterized: loss of typical antigen presentation, notion that T cells in principle are indeed able to mediate suppression of activated cells, and the presence of additional effective cytotoxicity against malignant MCL cells. suppressive ligands (2). Furthermore, while approximately 90% of all lymphomas arise from B cell lineage (MCL, being among them), there are of course important Three key immunologic treatment strategies in ramifications with regard to underlying deficiencies in the MCL normal T-cell response which ultimately allows for the Immunomodulation: checkpoint inhibition sustained proliferation of aberrant B lymphocytes necessary to create a lymphoma. Over the past 10–15 years, there has been a surge in the With regard to MCL in particular, we are currently development of “immunomodulatory” strategies aimed at aware of several unique aberrations identified in the treating a remarkable range of human disease (including preclinical setting which may contribute to an inadequate cancer, infection, autoimmunity, transplant rejection, and underlying T-cell response in these patients. First, in a more). As a brief overview, immunomodulatory “biologics” cohort of 17 unique MCL patients and two defined MCL are molecules designed to engage and interact with cell cell lines, Khodadoust et al. have identified the presence surface signaling molecules present on host immune cells, of MCL-specific MHC-I and MHC-II epitopes (3) as well thereby influencing the direction and/or magnitude of the © Annals of Lymphoma. All rights reserved. Ann Lymphoma 2019;3:6 | http://dx.doi.org/10.21037/aol.2019.05.01 Annals of Lymphoma, 2019 Page 3 of 7 lymphocyte response (11). In conditions characterized by tumor cells found to be positive for PD-L1 expression (9). hyper-activity of the host immunologic state (i.e., transplant With this in mind, there has been optimism from the rejection, autoimmunity), such molecules are used to field at the possibility of exploiting this feature through dampen excessive hyper-proliferation of immune cells, the use of checkpoint inhibitor therapies in select patients thus blunting their resultant activity. In conditions which with MCL. Furthermore, there are notable success stories persist at least partly due to evasion and/or inadequacy of with such strategies among patients with other forms of the host immune response (i.e., malignancy, infection), lymphoma. For example, in classic Hodgkin’s lymphoma, these molecules are utilized to stimulate, sensitize, and/or
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