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Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens

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Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens Journal of Fungi Review Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies Ioannis Kyriakidis 1 , Eleni Vasileiou 1 , Claudia Rossig 2 , Emmanuel Roilides 3 , Andreas H. Groll 4 and Athanasios Tragiannidis 1,4,* 1 Pediatric and Adolescent Hematology-Oncology Unit, 2nd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; [email protected] (I.K.); [email protected] (E.V.) 2 Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, D-48149 Münster, Germany; [email protected] 3 Infectious Diseases Unit, Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, 3rd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece; [email protected] 4 Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, Infectious Disease Research Program, University Children’s Hospital Münster, D-48149 Münster, Germany; [email protected] Citation: Kyriakidis, I.; Vasileiou, E.; * Correspondence: [email protected]; Fax: +30-231-099-4803 Rossig, C.; Roilides, E.; Groll, A.H.; Tragiannidis, A. Invasive Fungal Abstract: Since 1985 when the first agent targeting antigens on the surface of lymphocytes was Diseases in Children with approved (muromonab-CD3), a multitude of such therapies have been used in children with hemato- Hematological Malignancies Treated logic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric with Therapies That Target Cell patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager Surface Antigens: Monoclonal Antibodies, Immune Checkpoint [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, Inhibitors and CAR T-Cell Therapies. the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and 90 J. Fungi 2021, 7, 186. https:// axicabtagene ciloleucel), CD20 (rituximab and biosimilars, Y-ibritumomab tiuxetan, ofatumumab, doi.org/10.3390/jof7030186 and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (bren- Academic Editor: David S. Perlin tuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (90Y-labelled BW 250/183), CD248 (ontuxizumab) and Received: 9 February 2021 immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or Accepted: 2 March 2021 with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, Published: 5 March 2021 nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under Publisher’s Note: MDPI stays neutral blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and with regard to jurisdictional claims in tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab published maps and institutional affil- iations. vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications. Copyright: © 2021 by the authors. Keywords: invasive fungal diseases; monoclonal antibodies; immune checkpoint inhibitors; CAR Licensee MDPI, Basel, Switzerland. This article is an open access article T-cells; hematological malignancies; leukemia; lymphoma; children distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). J. Fungi 2021, 7, 186. https://doi.org/10.3390/jof7030186 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, 186 2 of 30 1. Introduction Molecular targeted therapy is gaining ground in pediatric cancer treatment, especially after the implementation of next-generation sequencing data in clinical practice, and seems to fulfill the “magic bullet” concept that was put forward by German Nobel laureate Paul Ehrlich back in 1900 [1,2]. Targeted therapy differs from the conventional cytotoxic therapy in its specificity of targeted pathways that can halt the growth and spread of cancer cells rather than killing indiscriminately every rapidly dividing cell. Both categories of targeted therapies i.e., monoclonal antibodies (mAbs) and small-molecule inhibitors, have shown great advances since their first members (rituximab in 1997 and imatinib in 2001, respectively) were approved for the treatment of blood cancer in adults [3]. Substantial experience of their use in children, although not widespread, has been achieved in the last decade. While most of these agents seem to be generally well tolerated, opportunistic infections including IFDs should be considered and promptly prevented and treated. However, assessing the exact contribution to infection rates in children with hematologic malignancies receiving biologic therapies is problematic, as many of them are more or less immunocompromised by default and thus at greater risk of infection. Preceding and concomitant immunosuppressive therapies usually render us uncapable of defining the exact relative risk for IFDs conferred by each drug [4]. Host defenses against fungi rely on the sophisticated interplay between: (i) mucocutaneous barrier integrity; (ii) cells of the innate immune system (e.g., dendritic cells and macrophages) that recognize specific pathogen-associated molecular patterns (PAMPs) and bind fungal cell walls using pattern recognition receptors (PRRs) like C-type lectin receptors (CLRs, e.g., dectin-1 recognizing β-glucan, mannose receptor, melanin sensing C-type Lectin receptor MelLec and CARD9 mediator) and Toll-like receptors (TLRs, e.g., TLR2); (iii) cell-mediated immunity via transduction of signals from RPRs and associated molecules (FcRγ, recognition of chitin by the intracellular receptors TLR9 and NOD2) and by phagocytosis, initiation of killing mechanisms (e.g., production of reactive oxygen species), and development of adaptive immunity—especially by CD4+ T-cells producing IFNγ (Th1) or IL-17 (Th17) that attract innate effector cells such as neutrophils and macrophages [5,6]. Based on these patterns, targeted therapies that interfere with host defense at any of the above stages of immune response suggest a predisposition towards the development of IFDs. An electronic literature search was carried out using the MEDLINE/PubMed and Cochrane Library search engines until January 2021 aiming to identify IFDs in children with hematologic malignancies treated with targeted therapies. Only English language publications and peer-reviewed papers were selected to conduct this review. Moreover, prevalence of IFDs and need for prophylaxis corresponding to each pharmacologic agent will be discussed. Table1 categorizes and describes all targeted therapies that have been used in children with hematological malignancies (clinical trial identifiers retrieved from: https://www.clinicaltrials.gov/—accessed on 16 December 2020). Table 1. Monoclonal antibodies, immune checkpoint inhibitors and CAR T-cell therapies in clinical trials for children with hematological malignancies. Clinical Trial Name Trade Name Target Clinical Study Identifier Monoclonal Antibodies (mAbs) Phase II study in relapsed NCT00089349, ALL, phase II in lymphomas, NCT00061945, Recombinant ALL or AML during AHSCT, NCT00040846, Alemtuzumab Lemtrada humanized rat IgG1κ phase II study in NCT00118352, mAb ! CD52 hematological malignancies NCT00027560, before PBSCT and AHSCT NCT02061800 J. Fungi 2021, 7, 186 3 of 30 Table 1. Cont. Clinical Trial Name Trade Name Target Clinical Study Identifier Monoclonal Antibodies (mAbs) Fully human mAb ! Phase II study in pediatric Avelumab Bavencio NCT03451825 PD-L1 lymphoma Murine mAb Phase I study in recurrent B43 N/A conjugated with NCT00004858 ALL or NHL genistein ! CD19 Chimeric mAb ! Prevention of organ Basiliximab Simulect NCT02770430, [7] CD25 transplant rejections Recombinant mouse Ph-negative CD19-positive NCT02101853, bi-specific T-cell B-ALL r/r or after AHSCT, Blinatumomab Blincyto NCT02393859, engager (BiTE) ! phase III study in relapsed NCT02187354, [8] CD19, CD3 B-ALL Recombinant chimeric IgG1 hamster mAb Phase II study in stage IIB, linked to IIIB or IV, r/r HL, systemic NCT01920932, monomethylauristatin ALCL, phase II study in r/r NCT01780662, Brentuximab vedotin Adcetris E ! CD30 ! HL, phase II study in NCT01979536, (or SGN-35) internalization, tubulin anaplastic large cell NCT02166463, polymerization lymphoma, phase III study NCT02744612 inhibition, M-phase in HL arrest and apoptosis NCT04026269, Camrelizumab (or Humanized IgG4κ Phase II study in r/r HL, NCT04514081, AiRuiKa SHR-1210) mAb ! PD-1 phase III study in r/r HL NCT04233294, NCT04510610 Phase II study in r/r Recombinant human leukemia and lymphoma, NCT03384654, Daratumumab
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