cancers Review Measles Virus as an Oncolytic Immunotherapy Christine E. Engeland 1,2,* and Guy Ungerechts 1,* 1 Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) and Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany 2 Center for Biomedical Education and Research (ZBAF), Institute of Virology and Microbiology, Faculty of Health, School of Medicine, Witten/Herdecke University, 58453 Witten, Germany * Correspondence: [email protected] (C.E.E.); [email protected] (G.U.) Simple Summary: Measles virus is currently under investigation as an innovative cancer treatment. The virus selectively replicates in and kills cancer cells. Furthermore, it can be genetically engineered to increase tumor specificity and therapeutic efficacy. Importantly, treatment with measles virus activates antitumor immune responses. A number of clinical trials using measles virus for cancer treatment have been completed or are ongoing. Future studies will further harness the possibilities of virus engineering and potential of combination immunotherapies to improve clinical outcome. Abstract: Measles virus (MeV) preferentially replicates in malignant cells, leading to tumor lysis and priming of antitumor immunity. Live attenuated MeV vaccine strains are therefore under investigation as cancer therapeutics. The versatile MeV reverse genetics systems allows for engi- neering of advanced targeted, armed, and shielded oncolytic viral vectors. Therapeutic efficacy can further be enhanced by combination treatments. An emerging focus in this regard is combination immunotherapy, especially with immune checkpoint blockade. Despite challenges arising from antiviral immunity, availability of preclinical models, and GMP production, early clinical trials have demonstrated safety of oncolytic MeV and yielded promising efficacy data. Future clinical trials with engineered viruses, rational combination regimens, and comprehensive translational research Citation: Engeland, C.E.; programs will realize the potential of oncolytic immunotherapy. Ungerechts, G. Measles Virus as an Oncolytic Immunotherapy. Cancers Keywords: oncolytic virus; measles virus; cancer immunotherapy; vector engineering; vaccination; 2021, 13, 544. https://doi.org/ 10.3390/cancers13030544 immune checkpoint blockade Academic Editor: David Wong Received: 31 December 2020 Accepted: 26 January 2021 1. Introduction—Measles Virus for Cancer Therapy Published: 1 February 2021 Measles virus (MeV) is a negative-strand RNA virus belonging to the family Paramyx- oviridae, genus Morbillivirus. Its genome has a length of approximately 16 kb and en- Publisher’s Note: MDPI stays neutral codes six structural and two non-structural proteins (Figure1a,b). The viral glycoproteins with regard to jurisdictional claims in hemagglutinin and fusion mediate receptor binding and fusion at the plasma membrane, published maps and institutional affil- respectively. While wild type MeV uses CD150/SLAM on lymphoid cells and epithelial iations. nectin-4 as receptors, vaccine strains of MeV infect cells primarily via CD46 [1]. This is due to mutations in the receptor attachment protein hemagglutinin H in vaccine strain MeV, resulting in high affinity of H for CD46 [2–6]. MeV infection results in syncytia formation as typical cytopathic effect (Figure1c). Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 544. https://doi.org/10.3390/cancers13030544 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 19 safety record [10]. Several years later, testing of Edmonston B measles vaccine strain de- rivatives for cancer treatment began. In many early studies, hematological malignancies were chosen as target entities [11–14]. This was supported by the natural lymphotropism of MeV. However, other malignancies including ovarian cancer [15] and glioblastoma [16] were soon found to also be sensitive to MeV oncolysis, while normal cells are spared [15,17]. Meanwhile, preclinical efficacy of oncolytic MeV has been demonstrated against a broad range of cancer entities (reviewed in [18]). In addition to Edmonston B derivatives, also the vaccine strains Moraten-Schwarz [19], Edmonston-Zagreb and AIK-C [20], rMV- Cancers 2021, 13, 544 Hu191 [21], as well as Leningrad-16 [22] have been shown to exert oncolytic effects2 of 18 in preclinical studies. FigureFigure 1. 1.Measles Measles as as an an oncolytic oncolytic virus. virus. (a ()a Schematic) Schematic of of the the measles measles virus virus particle. particle. The The viral viral RNA RNA genome genome is is encapsulated encapsulated byby the the nucleocapsid nucleocapsid (N) (N) protein protein and and is associated is associated with with the viral the viral polymerase polymerase (L, large (L, protein)large protein) and its and cofactor its cofactor phosphoprotein phospho- (P),protein forming (P), the forming ribonucleoprotein the ribonucleoprot complexein (RNP).complex The (RNP). matrix The (M) matrix protein (M) connects protein theconnects RNP and the theRNP viral and envelope. the viral enve- The surfacelope. The glycoproteins surface glycoproteins hemagglutinin hemagglutinin (H) and fusion (H) (F) and mediate fusion receptor (F) mediate binding receptor and cell binding fusion, and respectively. cell fusion, (b )respectively. Schematic of(b the) Schematic measlesvirus of the genome measles with virus open genome reading with frames open reading encoding frames the six encoding structural the proteins six structural flanked proteins by the flanked 30 leader by (ld) the 3′ leader (ld) and 5′ trailer (tr). (c) Syncytia formation as the typical cytopathic effect associated with measles virus infec- and 50 trailer (tr). (c) Syncytia formation as the typical cytopathic effect associated with measles virus infection. Human tion. Human colorectal cancer (KM12, top) and pancreatic adenocarcinoma (T3M4, bottom) cells were transfected with colorectal cancer (KM12, top) and pancreatic adenocarcinoma (T3M4, bottom) cells were transfected with plasmids encoding plasmids encoding the MeV glycoproteins H and F as well as enhanced green fluorescent protein as reporter. Control cells thewere MeV subjected glycoproteins to mock H transfection. and F as well Phase as enhanced contrast green and fluo fluorescentrescence protein images as were reporter. acquired Control with cells an Axiovert were subjected 200 micro- to mockscope transfection. (Zeiss) at 36 Phase h (KM12) contrast and and12 h fluorescencepost-transfection images (T3M4). were acquiredScale bar: with 200 µM. an Axiovert (d) Lymphoma 200 microscope remission (Zeiss) after atmeasles 36 h (KM12)infection. and Left 12 h panel: post-transfection The patient (T3M4).presented Scale with bar: orbital 200 µBurkitt’sm. (d) Lymphoma lymphoma. remission Middle panel: after measlesThe patient infection. was infected Left panel: with Themeasles; patient the presented typical skin with rash orbital is visible. Burkitt’s Right lymphoma. panel: With Middleout specific panel: anti-lym The patientphoma was treatment, infected with the orbital measles; mass the resolved. typical skinReproduced rash is visible. from RightLancet panel: 10 July Without 1971; 2 specific(7715): 105–106, anti-lymphoma with permission. treatment, the orbital mass resolved. Reproduced from Lancet 10 July 1971; 2 (7715): 105–106, with permission. Thus, MeV is one of several oncolytic platforms currently developed for cancer ther- apy.Originally, Advantages the of idea MeV to treatinclude cancer the patients excellen witht safety MeV profile arose afterof the case oncolytic reports whichvaccine linkedstrains measles and lack infection of genotoxicity, to tumor remissionits immunoge [7].nicity, One highly and especially cited example the plethora relates to of a engi- boy sufferingneering frompossibilities Burkitt’s offered lymphoma by the [8] MeV (Figure reverse1d). These genetics experiments system. ofSpecific nature challenges inspired the re- idealated of to using MeV MeV include in cancer pre-existing treatment. antiviral However, immunity, measles the is choice a severe of preclinical infectious diseasemodels [and9]. Thus,manufacturing. employing These a pathogenic assets and strain drawbacks of MeV inare cancer discussed therapy in more is out detail of question. within this Live re- attenuatedview article. MeV strains for vaccination were licensed in the 1960s and have a proven safety record [10]. Several years later, testing of Edmonston B measles vaccine strain derivatives for2. Measles cancer treatment Virus Oncotropism began. In many early studies, hematological malignancies were chosenMeasles as target vaccine entities strain [11–14 oncotropism]. This was supported correlates by with the CD46 natural overexpression lymphotropism on of malig- MeV. However, other malignancies including ovarian cancer [15] and glioblastoma [16] were nantly transformed cells [23]. Although viral entry occurs in benign cells and at low CD46 soon found to also be sensitive to MeV oncolysis, while normal cells are spared [15,17]. receptor density, a certain threshold of expression is required for syncytia formation and Meanwhile, preclinical efficacy of oncolytic MeV has been demonstrated against a cell death [24]. In myeloma, CD46 upregulation has