Prospects for Combined Use of Oncolytic Viruses and CAR T-Cells Adam Ajina1 and John Maher2,3,4*

Ajina and Maher Journal for ImmunoTherapy of Cancer (2017) 5:90 DOI 10.1186/s40425-017-0294-6 REVIEW Open Access Prospects for combined use of oncolytic viruses and CAR T-cells Adam Ajina1 and John Maher2,3,4* Abstract With the approval of talimogene laherparepvec (T-VEC) for inoperable locally advanced or metastatic malignant melanoma in the USA and Europe, oncolytic virotherapy is now emerging as a viable therapeutic option for cancer patients. In parallel, following the favourable results of several clinical trials, adoptive cell transfer using chimeric antigen receptor (CAR)-redirected T-cells is anticipated to enter routine clinical practice for the management of chemotherapy-refractory B-cell malignancies. However, CAR T-cell therapy for patients with advanced solid tumours has proved far less successful. This Review draws upon recent advances in the design of novel oncolytic viruses and CAR T-cells and provides a comprehensive overview of the synergistic potential of combination oncolytic virotherapy with CAR T-cell adoptive cell transfer for the management of solid tumours, drawing particular attention to the methods by which recombinant oncolytic viruses may augment CAR T-cell trafficking into the tumour microenvironment, mitigate or reverse local immunosuppression and enhance CAR T-cell effector function and persistence. Keywords: Oncolytic virus, Chimeric antigen receptor, CAR T-cell, Adoptive cell transfer, Combination strategies, Synergism, Solid tumours Background immune checkpoint inhibitors targeted against pro- This review focuses on the prospects for the synergistic grammed cell death protein 1 (PD-1; e.g. pembrolizumab combinatorial use of two distinct immunotherapeutic or nivolumab), cytotoxic T lymphocyte antigen 4 (CTLA-4; modalities – adoptive cell transfer (ACT) of chimeric e.g. ipilimumab) [2] or the combination of T-VEC with antigen receptor (CAR)-expressing T-cells and oncoly- systemic chemotherapy [3] or radiotherapy [4, 5]. Several tic virotherapy. The latter has a long historical pedigree other oncolytic viruses (OVs) are also undergoing clinical dating back to the 1950s, but has only very recently evaluation (e.g. GL-ONC1 [6], vvDD [7]). entered into routine clinical practice. This followed the Clinical use of CAR T-cell therapy on the other hand approval of talimogene laherparepvec (or T-VEC), a re- has emerged within the last decade. This has followed combinant granulocyte macrophage colony-stimulating on from the successful use of tumour infiltrating factor (GM-CSF)-containing human herpes simplex lymphocyte (TIL)-based ACT for patients with type I virus (HSV-1), for inoperable locally advanced or advanced melanoma, originally developed by Rosenberg metastatic malignant melanoma based upon compelling and colleagues at the National Cancer Institute (NCI) efficacy data from the phase III OPTiM trial [1]. T-VEC in the late 1980s [8]. Autologous CAR T-cell therapy is currently being investigated in a number of early and targeting the B-cell-specific cell surface protein CD19 late phase clinical trials in melanoma and other solid have induced lasting and deep remissions in patients malignancies. These include its co-administration with with refractory B-cell malignancies, such as acute lymphoblastic leukaemia (ALL) or chronic lymphocytic * Correspondence: [email protected] leukaemia (CLL) [9]. Several Phase II clinical trials 2King’s College London, CAR Mechanics Group, School of Cancer and investigating second generation anti-CD19 CARs have Pharmaceutical Sciences, Guy’s Hospital Campus, Great Maze Pond, London now reported and these agents are expected to enter SE1 9RT, UK 3Department of Clinical Immunology and Allergy, King’s College Hospital routine clinical practice imminently. However, the NHS Foundation Trust, London, UK development of effective CAR T-cell therapies for solid Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ajina and Maher Journal for ImmunoTherapy of Cancer (2017) 5:90 Page 2 of 27 tumours has proved far less straightforward, owing to clinical trials evaluating OVs either alone or in combin- several critical obstacles pertaining to safety and potency. ation with other therapies has expanded rapidly and This review attempts to present opportunities to over- these are summarised in detail in Table 1. Globally, two come these issues by highlighting potential for synergistic viruses, T-VEC and H101 have now achieved regulatory immunotherapy with oncolytic virotherapy. approval. H101 is a genetically modified oncolytic adenovirus that was approved in China in November Oncolytic virotherapy: the story so far 2005 for the treatment of nasopharyngeal carcinoma in The development of genetically engineered OVs came combination with systemic chemotherapy [15]. The to the fore in the 1990s with the first clinical trials of diversity of available OVs, each with their own hall- recombinant adenoviruses, such as ONYX-015 [10]. marks of tumour tropism and specificity, virulence and For a long time, it was assumed that the dominant oncolytic potential allows for the nuanced and optimal mechanism underpinning the anti-cancer effect of these selection of OVs for combined use with cellular therapies agents stemmed from their oncolytic potential. It is such as CAR T-cell therapy. Furthermore, many OVs have now apparent, however, that the lysis of virally infected undergone extensive iterative laboratory-based study cancer cells plays a relatively indirect role in inducing during the development of anti-viral vaccines over many tumour regression and long-term clinical benefit in decades. This provides reassurance with regards to safety most patients. Instead, it has become clear that clinical and tolerability following administration in human sub- efficacy of OVs (such as T-VEC) is strongly dependent jects. Oncolytic strains of vaccinia virus – alarge,com- upon their ability to convert tumours into living “vaccine plex, enveloped poxvirus – have the longest and most factories”. These provide immunological “danger signals” extensive history of administration in humans of any that include small molecules (e.g. uric acid [11] and ad- known virus due to their use in the eradication of small- enosine triphosphate (ATP)), and protein mediators such pox during the middle of the last century [16]. as high-mobility group box 1 (HMGB1) [12] and type I As gene-manipulating technologies have moved to the interferon (IFN) signalling [13]. By this means, OV infec- forefront of bio-scientific research, great strides have tion results in enhanced tumour-associated antigen pres- been made in understanding and delineating the mecha- entation (due to neo-antigen spreading), improved T-cell nisms of tumour tropism and specificity. Although this and natural killer (NK) cell trafficking into the tumour remains incompletely understood, it is recognised that microenvironment (TME) and enhanced effector function, many OVs are dependent upon cancer cells providing a leading to a “bystander effect” at local and distant sites of nucleotide-rich environment and expressing relatively disease. Efficacy of oncolytic virotherapy is therefore high levels of key molecules conducive to viral genomic dependent upon a complex interplay between functional replication, relative to normal tissue. Several mecha- innate and adaptive immune cells within the patient and nisms may underlie the tumour specificity of OVs. First, more specifically within the TME itself. Many solid some OV achieve preferential viral entry into cancer tumours present a significant barrier to this process cells by binding to cell surface molecules that are more whereby the TME is either non-permissive to entry of ef- highly expressed by certain tumours. This is illustrated fector immune cells or exerts immunosuppressive effects by the ability of many OV strains of coxsackievirus to on those cells that do manage to gain access [14]. The bind to intercellular adhesion molecule 1 (ICAM-1), ability of recombinant OVs to modulate the TME is now which is a cell adhesion molecule that is over-expressed being exploited further by rationally inserting transgenes in many tumours [17]). Alternatively, OVs may exploit to encode immunostimulatory cytokines, chemokines or specific aberrant signalling pathways in cancer cells co-stimulatory molecules into viral virulence genes, thus through one of many mechanisms. For example, vaccinia fulfilling a dual strategy of optimising tumour tropism and virus replication is favoured by heightened epidermal specificity. Oncolytic viruses are therefore highly attractive growth factor receptor (EGFR)-RAS signalling, as found agents to use in combination with cellular therapies when in many solid tumours [18]. Similarly, overexpression of targeting solid tumours. B-cell lymphoma (BCL) pro-survival proteins (such as A wide variety of OV vectors spanning numerous BCL-xL) is targeted by NDV, which is able to continuously

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