Available online at www.sciencedirect.com
ScienceDirect
Design and application of oncolytic viruses for cancer
immunotherapy
Erkko Ylo¨ sma¨ ki and Vincenzo Cerullo
The approval of the first oncolytic virus (OV) for the treatment of responses [1]. In particular, ICIs such as antibodies
metastatic melanoma and the recent discovery that the use of targeted against programmed cell death 1 (PD-1) or
oncolytic viruses may enhance cancer immunotherapies cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
targeted against various immune checkpoint proteins have have drastically changed the treatment paradigm for
attracted great interest in the field of cancer virotherapy. OVs many cancers. However, objective responses to ICI ther-
are designed to target and kill cancer cells leaving normal cell apies have predominantly been seen in patients with prior
unharmed. OV infection and concomitant cancer cell killing anti-tumour immune response (10–30% of patients are
stimulate anti-tumour immunity and modulates tumour responding to ICIs) [2]. OV therapies have been shown to
microenvironment towards less immunosuppressive modulate the tumour microenvironment (TME) towards
phenotype. The intrinsic capacity of OVs to turn a less immunosuppressive phenotype and to enhance
immunologically cold tumours into immunologically hot anti-tumour immune responses. Combining ICI therapies
tumours, and to increase immune cell and cytokine infiltration, with OVs may help patients overcome resistance to ICI
can be further enhanced by arming OVs with transgenes that therapies. OVs are currently in clinical evaluation in
increase their immunostimulatory activities and direct immune combination with multiple cancer immunotherapeutic
responses specifically towards cancer cells. These OVs, platforms. In this review, we discuss the current engi-
specifically engineered to be used as cancer neering strategies to enhance OVs and their application as
immunotherapeutics, can be synergized with other immune cancer immunotherapeutics (see Figure 1 for schematic
modulators or cytotoxic agents to achieve the most potent representation of the design strategies of a typical OV
immunotherapy for cancer. used in the clinics). In addition, we discuss the most
recent synergistic combinations of OVs with other immu- Address
notherapeutic platforms.
Laboratory of Immunovirotherapy, Drug Research Program, Faculty of
Pharmacy, University of Helsinki, Helsinki, Finland
Tumour microenvironment and immune
Corresponding authors: Ylo¨ sma¨ ki, Erkko (erkko.ylosmaki@helsinki.fi), evasion
Cerullo, Vincenzo (vincenzo.cerullo@helsinki.fi)
Cells of the TME consist of a heterogeneous population
of neoplastic cells together with a number of different
Current Opinion in Biotechnology 2020, 65:25–36 non-transformed cells including mesenchymal cells, for
This review comes from a themed issue on Pharmaceutical example, cancer stem cells (CSCs), mesenchymal stem
biotechnology cells (MSCs), endothelial cells (ECs), fibroblasts and
Edited by Lana Kandalaft and Michele Graciotti myofibroblasts, hematopoietic cells, for example, innate
and adaptive immune cells such as macrophages, T cells,
natural killer (NK) cells, B cells, neutrophils, DCs, and
mast cells (MCs) and myeloid-derived suppressor cells
https://doi.org/10.1016/j.copbio.2019.11.016
(MDSCs). In addition to cells, the TME consists of
ã
0958-1669/ 2019 The Author(s). Published by Elsevier Ltd. This is an secreted factors such as cytokines, and extracellular
open access article under the CC BY-NC-ND license (http://creative-
vesicles and proteins of the extracellular matrix
commons.org/licenses/by-nc-nd/4.0/).
(ECM) [3]. Cancer cells, as well as non-transformed cells,
for example, cancer-associated fibroblasts (CAFs),
adipocytes, T regulatory cells (Tregs), MDSCs and
Introduction tumour-associated macrophages (TAMs) support
Cancer immunotherapy aims to increase the amount and immune evasion and tumour growth by producing and
function of tumour-infiltrating immune cells such as releasing cytokines such as interleukin-10 (IL-10),
dendritic cells (DCs) and tumour-infiltrating lympho- chemokines such as chemokine C-X-C motif ligand 12
cytes (TILs) in order to elicit therapeutic efficacy. This (CXCL12), growth factors such as transforming growth
may be achieved via multiple different strategies. For factor beta (TGF-b), matrix remodelling factors such as
example, DC vaccinations that aim to increase tumour collagen, fibronectin and fibrin and other soluble factors
antigen presentation, TIL and chimeric antigen receptor such as adenosine into the TME [3,4]. The immunosup-
(CAR) T cell therapies that aim to increase cancer killing pressive environment is established via multiple mecha-
T cells, and immune checkpoint inhibitor (ICI) therapies nisms: TGF-b and IL-10 mediate an anti-inflammatory
that aim to enhance endogenous anti-tumour immune response by dampening the activity of tumour suppressor
www.sciencedirect.com Current Opinion in Biotechnology 2020, 65:25–36
26 Pharmaceutical biotechnology
Figure 1
Attachment of tumour antigen-containing peptides onto the Genetically encoded tumour antigens or immuno- viral capsid for increased induction of tumour-specific T cells stimulatory molecules such as GM-CSF
Modifications in E1 region for tumour-specific replication: - 24 base pair deletion in Rb-binding domain of E1A Adsorption - Tumour-specific promoter-driven E1A expression - Deletion of a segment in E1B that inactivates p53
L1 L2 L3 L4 L5 E1A E1B E3
ITR ITR E2B E2A E4 Adenovirius Adenovirius Genome
Fiber knob modifications for enhanced cancer cell targeting: Chimeric fiber where knob domain is replaced with that of another Ad serotype; e.g replacement of Ad5 knob with Ad3 knob (Ad5/3). RGD motif incorporation into the fiber knob.
Current Opinion in Biotechnology
Schematic representation of various strategies for the design of an oncolytic adenovirus. Modifications in the viral E1, E3 and fiber knob regions
are commonly used in oncolytic adenoviruses used in clinical trials. For more information on viral modifications, see Ref. Kaufman et al. [117]. Ad,
adenovirus; Rb, retinoblastoma protein; p53, cellular tumour antigen p53; ITR, inverted terminal repeat.
cells such as cytotoxic T cells (CTLs) and NK cells and danger-associated molecular patterns (DAMPs) such as
enhancing the activity of tumour promoting cells such as surface-exposed calreticulin (ecto-CRT), secreted adeno-
Tregs and tumour-associated neutrophils (TANs) [5,6]. sine triphosphate (ATP) and released high mobility group
In addition, cancer cells have acquired the ability to box 1 protein (HMGB1) [11,12]. In addition to DAMP
activate different immunosuppressive immune check- release, OV-mediated cancer cell lysis is usually associated
point pathways such as CTLA-4/CD80/86 and PD-1/ with the release of various pathogen-associated molecular
PD-L1 signalling pathways that, in normal cells, are patterns (PAMPs) including viral components such as
0
associated with immune homeostasis and prevent an nucleic acids (DNA, dsRNA, ssRNA, and 5 -triphosphate
overactivated immune response leading to autoimmune RNA), proteins and capsid components [12]. DAMPs and
reactions [7]. Despite the hostile and highly immunosup- PAMPs are recognised by pattern recognition receptors on
pressive environment of the TME, some tumour innate immune cellssuch asDCsandNK cellsandfunction
suppressor cells may still be activated to combat the as ‘danger’ and ‘eat me’ signals. This signalling attracts
growing lesion. Indeed, it has been shown in a variety more DCs to the TME which in turn leads to increased
of cancers that the number of infiltrating lymphocytes recruitment and maturation of tumour-specific T cells into
positively correlates to patient survival [8–10]. the TME[11,12].iii)SomeOVssuch asHSV-1andvaccinia
virus can infect and replicate in endothelial cells causing
Oncolytic viruses can stimulate anticancer disruption of tumour vessels potentially facilitating
immunity and modulate the TME immune cell migration into the TME [13,14]. iv) Tumour
OVs induce anticancer immunity by multiple mechanisms: cell infection by an OV leads to an inflammatory response
i) Virus-mediated lysis of tumour cells releases tumour- and localized cytokine production followed by infiltration
associated antigens and neoantigens (TAAs and TANs) of innate immune cells and CTLs that help repolarize the
which can becapturedandprocessed bytumour-infiltrating TME towards less immunosuppressive phenotype [15].
antigen presenting cells (in particular, DCs), ultimately
leading to a tumour-specific T cell response against a wide Main hurdles limiting the effects of armed OVs
spectrum of the released antigens. ii) OVs can promote for cancer immunotherapy
several forms of immunogenic cell death (ICD) including Although OVs can induce anticancer immunity by multiple
necrosis, necroptosis, pyroptosis, autophagic cell death mechanisms (as described in the previous section), in most
and immunogenic apoptosis, leading to the release of cases, clinical experience with OVs as a monotherapy has
Current Opinion in Biotechnology 2020, 65:25–36 www.sciencedirect.com
OVs in cancer immunotherapy Ylo¨ sma¨ ki and Cerullo 27