Abstract
Local administration of oncolytic viruses to tumours can promote anticancer immune responses that lead to the abscopal regression of distant metastases, especially in patients receiving systemic immune-checkpoint inhibitors. Growing preclinical evidence indicates that non-virally induced oncolysis, defined as chemical or physical treatment administered locally to destroy malignant lesions, can promote a similar effect owing to the release of danger-associated molecular patterns that lead to the recruitment of immune cells, thus inducing a systemic response against tumour antigens that protects against local disease relapse and also mediates distant antineoplastic effects. An accumulating body of preclinical evidence supports the implementation of therapies that combine oncolysis with local or systemic immunotherapies. In this Review, we summarize the available data on innovative non-viral oncolysis strategies, including intratumorally applied cytotoxicants, photodynamic therapy, laser therapy, microwave, radiofrequency or photothermal ablation, high-intensity focused ultrasonography and cryotherapy for the local treatment of patients with solid tumours.
Key points
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Oncolytic viruses are beginning to enter clinical use in patients with cancer despite practical considerations precluding their widespread use, highlighting the need for non-viral methods of oncolysis.
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Multiple distinct physical and/or chemical methods of non-viral oncolysis are available. Each type of oncolysis causes a distinct type of cell stress and tissue destruction with variable immunological outcomes.
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Immunogenic oncolysis initiates a local antitumour immune response through the destruction of immunosuppressive cells and the release of immunoactivatory danger-associated molecular patterns, leading to the recruitment of immune effectors.
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Various strategies for increasing the immune-mediated abscopal effects of oncolysis, including local or systemic immunotherapies, are being developed. The optimal schedule of such combination regimens must be carefully evaluated in future trials.
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Acknowledgements
We thank E. Deutsch (GRCC) for critical reading. A.M. gratefully acknowledges financial support from BMS, Fondation MSD Avenir, INSERM CIC 1428 Biotherapies, the Institut National du Cancer (INCa) and the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE). G.K. gratefully acknowledges financial support from the Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, the Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Chancellerie des universités de Paris (Legs Poix), a donation from Elior, the European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), the European Union Horizon 2020 Project Oncobiome, Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Fondation pour la Recherche Médicale (FRM), Gustave Roussy Odyssea, Inserm (HTE), the Institut National du Cancer (INCa), the Institut Universitaire de France, LabEx Immuno-Oncology, the LeDucq Foundation, the Ligue contre le Cancer (équipe labellisée), the RHU Torino Lumière, the Seerave Foundation, the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE).
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O.K. and G.K. researched data for the manuscript, all authors made a substantial contribution to discussions of content and wrote the manuscript, and O.K., L.Z. and G.K. reviewed and/or edited the manuscript prior to submission.
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G.K. and L.Z. have received research funding (contracts) from Lytix Ltd. A.M. has received funding from BMS, Roche and Transgene for academic sponsored clinical trials involving intratumoural immunotherapies (NCT02857569, NCT02977156 and NCT03892525) and has received honoraria and/or consulting fees from Amgen, AstraZeneca/Medimmune, Bioncotech, Boehringer Ingelheim, EISAI, Lytix pharma, MSD, Pillar Partners and Sanofi.
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Glossary
- Oncolysis
-
The lysis of malignant cells using locally applied physical or chemical methods.
- Oncolytic virus
-
A virus designed to infect and kill cancer cells.
- Dendritic cells
-
(DCs). A specialized subset of myeloid cells with the capacity to process and present antigens to cells that mediate the adaptive immune response. Such cells engulf proportions of tumour cells, digest their proteins and present the resulting peptides in the context of MHC class I molecules to CD8+ T lymphocytes.
- Necrosis
-
An unregulated form of cell death accompanied by early rupture of the plasma membrane.
- Coagulation
-
Denaturation of proteins that clot together. This effect is usually induced by heat.
- Apoptosis
-
The best characterized form of regulated cell death, involving activation of caspases, shrinkage of cells and the generation of apoptotic bodies.
- CD8:FOXP3 ratio
-
The ratio of CD8 (mostly expressed by cytotoxic T lymphocytes) to FOXP3 (mostly expressed by regulatory T cells) expression, which indicates the local immune tonus. A high ratio suggests the presence of an active immune response, whereas a low ratio is suggestive of immunosuppression.
- Immunogenic cell death
-
(ICD). A form of cell death occurring in virally infected or cancer cells that stimulates an immune response against antigens released by dead or dying cells.
- Immunogenicity
-
The capacity to elicit a protective immune response.
- Necroptosis
-
A regulated form of cell death that is distinctly different to apoptosis and involves the activation of specific effector molecules such as RIPK3 and MLKL.
- Antigenicity
-
The presence of antigenic determinants that are absent in non-malignant cells and tissues and can be recognized by specific B and T lymphocytes.
- Adjuvanticity
-
The presence of danger-associated molecules that activate the effector cells of the innate immune system.
- Penumbra
-
The area of the tumour surrounding the region of central necrosis.
- Tumour-associated antigens
-
(TAAs). Proteins that are either structurally different (often owing to mutations) to those present in non-malignant cells or expressed by malignant but not by non-malignant cells.
- Toll-like receptor
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(TLR). A pattern-recognition receptor that recognizes bacterial or viral motifs located within or on the surface of cells.
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Kepp, O., Marabelle, A., Zitvogel, L. et al. Oncolysis without viruses — inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol 17, 49–64 (2020). https://doi.org/10.1038/s41571-019-0272-7
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DOI: https://doi.org/10.1038/s41571-019-0272-7