Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.
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Date
2018-02Author
Brown, JS
Sundar, R
Lopez, J
Type
Journal Article
Metadata
Show full item recordAbstract
The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.
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Subject
Animals
Humans
Neoplasms
DNA Damage
Antineoplastic Combined Chemotherapy Protocols
Antigens, Neoplasm
Immunotherapy
Signal Transduction
Immunologic Surveillance
DNA Repair
Tumor Microenvironment
CTLA-4 Antigen
Programmed Cell Death 1 Receptor
B7-H1 Antigen
Research team
Medicine (de Bono Prostate)
Language
eng
Date accepted
2017-09-04
License start date
2018-02
Citation
British journal of cancer, 2018, 118 (3), pp. 312 - 324