Immune‐Related Adverse Events From Immune Checkpoint Inhibitors

Marrone, Kristen A.; Ying, Wendy; Naidoo, Jarushka

doi:10.1002/cpt.394

Cited by 92 publications

(69 citation statements)

References 70 publications

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“…Efficacies vary widely across tumor and treatment type, with objective response rates ranging between 5–60%(1,2). Immunotherapy is also often associated with severe immune-related adverse events, including hepatitis, colitis, and even death, with grade III/IV adverse events occurring in up to 50% of patients on PD-1/CTLA-4 inhibitor combination regimens(3,4). Early differentiation of treated responders from non-responders would help to triage non-responding patients away from ineffective therapies, reducing unnecessary side effects and allowing the opportunity for alternative therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response

et al. 2017

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While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders and conventional imaging modalities have not proved adequate. Here we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as a early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from non-responders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and non-responders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical applcation. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response

et al. 2017

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“…Currently, combinations of two or more agents that target different mechanisms have demonstrated a clear improvement in response rates, but have also highlighted several key challenges in systemically delivering multiple immunotherapeutics [22–24]. Firstly, enhanced efficacy is often accompanied by an increased rate and severity of drug-related adverse events caused by off-target toxicity [25, 26]. Secondly, providing treatment with two or more complex biological agents is associated with high costs [27].…”

Section: Introductionmentioning

confidence: 99%

Development of a versatile oncolytic virus platform for local intra-tumoural expression of therapeutic transgenes

et al. 2017

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Oncolytic viruses which infect and kill tumour cells can also be genetically modified to express therapeutic genes that augment their anti-cancer activities. Modifying oncolytic viruses to produce effective cancer therapies is challenging as encoding transgenes often attenuates virus activity or prevents systemic delivery in patients due to the risk of off-target expression of transgenes in healthy tissues. To overcome these issues we aimed to generate a readily modifiable virus platform using the oncolytic adenovirus, enadenotucirev. Enadenotucirev replicates in human tumour cells but not cells from healthy tissues and can be delivered intravenously because it is stable in human blood. Here, the enadenotucirev genome was used to generate plasmids into which synthesised transgene cassettes could be directly cloned in a single step reaction. The platform enabled generation of panels of reporter viruses to identify cloning sites and transgene cassette designs where transgene expression could be linked to the virus life cycle. It was demonstrated using these viruses that encoded transgene proteins could be successfully expressed in tumour cells in vitro and tumours in vivo. The expression of transgenes did not impact either the oncolytic activity or selective properties of the virus. The effectiveness of this approach as a drug delivery platform for complex therapeutics was demonstrated by inserting multiple genes in the virus genome to encode full length anti-VEGF antibodies. Functional antibody could be synthesised and secreted from infected tumour cells without impacting the activity of the virus particle in terms of oncolytic potency, manufacturing yields or selectivity for tumour cells. In vivo, viral particles could be efficaciously delivered intravenously to disseminated orthotopic tumours.

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“…16 They can dramatically improve clinical outcomes across cancers but may lead to serious immune-mediated toxicities affecting any organ. [17][18][19][20][21] Delayed recognition of toxicities could lead to patient harms. 10 Although published clinical trial reports include descriptions of common and severe toxicities, published toxicity data tend to be incomplete and focus on expected complications; reliable data sources are needed to enable timely understanding of previously unrecognized toxic effects.…”

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confidence: 99%