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Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions.

ABSTRACT: Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the "global response" of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the "global response" claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model's demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine "complement activation-related pseudoallergy" (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

SUBMITTER: Szebeni J

PROVIDER: S-EPMC7235862 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions.

Szebeni János J Bawa Raj R

Biomedicines 20200408 4

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views chal ...[more]

PMID: 32276476

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Project description:Background aimsThe use of natural killer (NK) cells as a cellular immunotherapy has increased over the past decade, specifically in patients with hematologic malignancies. NK cells have been used at the authors' institution for over 15 years. Most patients have a reaction to NK cell infusion. The authors retrospectively analyzed the reactions associated with NK cell infusions to characterize the types of reactions and investigate why some patients have higher-grade reactions than others.MethodsA retrospective chart review of NK cell infusions was performed at the authors' institution under nine clinical protocols from 2008 to 2016. An infusion reaction was defined as any symptom from the time of NK cell infusion up to 4 h after infusion completion. The severity of infusion reactions was graded based on Common Terminology Criteria for Adverse Events, version 4. Two major endpoints of interest were (i) infusion reaction with any symptom and (ii) grade ≥3 infusion reaction. Multivariable logistic regression models were used to investigate the association between variables of interest and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained for each variable.ResultsA total of 130 patients were receiving NK cell infusions at the authors' institution. The most common reported symptom was chills (n = 110, 85%), which were mostly grade 1 and 2, with only half of patients requiring intervention. There were 118 (91%) patients with infusion reactions, and only 36 (28%) were grade 3. There was one life-threatening grade 4 reaction, and no death was reported due to infusion reaction. Among grade ≥3 reactions, cardiovascular reactions (mainly hypertension) were the most common, and less than half of those with hypertension required intervention. NK cell dose was not associated with any of the grade 3 infusion reactions, whereas monocyte dose was associated with headache (grade ≤3, OR, 2.17, 95% CI, 1.19-3.97) and cardiovascular reaction (grade ≥3, OR, 2.13, 95% CI, 1.13-3.99). Cardiovascular reaction (grade ≥3) was also associated with in vitro IL-2 incubation and storage time. Additionally, there was no association between grade ≥3 infusion reactions and overall response rate (OR, 0.75, 95% CI, 0.29-1.95).ConclusionsThe majority of patients who receive NK cell therapy experience grade 1 or 2 infusion reactions. Some patients experience grade 3 reactions, which are mainly cardiovascular, suggesting that close monitoring within the first 4 h is beneficial. The association of monocytes with NK cell infusion reaction relates to toxicities seen in adoptive T-cell therapy and needs further exploration.

Dataset Information

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions.

Publications

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions.

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