Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity

Author:

Hammond Sean12,Olsson-Brown Anna1,Grice Sophie1,Gibson Andrew3,Gardner Joshua1,Castrejón-Flores Jose Luis4,Jolly Carol,Fisher Benjamin Alexis567ORCID,Steven Neil89,Betts Catherine10,Pirmohamed Munir1ORCID,Meng Xiaoli1,Naisbitt Dean John1ORCID

Affiliation:

1. Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK

2. ApconiX, Alderley Edge SK10 4TG, UK

3. Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, WA 6150, Australia

4. Instituto Politécnico Nacional, Unidad Profesional Interdisciplinaria de Biotecnología, Mexico City 07340, México

5. Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

6. National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK

7. Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

8. Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

9. Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

10. Pathology Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK

Abstract

Abstract An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.

Funder

Otsuka Pharmaceutical Development & Commercialization

MRC Clinical Training Fellow based at the University of Liverpool

North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics

Medical Research Council, Roche Pharma, Eli Lilly and Company Limited, UCB Pharma, Novartis, the University of Liverpool and the University of Manchester

MRC

Centre for Drug Safety Science

National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and the NIHR/Wellcome Trust Birmingham Clinical Research Facility

Publisher

Oxford University Press (OUP)

Subject

Toxicology

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