1167 Immunological drug-drug interactions: clinical, in-vitro and ex-vivo evidence for immune checkpoint inhibitor treatment increasing the susceptibility of patients to hypersensitivity reactions
Year: 2024
Type: conference-abstract
Abstract: Background Immune Checkpoint Inhibitors (ICIs) are an effective class of therapeutics used to enhance an individual’s anti-tumour response. However, the pharmacological activity of these efficacious immunotherapies also increases the propensity of an individual’s T-cells to prime to and respond to unintended antigens. The result of this on-target, off-tumour activity is an array of toxicities called immune related adverse events (irAEs). For a substantial portion of irAEs, the target antigens are self-antigens and as such, the toxicity often mimics autoimmune diseases. In recent years it has been recognised that an additional sub-class of irAEs may be attributable to drug hypersensitivity reactions to concomitantly administered medications. Previously we have generated experimental data to support a mechanistic role of PD-1 inhibitors in the initiation of drug hypersensitivity to the antirheumatic drug sulfasalazine in patients. Similarly, we have detailed a clinical case study of amidotrizoate hypersensitivity, presenting as Stevens Johnson Syndrome which was precipitated through the addition of atezolizumab despite previous tolerance to amidotrizoate. Herein, we present mechanistic in vitro data to further support both lines of inquiry. Methods Lymphocyte transformation tests were performed on PBMC derived from healthy donors and individuals hypersensitive to several drugs in order to evaluate recall responses in the presence and absence of PD-1 and PD-L1 blockade. De-novo T-cell priming responses to nitroso sulfamethoxazole were evaluated within a T-cell:monocyte derived DC based T-cell priming assay generated from drug naïve healthy donor derived PBMC with and without in-vitro PD-1 and PD-L1 blockade. Results As anticipated, PBMC recall responses in healthy donors to various antigens including the CEF/CEFT peptide pool were routinely enhanced by in vitro addition of immune checkpoint blocking antibodies. Ex vivo assessment of PBMC recall responses were used for causality assessment of clinically diagnosed. In vitro checkpoint inhibition during the priming phase of T-cell responses to nitroso sulfamethoxazole led to differential outcomes at the re-challenge phase across a dose range of compound. Importantly, at the lower levels of the dose-range, the effects imposed by ICIs on rechallenge response were more apparent. Conclusions The data lend further support to the idea that, in parallel to the debated mechanism seen with the anti-tumour efficacy of ICIs, aberrant T-cell responses to drugs may be propagated by ICIs through enhancement/reinvigoration of existing T-cell responses, or through reduction of the threshold to prime T-cells. A key challenge moving forward is how this subset of irAEs may be mitigated and managed. Ethics Approval Blood was collected from donors with approval from the Liverpool Research Ethics Committee to study de novo T-cell priming and recall responses. All participants gave written informed consent before the research commenced. Drug hypersensitive patients were also recruited as cases to the A Mechanistic Investigation into Drug and Chemical Induced Hypersensitivity Reactions (HYST) study (12/NW/0525) following initial identification and diagnosis of reactions. The patients gave written informed consent.
Institution: University of Liverpool
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065315