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

<h3>Background</h3> 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 <i>in vitro</i> data to further support both lines of inquiry. <h3>Methods</h3> 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. <i>De-novo</i> 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 <i>in-vitro</i> PD-1 and PD-L1 blockade. <h3>Results</h3> As anticipated, PBMC recall responses in healthy donors to various antigens including the CEF/CEFT peptide pool were routinely enhanced by <i>in vitro</i> addition of immune checkpoint blocking antibodies. <i>Ex vivo</i> assessment of PBMC recall responses were used for causality assessment of clinically diagnosed. <i>In vitro</i> 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. <h3>Conclusions</h3> 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. <h3>Ethics Approval</h3> 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.