Project Summary/Abstract
Immune checkpoint inhibitors (ICIs) have become standard of care for an increasing number of
malignancies with up to 230,000 patients eligible for ICI therapy annually in the US alone. Despite their
efficacy, ICIs are associated with morbid and potentially fatal toxicities, known as immune-related adverse
events (irAEs). Cutaneous irAEs (cirAEs) are the most frequently reported toxicities, occurring in 20-40% of all
treated patients with over 40 distinct morphologic subtypes reported in literature to date. Though these
toxicities vary in severity, they have a considerable burden on patient quality of life and may result in
interruption of life-saving ICI therapy or reliance on systemic immunosuppression that may blunt the anti-tumor
effect of ICIs. There is an urgent need to understand how and why these adverse reactions occur and reduce
their impact. This study will investigate the real-world epidemiology, downstream clinical implications, and risk
factors for the development of these toxicities using cross-validated institutional and population-level data.
Our first aim proposes a robust observational study to identify cutaneous eruptions with the strongest
associations with ICI therapy, which will, in turn, be used to identify clinical risk factors for the development of
these events and their downstream outcomes. This is particularly important as cirAE data from clinical trials of
ICIs was largely documented by non-dermatologists with resulting limited dermatologic phenotyping. Further,
there is currently a lack of large-scale data on cirAEs and an absence of definitional standards for what
constitutes a cutaneous immunotherapy toxicity, limiting all research in this field. We will further investigate the
impact of cirAEs on systemic immunosuppression utilization and survival.
Our second aim will identify germline associations for cirAE development using tissue samples
collected from ICI recipients at our institutions. Many autoimmune diseases have germline risk variants of large
effect in the HLA region and we hypothesize that HLA variation will also influence development of cirAEs. Our
preliminary data has demonstrated that patients with cirAEs were more likely to be HLA-DR4 carriers and that
polygenic risk scores (PRSs) for autoimmunity predisposition were also significantly associated with cirAEs.
Ongoing genotyping at our institution will enable validation of these results and expansion of our risk prediction
models to identify additional genetic variants within and outside the HLA region.
Results from Aims 1 and 2 will be integrated into a combined clinical and genetic risk stratification tool
for cirAE development in Aim 2c. Since cirAEs are the earliest ICI toxicities to occur and are highly correlated
with development of non-cutaneous irAEs, this risk stratification will, in turn, enable clinicians to prioritize more
intensive cancer therapies for patients least likely to develop toxicity as well as to provide enhanced
surveillance of vulnerable populations at highest risk of developing these events.