Pathway-guided treatment of immune checkpoint inhibitor therapy-induced colon toxicity

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Abstract Development of immune-related adverse effects (irAEs) is one of the significant challenges of current approved cancer therapy with immune checkpoint inhibitors (ICIs) of targeting anti-CTLA4 and/or anti-PD1/PDL1. Immune- mediated enterocolitis or inflammatory bowel disease is one of the most frequent and problematic irAE associated with ICI therapy (simplistically termed “ICI-colitis” in the grant). The development of severe ICI- associated enterocolitis is the most frequent cause of ICI therapy cessation and significant morbidity, which inevitably impedes the clinical benefits of ICI therapy. The underlying mechanism of ICI-colitis remains poorly understood. Due to the lack of mechanistic understanding, current treatment of ICI-colitis was empirically adopted from the approaches for the idiopathic inflammatory bowel diseases (IBD), using corticosteroids as the 1st line treatment and targeted anti-TNFα or anti-α4β7 integrin as the 2nd line treatment for corticosteroid failures. For patients with severe ICI-colitis, this approach frequently resulted in a significant delay in resuming ICI therapy or forced permanent cessation of ICI therapy, owing to the complications of corticosteroid use itself. Clearly, it is imperative to understand the molecular and cellular pathways of ICI-colitis to guide a more scientific and effective management and to achieve better clinical outcomes. In our preliminary studies with colon biopsies from a small cohort (n=18) of ICI-colitis patients, we discovered that ICI-colitis presented two subtypes by molecular pathology and the associated responsiveness to corticosteroid treatment. One subtype has the signature of CD8 T cell cytotoxicity in the colon and responsiveness to corticosteroids, whereas the other subtype has the molecular signature of the idiopathic IBD and is refractory to corticosteroids but responsive to the 2nd line treatment. The former type was associated with elevated tumor-secreted circulating soluble NKG2D ligand sMIC in the colon and elevated serum IL-18. Notably, we have established unique animal models to recapitulate the sMIC- associated ICI-colitis subtype. With our novel clinical findings and unique animal models, the objectives of this proposed study are: 1) to establish clinically achievable biochemical parameters that can be used to guide a more effective treatment of ICI-colitis through leveraging a larger cohort of archived clinically-annotated ICI-colitis patient samples; 2) to understand the cellular and molecular mechanisms underlying the subset of ICI-colitis associated with elevated circulating sMIC and IL-18; and 3) to explore more beneficial treatments for sMIC- associated ICI-colitis preclinically. Through the perpetual dialogue between human samples and mouse models, we anticipate that our study will provide the rationales for multi-institutional large cohort clinical trials to validate the parameters for guiding a more effective ICI-colitis management and for a more beneficial therapy to treat ICI- colitis in a subset of patients.