| dc.description.abstract | Background: Therapeutic inhibition of programmed cell death receptor-1 (PD-1) has revolutionized the treatment of melanoma. Immune checkpoint inhibitors (ICI) target specific interactions in the immune cascade, ultimately activating tumor-specific T cells to promote tumor destruction. This mechanism of action gives rise to a potential immune response against self-antigens that can lead to the emergence of immune-related adverse effects (irAEs). There is growing evidence that patients who suffer from a subset of tissue-specific irAEs may derive greater benefit from therapy. We hypothesize that there is a subset of immune cells that is responsible for organ-specific toxicities and that is distinct from immune populations that are responsible for ICI-induced tumor response in certain patients.
Methods: A retrospective analysis of 50 melanoma patients treated at the Massachusetts General Hospital has been previously performed, generating detailed response and toxicity clinical data. In parallel, proteomic data from plasma of these patients via a proximity extension array (Olink®) was generated, examining ~1000 markers of protein expression simultaneously. Samples were analyzed prior to treatment, as well as 6 weeks and 6-month following treatment initiation.
Results: Out of the 50 patients in this cohort, 60% (n=30) experienced at least one irAE of any grade. At 6 weeks and 6 months post treatment, NOS3 expression was increased among patients who did vs. did not experience an irAE. A large breadth of irAE classes were documented including gastrointestinal, musculoskeletal, cutaneous, endocrine, pulmonary, renal and hepatitis. Based on our hypothesis that a distinct group of immune cells is responsible for organ-specific toxicities, we examined the proteomic profiles of three groups of patients: (1) cutaneous and musculoskeletal toxicities (hypothesized shared mechanism of toxicity and response), (2) colitis (hypothesized distinct mechanism of toxicity), and (3) patients with no toxicities. While there were no markers that were statistically significant, a number of markers revealed trends over multiple iterations of analyses, most notably NOS3. Analysis of expression over time and correlations with other markers was also performed.
Discussion: Unbiased proteomic profiling and correlation with tissue-specific irAEs can yield insights into shared and exclusive markers of toxicities. The translational melanoma infrastructure at the MGH allows retrospective analysis of patients treated with ICI. This project importantly demonstrates the feasibility of retrospective analysis of irAEs using this data-set. Further investigation of protein markers of toxicities is warranted. | |
