9566 Background: Ipilimumab-related colitis has been well described, but the clinical presentation of colitis related to MONO or COMBO therapy has not. We aimed to characterize clinical features that define this serious adverse event. Methods: This retrospective study included melanoma pts with colitis screened from 6 academic centers treated with either MONO or COMBO therapy. Clinically relevant colitis was defined as diarrhea/colitis symptoms requiring systemic steroids. The onset, management, and outcomes related to colitis were summarized. Results: We screened 866 pts and identified 72 with clinically relevant colitis. For the MONO cohort, the incidence was 3.5% (23/657) and 23.4% (49/209) in the COMBO cohort. MONO-colitis occurred at a median 33 weeks (wks) into therapy, while median onset was 8 wks with COMBO therapy. One pt had grade 5 colitis from COMBO therapy. Despite the use of systemic steroids, COMBO-colitis needed more infliximab therapy (38.8% vs 26.1%). The median prednisone equivalent dose was higher for COMBO therapy (1.5 vs 1 mg/kg), and the median taper was shorter for MONO-colitis (4 vs 6 wks). Steroid dose-escalation for worsening symptoms during taper was more common with COMBO-colitis (42.9% vs 17.3%). Relapse was similar between cohorts (MONO: 26.1%, COMBO: 20.4%). Relapses occurred more frequently in COMBO therapy with tapers shorter than the median (38.1% vs 25.0%), and more frequently in MONO therapy with steroid doses lower than the median (60% vs 21.7%). MONO-colitis pts (17.4%) were less likely than COMBO-colitis pts (46.9%) to be restarted on PD-1 therapy. When restarted, only 13% with COMBO therapy relapsed as compared to 50% with MONO therapy. Objective response rates for MONO and COMBO cohorts were 72.7% and 56.1%, respectively. Conclusions: Colitis occurred with a much higher incidence in COMBO therapy. MONO-colitis was associated with a milder course with later onset, shorter duration and lower dose of steroids, fewer dose-escalations, and need for infliximab as compared to COMBO therapy. Relapse of colitis was generally associated with shorter steroid tapers for COMBO therapy and lower steroid doses for MONO therapy.
3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; > 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to several hundred (0.4%, 2.7%, and 3% of rearrangements, respectively), including high-frequency clones. Shared TCRβ sequences were also identified among and between colon-irSAE and Crohn’s specimens. Gene expression patterns of inflammation in colon-irSAE resembled that of Crohn’s disease in principle components and clustering analysis, highlighting likeness between these diseases/SAEs. NanoString digital spatial profiling of regions of inflammation across samples showed higher CD68 and PD-L1 positivity in colon-irSAE specimens versus normal colon or Crohn’s specimens and reduced beta-catenin levels in both Crohn’s and colon-irSAE specimens relative to normal controls. Finally, we detected a high degree of TCR clonality in the encephalitic brain, including a single sequence present in ~20% of > 12,000 T cells, suggesting a distinct antigen-specific response. Conclusions: We report the molecular characteristics of irSAE in colon and brain specimens from patients receiving ICIs. Highly clonal TCRβ sequences were frequently detected, particularly in a unique case of encephalitis-irSAE. Furthermore, we identify molecular distinctions and similarities between autoimmune and colon-irSAEs at the gene expression and proteomic levels.
180 Background: Anti-PD-1 therapy is effective in many cancers, but tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II (HLA-DR) expression on tumor cells can predict response to anti-PD-1. Thus, we sought to determine the molecular features of MHC-II+ tumors in the evolution of anti-PD-1 response. Methods: We performed RNA-seq on 58 anti-PD-1 treated melanoma and lung tumors, including a subset of matched specimens prior to treatment and at acquired resistance. We performed immunohistochemistry (IHC) for immunologic markers, including HLA-DR on tumor cells. In triple-negative breast cancers (TNBC; n = 103), we performed IHC and/or quantitative immunofluorescence (QIF) for LAG3, PD-L1, CD4, CD8, Fc-receptor-like 6 (FCRL6), and granzyme B (GZMB). QIF images were assessed by Automated Quantitative Analysis (AQUA). To determine the functional effect of MHC-II on tumor cells, we generated isogenic MHC-II+ mouse tumors and assessed immune responsiveness and efficacy of checkpoint inhibition. Results: We identified unique inflammatory signatures in HLA-DR+ tumors, correlating with enhanced pre-treatment CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and response to anti-PD-1. LAG3+ and FCRL6+ TILs were enriched in HLA-DR+ tumors. LAG3 and FCRL6, known inhibitory receptors which bind MHC-II, were elevated at anti-PD-1 resistance. Similarly, in > 100 TNBCs, HLA-DR+ tumor cells associated with increased CD4+ and CD8+ TILs and enhanced LAG3+ and FCRL6+ TILs. Further, presence of MHC-II-suppressing (LAG3+/FCRL6+) TILs associated with decreased GZMB+ CD8+ T cells, suggesting suppressed cytotoxicity. In mice, enforced expression of MHC-II on tumor cells enhanced CD4-enhanced anti-tumor immunity but was thwarted by LAG3+ TIL recruitment. Combined anti-LAG3 and anti-PD-1 therapy was selectively effective in MHC-II+ tumors. Conclusions: MHC-II+ tumors are immunologically active and may circumvent anti-tumor immunity by targeting MHC-II antigen presentation via recruitment of MHC-II-suppressing TILs. MHC-II expression may be useful to stratify patients to anti-PD-1/anti-LAG3 and eventually, anti-PD-1/anti-FCRL6 combinations.
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