Abstract 28P
Background
The S1609 DART trial is designed to assess the clinical relevance of combination dual ipilimumab and nivolumab in rare tumors. We focused on immune profiling 2 cohorts comprised of subtypes of neuroendocrine carcinomas; cohort 23 (nonpancreatic neuroendocrine (NET) and cohort 52 (pan high-grade neuroendocrine).
Methods
FFPE tissue collected at baseline and PBMCs and plasma collected at baseline and cycle 2 week 9 (C2W9) were utilized. Samples were subjected to multi-omics analyses including IHC, multiplex immunofluorescence (mIF), gene expression profiling, WES, TCR sequencing, CyTOF and Olink. Known viral TCRs were removed in silico from analysis. Hierarchical clustering based on an interacting distance of 25μm and minimum neighborhood size of 10 cells was used to identify neighborhoods of interacting cells in the TME from mIF. Biomarker data was dichotomized by median and Cox Proportional Hazard regression model used for multivariate survival analysis. For continuous biomarker data, we use Spearman’s rank correlation, Mann-Whitney U test, or Kruskal-Wallis test. We dichotomized biomarker data and used Chi-Square test for response analysis. Benjamini & Hochbert method was used for multiple-testing adjustment of p-values.
Results
Immune cells clustered in the tumor regions of responding patients and in the stroma of non-responding patients. Gene expression profiling showed a B cell signature correlated with superior response (p=0.0037) and longer progression-free survival (PFS, p=0.0067) and a tertiary lymphoid signature (TLS) associated with better response (p=0.05). Lymphoid aggregates were confirmed using H&E and correlated with B cell and TLS gene signatures. Response was associated with a decrease in IL8, an increase in IFNg, and expansion of CD4+ T cell memory subsets and activation by C2W9 in peripheral blood. TCRseq revealed high richness and density correlation with improved PFS (p=0.00011) at C2W9 but not at baseline.
Conclusions
With limited sample size fully acknowledged, multiomics analysis of NET cohorts revealed B cell/TLS signatures in tumor, diverse/dense T cells and expansion of CD4+ memory T cells in peripheral blood associate with improved outcome to ipi/nivo treatment.
Clinical trial identification
NCT02834013; Ethics Approval: The study was approved by the NCI Adult Central Institutional Review Board, approval number 02834013.
Editorial acknowledgement
Legal entity responsible for the study
University of Texas MD Anderson Cancer Center.
Funding
Scientific and financial support for the CIMAC-CIDC Network is provided through the National Cancer Institute (NCI) Cooperative Agreements U24CA224319 (to the Icahn School of Medicine at Mount Sinai CIMAC), U24CA224285 (to the MD Anderson Cancer Center CIMAC), U24CA224309 (to the Stanford University CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute) as well as funding through U10CA180888, U10CA180819; and in part by Bristol-Myers Squibb Company.
Disclosure
C. Haymaker: Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Other, Consulting: Avenge; Financial Interests, Personal, Other, Stock options as a member of the Scientific Advisory Board: Briacell; Financial Interests, Institutional, Research Grant: Iovance, Dragonfly, BTG, Sanofi, Avenge, KSQ; Non-Financial Interests, Personal, Advisory Role, Co-Chair of SAB: Mesothelioma Applied Research Foundation. S. Gnjatic: Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, EMD Serono, Pfizer, Takeda. J. Zhang: Financial Interests, Personal, Advisory Role: Merck, Johnson and Johnson, Novartis, AstraZeneca, GenePlus, Innovent, Catalyst, Henlius, Summit, Hengrui; Financial Interests, Institutional, Research Grant: Merck, Johnson and Johnson, Novartis, AstraZeneca, GenePlus, Innovent, Catalyst, Henlius, Summit, Hengrui. All other authors have declared no conflicts of interest.