128P - Whole blood transcriptomics identifies transcriptional patterns linked to outcomes in patients receiving immune checkpoint inhibitors

Background

Transcriptomics can assess cellular states in whole blood (WB). We aimed to identify transcriptional patterns in WB of patients treated with immune checkpoint inhibitors (ICI) related to outcome.

Methods

We prospectively collected pre-ICI patient WB samples and clinical data (PRIMERO cohort), including sex, age, tumor type, ICI type, other oncological treatments ≤3 months prior to ICI for metastatic disease, overall survival (OS) and progression-free survival (PFS) from ICI initiation, and tumor response. Censoring was applied when no OS or PFS occurred. Associations for OS and PFS were determined using all patients, for tumor response only patients with complete (CR), partial (PR) tumor response or progressive disease (PD) assessed with RECIST 1.1. mRNA-sequencing was performed on the PRIMERO samples. In addition, we built a dataset with >14,000 whole-blood transcriptomes of public repositories of healthy individuals and patients with various conditions (PUBLIC). We applied consensus-independent component analysis (c-ICA) to the PUBLIC data to obtain statistically independent transcriptional components (TCs), capturing prominent and subtle transcriptional patterns. TCs were characterized with gene-set enrichment analyses. We determined the activity of identified TCs in WB of the PRIMERO cohort and determined their association with OS, PFS, and tumor response in univariate and multivariate analyses.

Results

The PRIMERO cohort comprised melanoma (n=83), renal cell (n=28), non-small cell lung (n=17), squamous cell skin (n=10), or Merkel cell cancer (n=7) patients; 19 CR, 46 PR, 15 stable disease and 65 PD. Median OS and PFS were 20 and 4.5 months. c-ICA identified 1,262 TCs in PUBLIC data, 17 correlated with tumor response, PFS, and/or OS in the PRIMERO cohort. Of the 17 TCs, three reflected immune activation and 14 reflected a diverse biology linked to immune suppressive conditions that mimic immune exhaustion. One TC correlated with all outcome variables, comprising TCF19 and CCHRC1 as the most important genes.

Conclusions

WB transcriptomics can detect subtle transcriptional patterns linked to outcomes in ICI treated patients.

Clinical trial identification

Samples included in this study were obtained through two biobanks: the Oncological Life Study Immunotherapy cohort (OncoLifeS-Immunotherapy, NL7839) and the Clinical Cohort Study of Patients with Melanoma and NSCLC Receiving Checkpoint Inhibitors (POINTING, NCT04193956).

Editorial acknowledgement

During the preparation of this work the author(s) used Grammarly and ChatGPT in order to enhance correctness and clarity. After using this tool, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Legal entity responsible for the study

The authors.

Funding

UMCG Kanker Researchfonds.

Disclosure

M. Jalving: Financial Interests, Institutional, Advisory Board, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board, Advisory board: Merck; Financial Interests, Institutional, Advisory Board: Pierre Fabre. S. Oosting: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Genmab; Financial Interests, Institutional, Invited Speaker: Merck, Travel Congress Management B.V.; Financial Interests, Institutional, Research Grant, Investigator initiated research: Celldex; Financial Interests, Institutional, Research Grant, Investigator initiated study: Pfizer, Novartis; Financial Interests, Institutional, Research Grant, I am the principle investigator of EORTC 2120 for which EORTC has received funding from Merck.: Merck; Non-Financial Interests, Institutional, Product Samples: Celldex, Pfizer, Novartis; Other, Member of steering and safety monitoring committee, unpaid.: ALX Oncology. J.T.J.N. Hiltermann: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Boehringer Ingelheim, Pfizer; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Roche; Non-Financial Interests, Principal Investigator: BMS, AstraZeneca, Roche, Novartis, Merck, GSK, Amgen, Gilead. M. de Bruyn: Financial Interests, Personal, Stocks/Shares: Sairopa; Financial Interests, Institutional, Coordinating PI: Mendus; Financial Interests, Institutional, Research Grant: BioNovion, Aduro Biotech Europe, Vicinivax, Genmab, IMMIOS; Non-Financial Interests, Advisory Role: IMMIOS, Sairopa; Non-Financial Interests, Institutional, Other, Drug supply clinical trial: Merck Sharp & Dohme, BioNTech; Non-Financial Interests, Institutional, Product Samples: Surflay Nanotec, Demcon, Scinus. E.G..E. de Vries: Financial Interests, Institutional, Advisory Board, Member Data Safety Monitoring Committee: Daiichi Sankyo, NSABP; Financial Interests, Institutional, Advisory Board, Consultant: Crescendo Biologics; Financial Interests, Institutional, Research Grant, (Preclinical) imaging studies with bispecific antibodies: Amgen; Financial Interests, Institutional, Research Grant, Imaging studies with CD8 and PD-L1 tracers: Genentech; Financial Interests, Institutional, Research Grant, Imaging and treatment study with CD8 and LAG-3 antibody: Regeneron; Financial Interests, Institutional, Research Grant, Treatment studies with PD-L1 antibody: Roche; Financial Interests, Institutional, Research Grant, Preclinical imaging study and imaging and treatment study with PD-L1x4-1BB bispecific antibody (S095012): Servier; Financial Interests, Institutional, Research Grant, Imaging and treatment with a trispecific humabody T-cell enhancer, CB307: Crescendo Biologics; Non-Financial Interests, Other, 1. Member (current) and Chair (2017-2022) ESMO Cancer Medicines Working Group2. Member (current) and Chair (2013-2021) ESMO-MCBS Working Group3. Member ESMO Compliance Committee: ESMO; Non-Financial Interests, Other, Member supervisory board until March 2023: Netherlands Comprehensive Cancer Organisation; Non-Financial Interests, Other, Co-chair (2009-2022) RECIST committee: RECIST; Non-Financial Interests, Other, Member expert panel for selection of Essential Medicine List WHO (2019, 2021 and 2023): WHO; Non-Financial Interests, Other, Chair grant selection committee: Hanarth Fund; Non-Financial Interests, Other, Member of Royal Netherlands Academy of Arts & Sciences (KNAW): Royal Netherlands Academy of Arts & Sciences (KNAW). J.J. De Haan: Financial Interests, Institutional, Local PI, Institutional Financial Support for clinical trials: Astellas, Boehringer Ingelheim, Cogent, Incyte, Inhibrx, Zentalis, Zymeworks. All other authors have declared no conflicts of interest.