Abstract 864P
Background
Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape of metastatic melanoma patients. Despite the durability of response to ICI1,2, many patients with initial response develop resistance3. One potential way to overcome the mechanisms of resistance is to identify molecular signatures associated with response to treatment. Here, we are presenting the results of an integrated deep proteomic and transcriptomic analysis from biopsies of metastatic melanoma patients prior anti-PD1 treatment. The combination of whole proteome profiling with targeted transcriptomics allowed for identification of a molecular response signature specific to anti-PD1 therapy.
Methods
Formalin-fixed paraffin-embedded (FFPE) tumor biopsy tissues were used for unbiased whole proteome profiling using Biognosys’ TrueDiscoveryTM platform and analyzed using an optimized data-independent acquisition (DIA) LC-MS workflow. A deep spectral library was generated, and proteins were quantified using Spectronaut™ software (Biognosys). From the same tumor tissue, RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Statistical analysis was conducted with R.
Results
Patients were stratified into two groups: those who received clinical benefit (CR/PR or SD>1 year, n= 13) and those with no clinical benefit (PD or SD<1 year, n= 9). Response evaluation was done using RECIST criteria. For each sample 8,536 proteins and 770 RNA were evaluated with an overlap of 419 genes for which both proteomic and transcriptomic data were profiled. In the combined analysis, we found concordant levels for protein and RNA expression, such as STAT2 that is lower in responder group. However, other biomarker candidates such as MARCO and OAS1 showed a higher expression on protein level and a lower RNA expression in the responders.
Conclusions
Combination of deep and proteomics approaches with targeted transcriptomics assays provides a comprehensive image of responses to anti-PD1 treatment in metastatic melanoma patients. Identified candidates show striking changes in responder and non-responder groups and need further investigations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Messner: Financial Interests, Personal, Full or part-time Employment: Biognosys. J. Vowinckel: Financial Interests, Personal, Full or part-time Employment: Biognosys. K. Novy: Financial Interests, Personal, Full or part-time Employment: Biognosys. K. Kakalacheva - Beeler: Financial Interests, Personal, Full or part-time Employment: Biognosys. S. Warren: Financial Interests, Personal, Stocks/Shares: NanoString; Financial Interests, Personal, Full or part-time Employment: NanoString. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Pfizer/Array, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna, Bio-AI Health; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Invited Speaker, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR; Other, Travel Support: MSD. All other authors have declared no conflicts of interest.