Abstract 1672P
Background
Poly (ADP-ribose) polymerase inhibitors (PARPi) have immunomodulatory properties, which may enhance anti-PD-(L)1 therapy efficacy. However, the exact immunomodulatory mechanism is still debated. To explore this, we performed single-cell RNA and T cell receptor sequencing (scRNA + scTCR-seq) on sequential tumor biopsies collected at three timepoints in the ARIANES academic phase II basket trial, associating the PARPi rucaparib (R) to the anti-PD-L1 atezolizumab (A), in patients (pts) with DNA repair-deficient tumors.
Methods
scRNA + scTCR-seq was performed on fresh biopsies collected at baseline, on R monotherapy, and on R+A. We quantified over time the evolution of tumor and microenvironment (TME) cells, calculated differentially expressed genes and signatures within each cell population, and explored the clonal dynamics of tumor and T cells.
Results
Here we report results of the first two pts - BRCA2-mutant prostate (CRPC) and ATM-mutant lung (NSCLC) cancer - for whom, despite all challenges, we successfully profiled three sequential biopsies, with 11845 and 5484 single cells analyzed, respectively. We identified tumor and TME cells (including T and B cells, myeloid, plasma, dendritic, NK, endothelial cells, and fibroblasts) in all samples. Cellular composition over time showed pt-specific trends, e.g. increased T cell and myeloid cell infiltrates in the NSCLC and CRPC pt, respectively. Differential expression testing found a PARP1 upregulation in tumor cells of R-treated pts, and a T cell activation signature on R + A. NK-mediated cytotoxicity, JAK/STAT, cytosolic DNA sensing, and CCL5 increased on R and R + A in NK cells of the NSCLC pt. ScTCR-seq showed expansion of specific T cell clonotypes on R + A in the CRPC pt, and KLK3 expression initially decreased in CRPC tumor cells, in line with the evolution of its product (prostate-specific antigen) in blood.
Conclusions
ScRNA + scTCR-seq allows the dynamic, quantitative and qualitative assessment of single cell characteristics, confirming the potential of R + A to induce T cell activation and clonal expansion. This is to our knowledge the first study depicting at a single-cell resolution the clonal evolution of tumor and immune cells from pts on PARPi + anti-PD-L1 therapy.
Clinical trial identification
NCT04276376 (EudraCT 2018-001744-62).
Editorial acknowledgement
Legal entity responsible for the study
Institut Gustave Roussy.
Funding
Translational work for the ARIANES trial is collaboratively supported by the imCORE network.
Disclosure
P. Martin Romano: Financial Interests, Institutional, Principal Investigator, or co-investigator: for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, BBB Technologies Bv, Beigene, BicycleTx Ltd., Blueprint. A. Gazzah: Financial Interests, Institutional, Principal Investigator, and co-investigator: for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, BBB Technologies Bv, Beigene, BicycleTx Ltd., Blueprint. F. Bouquet: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-LaRoche; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-LaRoche. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase III trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase III trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase III trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase III trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion. S. Postel-Vinay: Financial Interests, Institutional, Principal Investigator, or co-investigator: AbbVie, Adaptimmune, Adlai Nortye USA Inc., Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd., Blueprint Medi; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche IMCore. All other authors have declared no conflicts of interest.