151P - Anti-tumor T cell response and immunoselection under combined GARP:TGF-?1/PD-1 blockade

Background

Livmoniplimab (livmo) is a monoclonal anti-GARP:TGF-β1 antibody currently tested in combination with budigalimab (budi) in phase 1 and 2 trials for several cancer indications. First results indicate a manageable safety profile and promising efficacy of the livmo + budi combination in patients with advanced urothelial carcinoma (UC) who progressed on a PD-(L)1 inhibitor. Here, we report in-depth analyses of blood and tumor biopsies collected from patients enrolled in NCT-03821935 at the CUSL in Belgium.

Methods

Between April 2021 and August 2023, blood and tumor biopsies were collected before and after one cycle of livmo+budi from 6 patients with metastatic anti-PD(L)1-refractory UC or non-small cell lung carcinoma. All 6 patients experienced disease progression after receiving the combination. Patient-derived material collected pre- and on-treatment was analysed by flow cytometry, WES, bulk and single-cell RNAseq, CITEseq, TCR repertoire sequencing and TCR reconstruction in reporter Jurkat cells to identify antigens recognized by T cell clonotypes.

Results

We observed signs of reduced TGF-β signaling and increased T cell activity in tumor-infiltrating lymphocytes collected on-treatment in 3 of 6 patients. Two CD8 T cell clonotypes identified in the metastasis from one patient were : i) not detected in the blood; ii) amplified 3 to 30 fold in the tumor biopsy after one cycle of treatment; iii) directed against a mutated BLZF1 peptide. Increase in the frequency of the two anti-BLZF1^mut T cell clones after one cycle of treatment correlated with a reduction in the ratio of mutated BLZF1 to mutated TP53 alleles in the metastasis, suggesting increased cytotoxic activity and immunoselection by the anti-BLZF1 oligoclonal T cell response in the course of treatment.

Conclusions

Our results indicate that tumor-infiltrating CD8 T cells against mutated antigens can be amplified in response to livmo + budi, and exert cytolytic activity and immunoselection on tumor cells expressing the cognate antigens. Given that all patients included were refractory to previous anti-PD(L)1 therapy, our data suggests that the biological anti-tumor activity observed in the biopsy from one patient results at least in part from the activity of livmo.

Clinical trial identification

NCT-03821935.

Legal entity responsible for the study

UCLouvain - de Duve Institute - Laboratory of Pr. Sophie LUCAS.

Funding

UCLouvain, de Duve institute, FNRS, AbbVie.

Disclosure

R. Galot: Financial Interests, Institutional, Invited Speaker: BMS; Other, Personal, Other, Travel expenses: Merck, MSD. S. Carlier: Financial Interests, Personal, Other, travel expanse: Merck, Teva. D. Schroeder: Financial Interests, Institutional, Invited Speaker, 1 presentation on 17/3/2023: AstraZeneca; Financial Interests, Personal, Other, Medical consultant: Institut de Pathologie et de Génétique Gosselies; Financial Interests, Institutional, Research Grant, Research grant paid to the laboratory in which I worked from Dec 2020 to Sep 2022: AbbVie; Other, Personal, Other, Travel and congress grant for ESMO Sarcoma congress March 2023: PharmaMar. M. Dillon: Financial Interests, Personal, Full or part-time Employment: AbbVie; Financial Interests, Personal, Stocks/Shares: AbbVie. C. Tribouley: Financial Interests, Institutional, Advisory Board: AbbVie. P.G. Coulie: Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Stocks/Shares: iTeos Therapeutics; Financial Interests, Personal, Advisory Board: UCLouvain. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Boehringer Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, Nektar, F-star, Seagen, Astellas, Genmab, Merus, GSK, CureVac; Financial Interests, Institutional, Advisory Board, Education: Merck-Serono; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, Sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Celyad, MSD, Novartis, KURA, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck-Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GSK; Non-Financial Interests, Personal, Leadership Role, Chair: EORTC head and neck group. S. Lucas: Financial Interests, Personal, Advisory Board, Consultancy fees for participation to 3 AbbVie Solid Tumor Advisory boards: AbbVie; Financial Interests, Personal, Stocks/Shares, Received stock options as consultant and collaborator of the biotech company Argenx (Ghent, Belgium): Argenx; Financial Interests, Institutional, Royalties, Co-inventor on a patent deposited by the UCLouvain and Argenx covering anti-GARP:TGFb1 antibody. Antibody was licensed to Argenx and sublicensed to AbbVie, leading to royalty payments to the UCLouvain (Université catholique de Louvain, Brussels, Belgium): Argenx; Financial Interests, Institutional, Local PI, Research Service Agreement funding work in my laboratory (UCLouvain - de Duve Institute): Argenx; Financial Interests, Institutional, Local PI, Sponsored Research agreement for translational research on patient-derived material from clinical trial testing livmoniplimab: AbbVie. All other authors have declared no conflicts of interest.