Introduction

Targeted therapies have revolutionized the management of immune-mediated inflammatory diseases (IMIDs), however, there is a substantial number of patients who respond poorly to a given drug. There is a big need to understand the factors that are associated with this heterogeneity.

Aims & Methods

The DoCTIS project (1) aims to characterize molecular variation both at the disease and drug response levels across six different IMIDs. We applied single cell RNA sequencing to 360 peripheral blood mononuclear cell (PBMC) samples from 176 patients from six prevalent IMIDs –psoriasis (PS), psoriatic arthritis (PsA), Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)- treated with five different drugs targeting TNF, IL12p40, IL6R, BLySS, IL17 and JAK pathways. All patients were analyzed at two time points including baseline and at the week of clinical response creating an immune landscape of more than two million peripheral immune cells.

Results

We found large inter-disease differences both at the compositional and genetic regulatory programs. ScRNA-Seq analysis revealed large differences at the systemic level between the six IMIDs. Compositional analyses demonstrated that the circulating immune cell profiles of UC and CD were more similar to each other than to the rest of IMIDs, and also identified differences in pDC, MAIT, NK CD16- and T CD4+ Memory subsets between both diseases. At the transcriptional level, we found the expected upregulated interferon response signature affecting multiple cell types in SLE, but also novel findings like strong regulatory differences in B and CD14+ monocyte compartments between UC and CD, two diseases with a highly shared genetic risk. The impact of each drug was found to be largely disease-specific. Furthermore, we found multiple regulatory features associated with the effect of each drug as well the association to response.

Conclusion

The scRNA-Seq atlas developed in DoCTIS provides a unique resource for the understanding of drug response and disease heterogeneity across immune-mediated inflammatory diseases.

References

1. Decision on Optimal Combinatorial Therapies in IMIDS using Systems Approaches (DoCTIS). https://doctis.eu/

Disclosure

Antonio Julià: None declared, Yolanda Guillén: None declared, Paloma Vela Casasempere: None declared, Antonio Fernández Nebro: None declared, Carlos Marras: None declared, Santos Castañeda Bristol-Myers Squibb, Eli Lilly, Bristol-Myers Squibb, Jaime Calvo Alén: None declared, Jesús Tornero Molina: None declared, Juan de Dios Cañete Crespillo: None declared, Eugeni Domènech: None declared, Javier Gisbert: None declared, Jose M Carrascosa: None declared, Eduardo Fonseca: None declared, Luis Bujanda Fernández de Pierola: None declared, Valle García Sánchez: None declared, Britta Siegmund: AbbVie, AlfaSigma, BMS, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Janssen, Pfizer, and Takeda, Abivax, Boehringer Ingelheim, Endpoint Health, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Giampiero Girolomoni: AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Pierre Fabre, Samsung bioepis and Sanofi, Almirall, Amgen, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Samsung bioepis and Sanofi, Pfizer, Holger Heyn: Mirxes, Moderna, Nanostring, Omniscope, Singularity, Laura Jimenez: None declared, Pere Santamaría: None declared, Edgar Angelats: None declared, Rick Myers: None declared, Sergio H. Martínez-Mateu: None declared, Juan Angel Patiño Galindo: None declared, Ernest Choy: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Fresenus Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm, and Sanofi, Bio-Cancer, Biogen, Novartis, PFizer, and Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Fresenus Kabi, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, and UCB Pharma, Sara Marsal: None declared

Introduction

An important issue for unresectable advanced stage hepatocellular carcinoma (uHCC) patients with Child-Pugh class B liver cirrhosis (CP-B), is lack of safe treatment options that show therapeutic efficacy, thus it is considered to be an unmet need. Atezolizumab plus bevacizumab (At/Bv) and durvalumab plus tremelimumab (Dur/Tre) have each been used as first-line systemic immunotherapy for uHCC.

Aims & Methods

The present study aimed to elucidate clinical outcomes of uHCC patients with CP-B treated with those combination treatments. The records of 169 uHCC patients with CP-B in Japan, treated with At/Bv or Dur/Tre as first-line systemic therapy from 2020 to 2024 at participating institutions were examined (median age: 73 years, males: 143, Child-Pugh score 7:8:9 = 121:43:5, BCLC stage B:C = 65:104, At/Bv:Dur/Tre = 131:38). Each regimen was analyzed for therapeutic efficacy and safety, and the results compared, in a retrospective manner.

Results

Using RECIST, ver. 1.1, the objective response rate (ORR) was shown to be 25.9% in the At/Bv group, and 18.4% in the Dur/Tre group (p=0.08). Disease control rate (DCR) was significantly higher in the At/Bv group (64.9% vs. 39.5%, p=0.01). There were no significant differences between the groups for progression-free survival (PFS) [At/Bv vs. Dur/Tre=5.3 vs. 3.5 months (95% CI: 3.9–6.5 and 2.3–7.2, respectively), p=0.90], overall survival (OS) [10.5 vs. 12.5 months (95% CI: 9.1–13.3 and 7.9–NA, respectively), p=0.58], or post-progression survival (PPS) [4.9 vs. 7.5 months (95% CI: 3.7–7.5 and 2.2–NA, respectively), p=0.60]. The rate of incidence of immune-related adverse events (irAEs) of any grade was 11.5% in the At/Bv group and 23.7% in the Dur/Tre group (p=0.07), while irAEs of grade 3 or higher were noted in 3.1% and 15.8%, respectively (p=0.02) significantly greater in the Dur/Tre group).

Conclusion

The incidence rate of irAEs in each group was similar to that observed in clinical trials previously performed for these regimens. uHCC patients with CP-B, who received Dur/Tre had a greater rate of incidence of high-grade irAEs, while the At/Bv group had a better DCR, though there were no significant differences for PFS, OS, or PPS between the groups. Neither treatment was found to sufficiently improve the prognosis of uHCC patients with CP-B. Development of safe and effective treatment options for patients affected by uHCC, that can be administered even to those with CP-B remains necessary.

Disclosure

Atsushi Hiraoka: lecture fee Chugai, AstraZeneca, and Lilly.