Abstract 111P
Background
T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory receptor of T cell and natural killer cell activity. Etigilimab (etig), is an FCgR competent, humanized anti-TIGIT IgG1 monoclonal antibody that blocks its interaction with PVR (poliovirus receptor) and inhibits downstream signaling. As co-targeting TIGIT in combination with anti-PD-1 could enhance anti-tumor immunity, biomarker effects of this combination are being studied in ACTIVATE, an open-label Phase Ib/II basket study evaluating efficacy, safety, tolerability and PK/PD of etig+nivo.
Methods
Biomarker monitoring was included as an exploratory endpoint following etig+Nivo combination treatment. Peripheral blood (PB) samples were evaluated for changes in gene expression by RNASeq or activation of immunological modulators by flow cytometry. Plasma samples were evaluated for changes in cytokines and circulating tumor DNA (ctDNA). Tissue (FFPE) samples were analyzed at baseline to determine expression of various immune parameters including PD-L1 by cIHC or multiplex F-IHC.
Results
Reduction in total Tregs and TIGIT+ Tregs with no obvious decreases in total CD8 T-cells resulting in an increased CD8:Treg ratio were noted, in line with previous observations (Huang Y, et al., Keystone 2019 ). In addition, increases in proliferating CD4 & CD8 effector memory (EM) populations as well as NK-cells and PD-1+ T-cells were observed. NK cells and CD4 EM T-cells showed increases in IFN-g production while CD4 EM T cells also showed increases in IL-2 production. Finally, T Progenitor Exhausted like (TPEX) cells decreased while T Stem Cell Like Memory (TSCM) cells increased demonstrating target biomarker modulation. Additionally, reduction in ctDNA levels were noted in some subjects between Days 36 – Days 78.
Conclusions
These interim biomarker data from Etig+nivo combination therapy demonstrated robust target engagement and evidence of dual TIGIT/PD-1 blockade as seen by decreases in TIGIThi cells (e.g., Tregs) and an associated increase in proliferating and cytokine producing T-cells in circulation.
Clinical trial identification
NCT04761198.
Editorial acknowledgement
Legal entity responsible for the study
Mereo Biopharma.
Funding
Mereo Biopharma.
Disclosure
G. Sarikonda: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares of Mereo Biopharma: Mereo Biopharma. B.K. Wallace: Financial Interests, Personal, Full or part-time Employment: Mereo Biopharma. C. Wiesner: Financial Interests, Personal, Other, Consulting for Mereo Biopharma: Mereo Biopharma. S. Krishnan: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares of Mereo Biopharma: Mereo Biopharma. J.A. Lewicki: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares of Mereo Biopharma: Mereo Biopharma. A.M. Kapoun: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares of Mereo Biopharma: Mereo Biopharma.