Abstract 2961: HLA-G-TCB (RG6353), a T cell bispecific antibody for the treatment of solid tumors in monotherapy and combination with immunomodulator agents

T-cell bispecific antibodies (TCB) represent a class of therapeutic agents that specifically activate T cells to attack and kill tumor cells. TCBs have demonstrated efficacy in the clinic and are also approved. TCB mediated efficacy in solid tumors, however, has been more challenging to demonstrate....

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.2961-2961
Hauptverfasser: Majety, Meher, Hage, Carina, Bujotzek, Alexander, Schneider, Anneliese, Lechmann, Martin, Nair, Nitya, Zimmerman, Stefan, Morel, Anthony, Klein, Christian, Umana, Pablo
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:T-cell bispecific antibodies (TCB) represent a class of therapeutic agents that specifically activate T cells to attack and kill tumor cells. TCBs have demonstrated efficacy in the clinic and are also approved. TCB mediated efficacy in solid tumors, however, has been more challenging to demonstrate. HLA-G-TCB specifically targets human leukocyte antigen G (HLA-G) on tumor cells and cluster of differentiation 3 epsilon chain (CD3ε) expressed on T cells. HLA-G is expressed in a broad range of solid tumor indications and its role in mediating immune suppression makes it an attractive cancer immunotherapy target. Anti-tumor activity of HLA-G-TCB was demonstrated in vitro using different HLA G positive tumor cell lines. T-cell activation, IFN ; secretion, and cytotoxicity induced by HLA G-TCB were shown to be dose dependent and correlating to the HLA G density on cell surface and the percentage of HLA G positive cells. Administration of HLA-G TCB as monotherapy (5mg/kg) to hematopoietic stem cell-humanized NSG mice (Humice) bearing SKOV3 HLA-G tumors resulted in strong tumor growth inhibition resulting in tumor-free animals (7 out of 8). Additionally, in a patient derived xenograft (PDX) tumor model with physiological (low/patchy) HLA-G expression, a significant dose-dependent efficacy ranging from 10-90% was achieved in monotherapy (0.05-5 mg/kg). Treatment of Humice bearing PDX tumors with a combination of HLA-G-TCB and a co-stimulatory immunomodulator resulted in remarkable anti-tumor activity resulting in tumor eradication in 100% of the mice treated with the combination (8 out of 8). A strong synergistic effect was also observed in checkpoint inhibitor resistant PDX tumor model, also resulting in tumor-free mice (5 out of 8) treated with a combination of HLA-G TCB and an immunomodulatory bispecific antibody. In line with the mode of action of TCBs, tumor growth inhibition was accompanied by increased cytokine secretion (including IFN ;), tumoral T cell infiltration and activation as reflected by increased expression of T cell activation markers including CD69, CD25 and Granzyme B. Evaluation of HLA-G expression on tumor cell lines upon IFN ; stimulation in vitro and in PDX tumors treated with HLA-G TCB revealed that HLA-G expression can be upregulated upon IFN ; stimulation and TCB treatment respectively and may positively impact the anti-tumor activity of HLA-G-TCB in vivo. These promising preclinical findings reflect the potential and support the clinica
ISSN:1538-7445
1538-7445
DOI:10.1158/1538-7445.AM2023-2961