Mechanistically, animals treated with the combination showed a trend for ≥1.5-fold increase in the average density of CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs), as well as proliferating (Ki67+) and cytotoxic (GZMB+) CD8+ TILs relative to each single agent, consistent with an amplified anti-tumor immune response. Together, these preclinical results suggest that combining GEN1046-induced conditional 4-1BB stimulation with complete PD-1 blockade can improve the anti-tumor immune response via distinct and complementary immune modulatory effects. The combination of GEN1046 with pembrolizumab is currently being investigated in ongoing clinical studies in patients with advanced NSCLC, who are treatment-naïve (NCT03917381) or have progressed on prior CPI-containing therapy (NCT05117242).
1 year ago
Combination therapy
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CD8 (cluster of differentiation 8) • PD-L2 (Programmed Cell Death 1 Ligand 2) • CD4 (CD4 Molecule) • GZMB (Granzyme B)
These findings support that patient selection and/or anti–PD-1 combination therapy may lead to improved clinical efficacy. Further analyses are ongoing and updated results will be presented.
almost 2 years ago
P1 data • PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • GZMB (Granzyme B)
GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity (disease control rate: 65.6% [40/61]), including patients resistant to prior PD-(L)1 immunotherapy.
Moreover, DuoBody-PD-L1×4-1BB exhibits anti-tumor activity and induces memory immune responses in vivo. DuoBody-PD-L1×4-1BB is currently being evaluated in patients with advanced solid tumors in a first-in-human clinical trial (NCT03917381).
almost 3 years ago
Preclinical • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • LAMP1 (Lysosomal Associated Membrane Protein 1) • GZMB (Granzyme B)
Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.
over 3 years ago
Clinical • P1/2 data • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma)
Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.
over 3 years ago
Clinical • P1/2 data • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma)