3 results on '"Radoiane Helbaj"'
Search Results
2. 286 Tumor targeting and tissue biodistribution of RO7122290, a novel FAP-targeted 4–1BB (CD137) agonist, in patients with advanced solid tumors, using [89Zr]-RO7122290 as a PET tracer
- Author
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Marc Huisman, Ignacio Melero, Oliver Krieter, Ronald Boellaard, Florian Heil, María José García Velloso, Camilla Matheisen, Guus van Dongen, Iván Peñuelas, Radoiane Helbaj, Maria E. Rodriguez-Ruiz, Mariano Ponz-Sarvise, Maurizio Ceppi, Danielle Vugts, Michael Hettich, Ernesto Guarin, Francois Iglesias, Marta Cañamero, and Miguel F. Sanmamed
- Subjects
Agonist ,Biodistribution ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,Standardized uptake value ,Pharmacology ,medicine.disease ,Primary tumor ,Fibroblast activation protein, alpha ,Atezolizumab ,Biopsy ,Medicine ,Lymph ,business - Abstract
Background RO7122290 (RO) is a potent next generation 4-1BB agonist simultaneously targeting fibroblast activation protein (FAP). FAP is highly expressed on cancer-associated fibroblasts in many solid tumors, while expression in healthy tissue is low. 4 1BB stimulation via FAP mediated cross linking augments the cytotoxicity, proliferation, and longevity of immune effector cells in FAP-positive tumors. RO was labelled with Zirconium-89 (89Zr) to visualize FAP-dependent tumor accumulation and assess the biodistribution in patients (pts) after successful proof of principle of 89Zr-based PET in preclinical pilot studies. Methods Pts with advanced and/or metastatic solid tumors were eligible for this sub-study of an ongoing Phase 1/1b trial (EUDRACT 2017-003961-83). RO was administered intravenously once at a total dose of 5, 45, 200 or 500 mg consisting of RO (cold) + 5 mg 89Zr-RO (hot, 37.0 [± 3.4] MBq).Up to three 89Zr-PET scans were performed over a period of nine days followed by a single tumor biopsy before pts could switch to Part A (single agent) and subsequently to Part B (combination with atezolizumab) of the main study to continue treatment. Tracer uptake was calculated as peak standardized uptake value (SUVPeak) of the lesion with the highest uptake. Results 14 pts were exposed to a total dose of 5, 45, 200 (all n=3) or 500 mg (n=5); median age was 60 years (range 26–74) with seven male and female pts each. Primary tumor sites included colon (n=4), lung (n=3), thymus (n=2), anus (n=1), breast (n=1), bile duct (n=1), pleura (n=1), and uvea (n=1). In healthy tissues, uptake of 89Zr-RO was predominantly observed in the liver and spleen across all doses and in non-malignant lymph nodes in 2/3 patients at 5 mg. Consistent with the target expression, tracer uptake was detected in FAP-positive scarring tissue and tissues with ongoing remodeling. Intra-tumoral accumulation of 89Zr-RO was observed at all doses. 96 hours p.i., SUVPeak values were 12.1 [± 4.1], 10.0 [± 4.9], and 7.0 [± 3.7] for the 5, 45 and 200 mg cohorts, respectively, while SUVPeak for the 500 mg cohort was even lower at 4.9 [± 0.5]. Conclusions 89Zr-PET confirmed tumor-specific uptake and expected biodistribution pattern of 89Zr-RO. The decrease in SUV with increasing doses suggest that more cold antibodies saturated FAP binding sites in the tumor. 89Zr-PET results supported together with clinical PK, PD, safety and response data the selection of the recommended phase 2 dose and schedule of RO in combination with atezolizumab.
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- 2020
3. 370 Pharmacodynamic assessment of a novel FAP-targeted 4–1BB agonist, administered as single agent and in combination with atezolizumab to patients with advanced solid tumors
- Author
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Alejo Rodriguez-Vida, Analia Azaro, Michael Hettich, Radoiane Helbaj, Christian Heichinger, Ignacio Melero, Tamara Tanos, Ernesto Guarin, Tatiana Hernandez, Iben Spanggaard, Chia-Huey Ooi, Oliver Grimm, Florian Heil, Irene Moreno, Jose Duarte, Josep Tabernero, Marta Cañamero, Christina Claus, Maurizio Ceppi, Maria Martinez Garcia, Eveline Nueesch, Oliver Krieter, Miguel F. Sanmamed, Emiliano Calvo, Alexandra-Cristina Nica, Iakov I. Davydov, Kristoffer Staal Rohrberg, and Victor Moreno
- Subjects
medicine.diagnostic_test ,biology ,Chemistry ,T cell ,CD3 ,T-cell receptor ,Cell ,Priming (immunology) ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Flow cytometry ,Proinflammatory cytokine ,medicine.anatomical_structure ,medicine ,Cancer research ,biology.protein ,CD8 - Abstract
Background RO7122290 (RO) is a bispecific antibody-like fusion protein that simultaneously targets FAP, abundantly expressed by cancer-associated fibroblasts in most solid tumors, and 4-1BB, transiently expressed on activated T cells. Pre-clinical experiments revealed strong intra-tumoral CD8+ T cells infiltration in FAP-positive tumors, cytokines induction and significant anti-tumor activity mediated by RO (signal 2 of T cell activation), upon TCR/CD3 engagement (signal 1) or in combination with atezolizumab (ATZ). In this first-in-human study, the pharmacodynamic (PD) effects of RO were assessed, both as single agent (SA) (Part A) and in combination with ATZ (Part B). Methods Pts with advanced and/or metastatic solid tumors were eligible for this ongoing Phase 1/1b trial (EUDRACT 2017-003961-83). RO was administered intravenously, weekly (QW) at escalating dose levels (DLs). In Part A, 62 pts were treated at 13 DLs of RO, dose range 5–2000 mg. In Part B, 39 pts were treated at 8 DLs of RO, dose range 45–2000 mg, with ATZ 1200 mg Q3W. Secondary biomarker objective was characterization of PD effects in tumor tissue and blood. The endpoints were change from baseline in intra-tumoral density (cell/mm2) and proliferation (Ki67) of CD8+ T cells measured by immunohistochemistry (IHC), and change in activation (4-1BB) and proliferation (Ki67) of peripheral CD8+ T cells measured by flow cytometry. Exploratory objectives were characterization of PD effects in plasma/serum and measurement of intra-tumoral immune activation. The endpoints were change in peripheral cytokines (TNF-alfa, IFN-gamma, IL-6) and soluble(s) factors (sCD25, s4-1BB) concentration measured by ELISA, and intra-tumoral changes in gene expression measured by RNAseq. Results In the periphery, we observed transient expression of 4-1BB on CD4+ and CD8+ T cells, along with secretion of s4-1BB and inflammatory cytokines, suggesting 4-1BB targeting and potent T cell activation. The concomitant induction of proliferating T cells indicated the potential association to priming and formation of tumor-reactive T cells. In the tumor, we detected increased CD8+ T cells infiltration and proliferation, in both Parts. Proliferating CD8+ T cells increased in both tumor nests and surrounding stroma, with a preferential accumulation in the latter. RNAseq analysis revealed induction of 4-1BB, PD-1 and IFN-gamma, indicating intra-tumoral T cells activation in Part B. Conclusions PD activity was consistent with the postulated MoA, confirming RO to be a potent tumor-targeted 4-1BB agonist in the clinical setting. Our observations suggest that RO can synergize with endogenous T cell receptor stimulation, both as SA and in combination with ATZ.
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- 2020
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