The PET-Tracer 89Zr-Df-IAB22M2C Enables Monitoring of Intratumoral CD8 T-cell Infiltrates in Tumor-Bearing Humanized Mice after T-cell Bispecific Antibody Treatment
| Autor: | Marine Richard, Jason Romero, Daulet Satpayev, Peter Brünker, Filippo Marchioni, Mudita Pincha, Tapan K. Nayak, Pablo Umana, Nicolini Valeria G, Claudia Ferrara, Marina Bacac, Maria Amann, Christoph M. Griessinger, Fang Jia, Charles Zamilpa, Michael Torgov, Christian Klein, Tove Olafsen, Jean Tessier, Dominik Rüttinger, Alessandro Mascioni, Christina Claus, Ian Andrew Wilson, Jean Gudas, Johannes Sam, Preethi Latha Bhavani Mohan, Ziyue Karen Jiang, Green Zhang, Chenyu Lee |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research biology business.industry T cell medicine.medical_treatment biology.organism_classification Peripheral blood mononuclear cell HeLa 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Carcinoembryonic antigen Oncology Cancer immunotherapy 030220 oncology & carcinogenesis medicine Cancer research biology.protein Cytotoxic T cell Antibody business CD8 |
| Zdroj: | Cancer Research. 80:2903-2913 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-19-3269 |
| Popis: | CD8-expressing T cells are the main effector cells in cancer immunotherapy. Treatment-induced changes in intratumoral CD8+ T cells may represent a biomarker to identify patients responding to cancer immunotherapy. Here, we have used a 89Zr-radiolabeled human CD8-specific minibody (89Zr-Df-IAB22M2C) to monitor CD8+ T-cell tumor infiltrates by PET. The ability of this tracer to quantify CD8+ T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL. In vitro cytotoxicity assays with peripheral blood mononuclear cells and CEA-expressing MKN-45 gastric or FOLR1-expressing HeLa cervical cancer cells confirmed noninterference of the anti-CD8-PET-tracer with the mode of action of CEA-TCB/CEA-4-1BBL and FOLR1-TCB at relevant doses. In vivo, the extent of tumor regression induced by combination treatment with CEA-TCB/CEA-4-1BBL in MKN-45 tumor–bearing humanized mice correlated with intratumoral CD8+ T-cell infiltration. This was detectable by 89Zr-IAB22M2C-PET and γ-counting. Similarly, single-agent treatment with FOLR1-TCB induced strong CD8+ T-cell infiltration in HeLa tumors, where 89Zr-Df-IAB22M2C again was able to detect CD8 tumor infiltrates. CD8-IHC confirmed the PET imaging results. Taken together, the anti-CD8-minibody 89Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8+ T-cell infiltrates upon either single or combination treatment with TCB antibody–based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in clinical phase II, is a promising monitoring tool for intratumoral CD8+ T cells in patients treated with cancer immunotherapy. Significance: Monitoring the pharmacodynamic activity of cancer immunotherapy with novel molecular imaging tools such as 89Zr-Df-IAB22M2C for PET imaging is of prime importance to identify patients responding early to cancer immunotherapy. |
| Databáze: | OpenAIRE |
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