ArticleScience translational medicine2019
Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.
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Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 185 papers, 1 of them a synthesis that pooled it.
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185citing papers in PubMed, 1 pooled it
23.1field-weighted citation impact, top 1% of its field
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
185 citing papers in PubMed, 1 synthesis or guideline pooled it, 256 citations in OpenAlex.
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- P329G-engager: a universal mix & match antibody-based adaptor platform for cancer immunotherapy.mAbs · 2026Article
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- Bispecific Antibody-Based Combination Therapies for B-Cell Lymphomas: Current Evidence and Future Perspectives.International journal of cancer · 2026Review
- Next-generation immune cell engagers for B cell depletion in autoimmune diseases.Nature reviews. Drug discovery · 2026Review
- Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.Nature medicine · 2026Article
- Realizing the potential of agonistic antibody immunotherapy.Nature reviews. Drug discovery · 2026Review
- Clinical significance of CD161Journal for immunotherapy of cancer · 2026Article
- Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial.Nature medicine · 2026Article
- From T cell engagers to next-generation immune cell engagers for cancer immunotherapy.Antibody therapeutics · 2026Review
- Molecular features of response and resistance to glofitamab, a T-cell engager for treatment of large B-cell lymphoma.Blood advances · 2026Article
- Cancer-associated fibroblast targeting therapies as a tool to enhance responses to radiotherapy and immunotherapy.Journal for immunotherapy of cancer · 2026Review
- Pathological insights of human CD34+ hematopoietic stem cell-engrafted NSG mice: Implications for the safety assessment of cancer immunotherapy drugs.Veterinary pathology · 2026Article
- De novo masking domains that gate TNF-family ligand assembly and activity.bioRxiv : the preprint server for biology · 2026Article
- Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas.Molecular cancer · 2026Article
- Precision modeling of tumor antigen-specific T-cell responses in humanized mice for preclinical assessment of cancer immunotherapies.Journal for immunotherapy of cancer · 2026Article
- HIV- and cytomegalovirus-specific human memory CD8+ T cells are activated and expanded independent of co-stimulatory signaling by T-cell receptor-specific immunotherapeutics.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Immune cell engagers in lung cancer.Frontiers in immunology · 2026Review
125 more citing papers are in PubMed but not listed here.
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Authors and funding
57 authors at 7 institutions in 4 countries.
Christina ClausRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.ORCID 0000-0001-6316-5855
Claudia FerraraRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Wei XuRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Johannes SamRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Sabine LangRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Franziska UhlenbrockUniversity of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland.
Rosmarie AlbrechtRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Sylvia HerterRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Ramona SchlenkerRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Tamara HüsserRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Sarah DiggelmannRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
John ChallierRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Ekkehard MössnerRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Ralf J HosseRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Thomas HoferRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Peter BrünkerRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Catherine JosephRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Jörg BenzRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Philippe RinglerUniversity of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.ORCID 0000-0003-4346-5089
Henning StahlbergUniversity of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.ORCID 0000-0002-1185-4592
Matthias LauerRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Mario PerroRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Stanford ChenRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Christine KüttelRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Preethi L Bhavani MohanRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Valeria NicoliniRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Martina Carola BirkRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Amandine OngaroRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Christophe PrinceRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Reto GianottiRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Gregory DuganWake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Christopher T WhitlowWake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.ORCID 0000-0003-2392-8293
Kiran Kumar Solingapuram SaiWake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
David L CaudellWake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Armando G Burgos-RodriguezCaribbean Primate Research Center, PO Box 1053, Sabana Seca, Puerto Rico 00952, USA.
J Mark ClineWake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.ORCID 0000-0003-4844-1238
Michael HettichRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Maurizio CeppiRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Anna Maria GiustiRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Flavio CrameriRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Wouter DriessenRoche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Peter N MorcosRoche Innovation Center New York, pRED, 430 E 29th St, New York, NY 10016, USA.
Anne Freimoser-GrundschoberRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.ORCID 0000-0001-5715-3639
Victor LevitskyRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.ORCID 0000-0003-3417-0545
Maria AmannRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Sandra Grau-RichardsRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Thomas von HirschheydtRoche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.
Stella TournavitiRoche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.
Michael MølhøjRoche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.
Tanja FautiRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Viola Heinzelmann-SchwarzUniversity Hospital Basel, Gynecological Oncology, Spitalstrasse 21, 4031 Basel, Switzerland.
Volker TeichgräberRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Sara ColombettiRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Marina BacacRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
Alfred ZippeliusUniversity of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland.
Christian KleinRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.ORCID 0000-0001-7594-7280
Pablo UmañaRoche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland. pablo.umana@roche.com.ORCID 0000-0001-8206-2771
Roche (Switzerland) · CHWake Forest University · USSonneberg Observatory · DEDepartment of Biomedicine Basel · CHUniversity of Basel · CHCaribbean University · PRUniversity Hospital of Basel · CH
Funding
Tumor Tissue CoreP30CA012197 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI Ruben A. Mesa · 1985 to 2026
$55.4MTranslational Science InitiativeP40OD012217 · OD · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI CARLOS A SARIOL · 2012 to 2026
$40.4MWake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3MNCATS NIH HHS UL1 TR001420NCI NIH HHS P30 CA012197NIH HHS P40 OD012217
Abstract
Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8
Indexed as
Antibodies, BispecificCD8-Positive T-LymphocytesCell LineCell ProliferationColorectal NeoplasmsHumansImmunotherapyLymph NodesNeoplasmsAntibodies, Bispecific
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