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+T cells. FAP– and CD19–4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.
LSR was not superior to OSR regarding postoperative quality of life and incidence of complications in this trial.
Immune cell costimulation via 4-1BB agonism has shown anti-tumor activity in the clinic and is an important element of next-generation chimeric-antigen-receptor (CAR) adoptive T-cell therapy approaches. However, the clinical development of first-generation, 4-1BB agonistic antibodies has been hampered by significant hepatic toxicity. Activity of such first-generation, 4-1BB agonistic antibodies typically depends on their hyperclustering via Fc-gamma-receptor (FcgR)-binding. Here we describe a next generation, tumor-targeted 4-1BB agonist whose activity is independent of FcgR-binding. The molecule consists of an IgG fusion protein composed of a trimeric, human 4-1BB ligand (4-1BBL), a targeting Fab moiety recognizing fibroblast activation protein (FAP), and a heterodimeric Fc region engineered to be devoid of interactions with FcgRs and C1q. The molecule mediates potent costimulation of CD8 T-, CD4 T- and NK-cells, but only in the presence of FAP-expressing cells, such as cancer associated fibroblasts, which are highly prevalent in many solid tumors. This FAP-targeted 4-1BB agonist is significantly more potent and efficacious than first generation, standard 4-1BB agonistic antibodies when compared side-by-side in preclinical models. We show its activity in a variety of preclinical models including reporter cell assays, assays with primary T- and NK-cells, ex-vivo assays with patient tumor-derived material including cancer cells, stroma cells and tumor-infiltrating lymphocytes, fully immunocompetent murine tumor models (employing a surrogate, murinized molecule targeting murine FAP and carrying murine 4-1BBL), and in human hematopoietic stem cell-humanized mice with human tumor xenografts. We also demonstrate its activity in combination with checkpoint inhibitors and with T-cell redirecting approaches, such as a CEA-CD3 T-cell bispecific antibody. We show that hepatic toxicity of first generation, standard 4-1BB antibodies is dependent on FgR interactions and the next generation, FcgR-independent and FAP-targeted molecule described here is safe and does not induce any hepatotoxicity in preclinical models including non-human primates where it was tested at doses of up to 50 mg/kg and where it showed a long circulatory half-life. Its combination with T-cell bispecific antibodies induces a massive T cell accumulation in the tumor, accompanied with an elevated CD8/Treg ratio, as compared to the respective monotherapies. Therefore, we conclude that the tumor-targeted cross-linking of 4-1BB provides a safe and effective way for the co-stimulation of T cells for cancer immunotherapy and its combination with T-cell bispecific antibodies may provide an alternative, but more convenient, off-the-shelf approach to CAR T-cell therapies. The molecule is scheduled to enter clinical trials soon. Citation Format: Christina Claus, Claudia Ferrara, Sabine Lang, Rosmarie Albrecht, Sylvia Herter, Maria Amann, Sandra Richards-Grau, Johannes Sam, Sara Colombetti, Marina Bacac, Christian Klein, Pablo Umana. A novel tumor-targeted 4-1BB agonist and its combination with T-cell bispecific antibodies: an off-the-shelf cancer immunotherapy alternative to CAR T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3634. doi:10.1158/1538-7445.AM2017-3634
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