Novel carcinoembryonic antigen T-cell bispecific (CEA-TCB) antibody: Preliminary clinical data as a single agent and in combination with atezolizumab in patients with metastatic colorectal cancer (mCRC)

Argilés, Guillem; Saro, Jose; Segal, Neil H.; Melero, Ignacio; Ros, Willeke; Marabelle, Aurélien; Rodríguez, Maria E.; Albanell, Joan; Calvo, Emiliano; Moreno, Víctor; Cleary, James M.; Eder, Paul S.; Paz-Ares, L.; Hurwitz, Herbert I.; Bacac, Marina; Perro, Mario; Bouseida, S.; Bové, Daniel Sabanés; Sreckovic, Sasha; Jamois, C.; Silva, A.; Klein, Christian; Umaña, Pablo; Karanikas, Vaios; Tabernero, Josep

doi:10.1093/annonc/mdx302.003

Cited by 21 publications

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“…[32][33][34] CEA-TCB treatment has shown efficacy in mouse tumor models 31 and early clinical trials. 35 Therefore, our study provides validation of combining 4-1BB-targeted therapy with TCR-directed compounds by showing efficacy of such treatment in primary tumor suspensions. The importance of 4-1BB signaling in antitumor responses has been also demonstrated in humanized mouse models, chimeric antigen receptors (CAR)-T cells and in primary TIL suspensions.…”

Section: Discussionmentioning

confidence: 71%

Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer

Trüb

Uhlenbrock

Claus

et al. 2020

J Immunother Cancer

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BackgroundThe costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.MethodsWe analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.ResultsCombination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.ConclusionsOur study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.

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Section: Discussionmentioning

confidence: 71%

Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer

Trüb

Uhlenbrock

Claus

et al. 2020

J Immunother Cancer

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“…Subsequently, huPBMCs were treated with different combinations of FAP-4-1BBL, carcinoembryonic antigen-targeted T cell bispecific antibody (CEA-TCB) ( fig. S5E) (29)(30)(31), and PD-L1-blocking antibody (atezolizumab) for 4 days in the presence of PD-L1 + CEA + MKN45 human gastric cancer cells, as well as FAP + fibroblasts. Combination of FAP-4-1BBL and CEA-TCB increased proliferation and 4-1BB and CD25 expression on CD8 + T cells (Fig.…”

Section: Fap-4-1bbl Increases T Cell Activation Proliferation and Cmentioning

confidence: 99%

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

et al. 2019

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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.

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“…However, the combination of trastuzumab and pertuzumab is being evaluated in ERBB2 ‐overexpressed, ‐amplified, or ‐mutated tumors in the My Pathway basket trial . Preliminary data have shown activity and safety of this combination in heavily pretreated colorectal ( n = 34) and biliary cancers ( n = 8), with overall response rates of 37% and 50%, respectively . Margetuximab is also a monoclonal antibody targeting ERBB2 that is engineered for increased Fc‐domain binding affinity to both low affinity variants of the activating Fcγ receptor, CD16 .…”

Section: Introductionmentioning

confidence: 99%

Emergence of ERBB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers

et al. 2019

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The oncogenic role ERBB2 amplification is well established in breast and gastric cancers. This has led to the development of a well-known portfolio of monoclonal antibodies and kinase inhibitors targeting the ERBB2 kinase. More recently, activating mutations in the ERBB2 gene have been increasingly reported in multiple solid cancers and were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations define a distinct molecular subtype of solid tumors and serve as actionable targets. However, efforts to target ERBB2 mutation has met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. Given the current impetus to deliver molecularly targeted treatments for cancer, there is an important need to understand the therapeutic potential of ERBB2 mutations. Here we review the distribution of ERBB2 mutations in different tumor types, their potential as a novel biomarker that defines new subsets in many cancers, and current data on preclinical and clinical efforts to target these mutations. The Oncologist 2019;24:e1303-e1314 Implications for Practice: A current trend in oncology is to identify novel genomic drivers of solid tumors and developing precision treatments that target them. ERBB2 amplification is an established therapeutic target in breast and gastric cancers, but efforts to translate this finding to other solid tumors with ERBB2 amplification have not been effective. Recently the focus has turned to targeting activating ERBB2 mutations. The year 2018 marked an important milestone in establishing ERBB2 mutation as an important actionable target in multiple cancer types. There have been several recent preclinical and clinical studies evaluating ERBB2 mutation as a therapeutic target with varying success. With increasing access to nextgeneration sequencing technologies in the clinic, oncologists are frequently identifying activating ERBB2 mutations in patients with cancer. There is a significant need both from the clinician and bench scientist perspectives to understand the current state of affairs for ERBB2 mutations.The Oncologist 2019;24:e1303-e1314 www.TheOncologist.com Cancer Diagnostics and Molecular Pathology mostly (in nearly 80%-90% of cases) mutually exclusive and thus represent independent driver events in tumorigenesis [2][3][4][5]. Together, ERBB2 gene amplification and mutation form a sizeable molecular subtype in several cancers and are potential actionable events. Because several ERBB2 kinase inhibitors are already clinically available, it is now important to comprehensively review the available evidence regarding the functional role of ERBB2 mutations in tumorigenicity and drug sensitivity.Frequencies from studies that involved highest number of samples for a particular cancer (studies with less than 100 samples were excluded) were collected and shown along with references. Data collected from cBioPortal. ...

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Novel carcinoembryonic antigen T-cell bispecific (CEA-TCB) antibody: Preliminary clinical data as a single agent and in combination with atezolizumab in patients with metastatic colorectal cancer (mCRC)

Cited by 21 publications

References 0 publications

Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer

Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

Emergence of ERBB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers

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