1025MO First-in-human (FIH) phase I study of RO7122290 (RO), a novel FAP-targeted 4-1BB agonist, administered as single agent and in combination with atezolizumab (ATZ) to patients with advanced solid tumours

Melero, Ignacio; Sanmamed, Miguel F.; Calvo, Emiliano; Moreno, Irene; Moreno, Víctor; Guerrero, Tatiana Hernandez; Martinez-García, Maria; Rodríguez‐Vida, Alejo; Tabernero, Josep; Pedrazzoli, A; Spanggaard, Iben; Rohrberg, Kristoffer Staal; Guarin, Ernesto; Nueesch, E.; Chesne, Evelyne; Ceppi, Maurizio; Sweere, U.; McIntyre, Christine; Lichtenegger, Felix S.; Krieter, Oliver

doi:10.1016/j.annonc.2020.08.1145

Cited by 17 publications

(19 citation statements)

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“…The bispecific antibody targeting FAP/4-1BB enhanced T-cell stimulation in vivo and led to tumor remission in mouse models ( 106 ). An ongoing phase I trial is currently testing RO7122290 in monotherapy or in combination with atezolizumab in patients with advanced solid tumors ( 107 ).…”

Section: Immunosuppression In Ovarian Cancermentioning

confidence: 99%

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Chardin

Léary

2021

Front. Oncol.

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Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

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Section: Immunosuppression In Ovarian Cancermentioning

confidence: 99%

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Chardin

Léary

2021

Front. Oncol.

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“…Clinical response as monotherapy was limited and likewise did not appear promising when combined with atezolizumab. It is uncertain whether anti-drug antibodies (ADAs) may have negatively impacted efficacy because ADA in 20% of the evaluable patients with loss of efficacy in 40% of the positive patients was reported [ 80 ]. RO7227166 is also being investigated in a phase I study.…”

Section: Technological Advances To Mitigate Hepatotoxicity For Cd137 Targeting Moleculesmentioning

confidence: 99%

“…CD137 targeting bispecific molecules are attractive agents with less safety concerns for CRS than CD3 targeting bispecific molecules and may be able to provide prolonged efficacy of T cell activation even a TAA is lost. Previous clinical studies of HPN424 and RO7122290 showed the potential of combination studies with PD-L1 inhibitors [ 75 , 80 ]. Utomilumab in combination with pembrolizumab was assessed in 33 patients with solid tumors and the combination achieved a 26% ORR including 1 CR, however, the effect of the combination compared with pembrolizumab monotherapy is unclear [ 60 ].…”

Section: Potential Combination Partners For Cd137 Targeting Moleculesmentioning

confidence: 99%

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Hashimoto¹

2021

Cancers

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Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.

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“…More recent strategies are focused on bispecific approaches aimed at promoting tumor-target mediated clustering of CD137 to limit systemic and liver toxicities [9][10][11] and early patient data shows encouraging evidence of safety and clinical benefit with correlative pharmacodynamics. 12 13 We recently reported that fully synthetic bicyclic peptides (Bicycles), discovered via phage display and optimized using structuredriven design and medicinal chemistry, can be used as building blocks to create novel synthetic immune agonists. These Bicycle tumor-targeted immune cell agonists (Bicycle TICAs) could achieve clustering and activation of CD137 using a highly expressed tumor Open access antigen to provide a scaffolding function to oligomerize the CD137 Bicycle presented to immune cells.…”

Section: Background Cd137 (4-1bb/tnfrsf9mentioning

confidence: 99%

BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces tumor localized CD137 agonism

Hurov¹,

Lahdenranta²,

Upadhyaya³

et al. 2021

J Immunother Cancer

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BackgroundCD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™).MethodsNectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action.ResultsTranscriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists.ConclusionBT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.

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1025MO First-in-human (FIH) phase I study of RO7122290 (RO), a novel FAP-targeted 4-1BB agonist, administered as single agent and in combination with atezolizumab (ATZ) to patients with advanced solid tumours

Cited by 17 publications

References 0 publications

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces tumor localized CD137 agonism

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