Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti–PD-1 Antibody, in Advanced Solid Tumors

Curigliano, Giuseppe; Gelderblom, Hans; Mach, Nicolas; Doi, Toshihiko; Tai, David; Forde, Patrick M.; Sarantopoulos, John; Bédard, Philippe L.; Lin, Chia Chi; Hodi, F. Stephen; Wilgenhof, Sofie; Santoro, Armando; Sabatos-Peyton, Catherine; Longmire, Tyler; Xyrafas, A.; Sun, Haiying; Gutzwiller, Sabine; Manenti, Luigi; Naing, Aung

doi:10.1158/1078-0432.ccr-20-4746

Cited by 191 publications

(129 citation statements)

References 37 publications

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“…Importantly, a number of preclinical studies have shown that, compared with the use of anti-PD-1 antibody alone, the combined treatment of blocking Tim-3 and PD-1 can significantly improve the survival rate of mice (59,87). Moreover, several ongoing clinical trials have also evaluated the safety and efficacy of the combination therapy (88,89). Therefore, the combined blockade of Tim-3 and PD-1 pathway might be a promising strategy for tumor immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Five patients receiving combination treatment had partial responses (6%; lasting 12-27 months) in colorectal cancer (n = 2), non-small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy (88). It suggested that sabatomimab combined with spartalizumab was well tolerated and showed preliminary signs of antitumor activity.…”

Section: Clinical Trials Of Targeting Both Pd-1 and Tim-3 In Human Tumorsmentioning

confidence: 99%

“…A phase I/II study evaluated the safety and efficacy of sabatomimab with or without spartalizumab in patients with advanced solid tumors (88). Among 219 patients, the most common were ovarian cancer (17%) and colorectal cancer (7%).…”

Section: Clinical Trials Of Targeting Both Pd-1 and Tim-3 In Human Tumorsmentioning

confidence: 99%

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Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade

Tian

2021

Front. Oncol.

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Programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) blocking therapy has completely changed the treatment pattern of malignant tumors. It has been tested in a wide range of malignant tumors and achieved clinical success. It might be a promising cancer treatment strategy. However, one of the important disadvantages of PD-1/PD-L1 blocking therapy is that only a few patients have a positive response to it. In addition, primary or acquired drug resistance can also lead to cancer recurrence in patients with clinical response. Therefore, it is very important to overcome the resistance of PD-1/PD-L1 blocking therapy and improve the overall response rate of patients to the immunotherapy. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) belongs to the co-inhibitory receptor family involved in immune checkpoint function. Due to adaptive resistance, the expression of Tim-3 is up-regulated in PD-1/PD-L1 blocking therapy resistant tumors. Therefore, blocking the immune checkpoint Tim-3 might antagonize the resistance of PD-1/PD-L1 blocking therapy. This review systematically introduces the preclinical and clinical data of combined blockade of Tim-3 and PD-1/PD-L1 in cancer immunotherapy, and discusses the prospect of overcoming the drug resistance of PD-1/PD-L1 blockade therapy through blockade of Tim-3.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Trials Of Targeting Both Pd-1 and Tim-3 In Human Tumorsmentioning

confidence: 99%

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Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade

Tian

2021

Front. Oncol.

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“…Regarding combined checkpoint inhibitors, a phase I study found manageable safety and promising antitumor activity with the antilymphocyte activation gene (LAG-3) antibody plus pembrolizumab in MSS mCRC ( 54 ). Anti-TIM-3 antibody combined with anti-PD-1 antibody showed preliminary signs of antitumor activity in solid tumors ( 55 ).…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients

et al. 2021

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Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the treatment outcomes of immunotherapy in microsatellite-stable (MSS) CRC remain unsatisfactory. As the majority of CRC cases display a molecular MSS/mismatch repair-proficient (pMMR) profile, it is particularly meaningful to explore the clinical applications of adaptive immune therapy in MSS CRC patients. In this review, we summarized the therapeutic approaches of adoptive immune therapies, including cytokines, therapeutic cancer vaccines, adoptive T-cell therapy, and immune checkpoint inhibitors, in the treatment of MSS CRCs.

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“…There are several anti-TIM-3 monoclonal antibodies in (pre)clinical development [ 62 ], such as (i) sabatolimab which is currently evaluated for the treatment of advanced solid tumors [ 63 ] and myelodysplastic syndromes [ 64 ], (ii) the fully human anti-TIM-3 antibody M6903 in preclinical development [ 65 ], (iii) LY3321367 currently tested in advanced solid tumors [ 66 ], and a few other antibodies [ 49 , 67 ] ( Table 1 ). Over the past two years, TIM-3 has emerged as an important immune-checkpoint molecule and recent data demonstrated that the receptor plays multiple roles, well beyond CD4 + /CD8 + T cells, notably as a key regulator of dendritic cell functions via the regulation of inflammasome activation [ 68 ].…”

Section: The Tim-3 Immune Checkpoint and Its Targeting With Antibodiesmentioning

confidence: 99%

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti–PD-1 Antibody, in Advanced Solid Tumors

Cited by 191 publications

References 37 publications

Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade

Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade

Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

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