Single-Dose Anti–PD-L1/IL-15 Fusion Protein KD033 Generates Synergistic Antitumor Immunity with Robust Tumor-Immune Gene Signatures and Memory Responses

Martomo, Stella A.; Lü, Dan; Polonskaya, Zhanna; Luna, Xenia; Zhang, Zhikai; Feldstein, Sam; Lumban-Tobing, Radovan; Almstead, Danielle K.; Miyara, Faical; Patel, Jeegar

doi:10.1158/1535-7163.mct-20-0457

Cited by 21 publications

(27 citation statements)

References 33 publications

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“…The antibodies targeting the immune checkpoint have become the protagonist of immunocytokines with the breakthrough progress of immune checkpoint inhibitors for tumor treatment in the past few years. Recently, Martomo et al preliminarily explored the antitumor activity of anti-PD-L1/IL-15 fusion protein KD033 on various solid tumor models in mice, whereas they did not provide further rationale for KD033 to treat patients with cold tumors or resistance to ICIs [32] . LH01 is different in structure compared to KD033: the antibody part is atezolizumab and the sushi domain is 85 amino acids in length with higher binding affinity to IL-15 than the 65 amino acids of KD033 [15] .…”

Section: Discussionmentioning

confidence: 99%

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Shi

Liu

et al. 2023

Molecular Therapy

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Section: Discussionmentioning

confidence: 99%

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Shi

Liu

et al. 2023

Molecular Therapy

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“…The antibodies targeting the immune checkpoint have become the protagonist of immunocytokines with the breakthrough progress of immune checkpoint inhibitors for tumor treatment in the past few years. Recently, Martomo et al preliminarily explored the antitumor activity of anti-PD-L1/IL-15 fusion protein KD033 in a single dose on various solid tumor models in mice, whereas they did not provide further rationale for KD033 to treat patients with cold tumors and resistance to ICIs [32] . LH01 is different in structure compared to KD033, of which the antibody part is atezolizumab and the sushi domain is 85 amino acids in length with higher binding affinity with IL-15 than 65 amino acids [15] .…”

Section: Discussionmentioning

confidence: 99%

“…6D). Both dose on various solid tumor models in mice, whereas they did not provide further rationale for KD033 to treat patients with cold tumors and resistance to ICIs [32] .…”

Section: Combination Therapy With Lh01 and Bevacizumab Exerts Synergi...mentioning

confidence: 91%

“…around tumor [31] . In a HT29 xenograft model, mice experienced a slight and to treat patients with cold tumors or resistance to ICIs [32] . LH01 is different in structure compared to KD033: the antibody part is atezolizumab and the sushi domain is 85 amino acids in length with higher binding affinity to IL-15 than the 65 amino acids of KD033 [15] .…”

Section: Lh01 Induces Both Innate and Adaptive Immune Cell Activation...mentioning

confidence: 99%

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A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Shi

Liu

et al. 2022

Preprint

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Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase response rate to checkpoint blockade, in this study we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to IL-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-Sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 led to activation of both the innate and adaptive immune response and decreased levels of transforming growth factor-β1 (TGF-β1) within the TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.

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“…As the delivery of IL-15 is reported through trans presentation, a novel approach investigated an immune cytokine known as KD033 that both targets PDL-1 and directly delivers IL-15/IL-15Ra complex to immune cells resident in TME. 7 days after a single dose of KD033, a dose-dependent increase in peripheral NK cells and NKT-like cells were induced (72). Furthermore, Rui Ma; et al developed a new oncolytic herpes virus expressing IL-15/IL-15Ra and demonstrated in a murine glioblastoma model therapeutic efficacy (73).…”

Section: Cytokines Induce Nk Cells' Cytotoxicitymentioning

confidence: 99%

Contribution of natural killer cells in innate immunity against colorectal cancer

et al. 2023

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Natural killer cells are members of the innate immune system and promote cytotoxic activity against tumor or infected cells independently from MHC recognition. NK cells are modulated by the expression of activator/inhibitory receptors. The ratio of this activator/inhibitory receptors is responsible for the cytotoxic activity of NK cells toward the target cells. Owing to the potent anti-tumor properties of NK cells, they are considered as interesting approach in tumor treatment. Colorectal cancer (CRC) is the second most common cause of death in the world and the incidence is about 2 million new cases per year. Metastatic CRC is accompanied by a poor prognosis with less than three years of overall survival. Chemotherapy and surgery are the most adopted treatments. Besides, targeted therapy and immune checkpoint blockade are novel approach to CRC treatment. In these patients, circulating NK cells are a prognostic marker. The main target of CRC immune cell therapy is to improve the tumor cell’s recognition and elimination by immune cells. Adaptive NK cell therapy is the milestone to achieve the purpose. Allogeneic NK cell therapy has been widely investigated within clinical trials. In this review, we focus on the NK related approaches including CAR NK cells, cell-based vaccines, monoclonal antibodies and immunomodulatory drugs against CRC tumoral cells.

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Single-Dose Anti–PD-L1/IL-15 Fusion Protein KD033 Generates Synergistic Antitumor Immunity with Robust Tumor-Immune Gene Signatures and Memory Responses

Cited by 21 publications

References 33 publications

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Contribution of natural killer cells in innate immunity against colorectal cancer

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