Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy
©2021 American Association for Cancer Research..
CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:81 |
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| Enthalten in: |
Cancer research - 81(2021), 7 vom: 01. Apr., Seite 1788-1801 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kharkwal, Shalu Sharma [VerfasserIn] |
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| Links: |
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| Themen: |
Alpha-galactosylceramide |
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| Anmerkungen: |
Date Completed 11.08.2021 Date Revised 05.10.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/0008-5472.CAN-20-2219 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320455920 |
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| 245 | 1 | 0 | |a Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy |
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| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a CD1D protein, human |2 NLM | |
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| 700 | 1 | |a Johndrow, Christopher T |e verfasserin |4 aut | |
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| 700 | 1 | |a Kharkwal, Himanshu |e verfasserin |4 aut | |
| 700 | 1 | |a Saavedra-Avila, Noemi A |e verfasserin |4 aut | |
| 700 | 1 | |a Carreño, Leandro J |e verfasserin |4 aut | |
| 700 | 1 | |a Rothberg, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jinghang |e verfasserin |4 aut | |
| 700 | 1 | |a Garforth, Scott J |e verfasserin |4 aut | |
| 700 | 1 | |a Jervis, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lianjun |e verfasserin |4 aut | |
| 700 | 1 | |a Donda, Alena |e verfasserin |4 aut | |
| 700 | 1 | |a Besra, Amareeta K |e verfasserin |4 aut | |
| 700 | 1 | |a Cox, Liam R |e verfasserin |4 aut | |
| 700 | 1 | |a Almo, Steven C |e verfasserin |4 aut | |
| 700 | 1 | |a Howell, Alan |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Elizabeth E |e verfasserin |4 aut | |
| 700 | 1 | |a Zauderer, Maurice |e verfasserin |4 aut | |
| 700 | 1 | |a Besra, Gurdyal S |e verfasserin |4 aut | |
| 700 | 1 | |a Porcelli, Steven A |e verfasserin |4 aut | |
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