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In situ modulation of dendritic cells by injectable thermosensitive hydrogels for cancer vaccines in mice.

Liu Y, Xiao L, Joo KI, Hu B, Fang J, Wang P - Biomacromolecules (2014)

Bottom Line: Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes.We demonstrate that GM-CSF-releasing mPEG-PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response.This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells.

View Article: PubMed Central - PubMed

Affiliation: Mork Family Department of Chemical Engineering and Materials Science, ‡Department of Biomedical Engineering, and §Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, California 90089, United States.

ABSTRACT
Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes. The development of biomaterials capable of modulating DCs in situ to enhance antigen uptake and presentation has emerged as a novel method toward developing more efficient cancer vaccines. Here, we propose a two-step hybrid strategy to produce a more robust cell-based cancer vaccine in situ. First, a significant number of DCs are recruited to an injectable thermosensitive mPEG-PLGA hydrogel through sustained release of chemoattractants, in particular, granulocyte-macrophage colony-stimulating factor (GM-CSF). Then, these resident DCs can be loaded with cancer antigens through the use of viral or nonviral vectors. We demonstrate that GM-CSF-releasing mPEG-PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response. Moreover, this two-step hybrid strategy generates a high level of tumor-specific immunity, as demonstrated in both prophylactic and therapeutic models of murine melanoma. This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells.

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Two-step hybrid strategyconfers potent antitumor immunity. (A)Schematic diagram showing the immunization and tumor challenge procedurein the prophylactic model. (B) Kaplan–Meier survival plot ofmice treated with PBS (Ctrl), empty hydrogel scaffolds (Emp-gel),GM-CSF hydrogel scaffolds (GM-gel), followed by immunization withDC-LV-OVA only or with adjuvant MPL (Emp-gel + MPL, GM-gel + MPL; n = 10). A tumor size of 2000 mm3 was used asa surrogate end point of survival, P < 0.001.(C) Schematic diagram showing tumor inoculation on day 1 and hydrogelimplantation 1 day later, followed by two immunizations in the therapeuticmodel. (D) Tumor growth was plotted as mean ± SEM (n = 8) as a function of days after B16-OVA tumor challenge (** indicates P < 0.01).
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fig5: Two-step hybrid strategyconfers potent antitumor immunity. (A)Schematic diagram showing the immunization and tumor challenge procedurein the prophylactic model. (B) Kaplan–Meier survival plot ofmice treated with PBS (Ctrl), empty hydrogel scaffolds (Emp-gel),GM-CSF hydrogel scaffolds (GM-gel), followed by immunization withDC-LV-OVA only or with adjuvant MPL (Emp-gel + MPL, GM-gel + MPL; n = 10). A tumor size of 2000 mm3 was used asa surrogate end point of survival, P < 0.001.(C) Schematic diagram showing tumor inoculation on day 1 and hydrogelimplantation 1 day later, followed by two immunizations in the therapeuticmodel. (D) Tumor growth was plotted as mean ± SEM (n = 8) as a function of days after B16-OVA tumor challenge (** indicates P < 0.01).

Mentions: The utility of this two-step hybrid strategy (illustratedin Scheme 1) that first recruits DCs and thenprograms them within the GM-CSF hydrogel as a cancer vaccine was evaluatedin a murine melanoma model. In the prophylactic tumor model, micewere immunized with DC-LV-OVA alone or with MPL adjuvant 7 days afterinjection of hydrogels, as illustrated in Figure 5A. A total of 10 days after immunization, mice were inoculatedwith B16-OVA tumor cells, which stably express the model tumor antigenOVA. Using a tumor size of 2000 mm3 as a surrogate endpoint of survival, none of the PBS-injected (control) mice survivedfor more than 30 days (Figure 5B). Mice injectedwith empty hydrogels showed moderately improved immune protectioncompared to mice injected with PBS, suggesting that the residenceprovided by hydrogels could be beneficial to enhance antigen uptakeefficiency of APCs. However, a longer overall survival (p < 0.001) was observed in mice injected with GM-CSF hydrogelscompared to mice injected with empty hydrogels, indicating the benefitof recruiting DCs with GM-CSF. The benefit of GM-CSF-encapsulatedhydrogel was further confirmed by a significantly longer median survivaltime in GM-CSF-treated mice that received both DC-LV-OVA and MPL treatmentcompared to empty hydrogel-injected mice with the same immunizationcondition (p < 0.001).


In situ modulation of dendritic cells by injectable thermosensitive hydrogels for cancer vaccines in mice.

Liu Y, Xiao L, Joo KI, Hu B, Fang J, Wang P - Biomacromolecules (2014)

Two-step hybrid strategyconfers potent antitumor immunity. (A)Schematic diagram showing the immunization and tumor challenge procedurein the prophylactic model. (B) Kaplan–Meier survival plot ofmice treated with PBS (Ctrl), empty hydrogel scaffolds (Emp-gel),GM-CSF hydrogel scaffolds (GM-gel), followed by immunization withDC-LV-OVA only or with adjuvant MPL (Emp-gel + MPL, GM-gel + MPL; n = 10). A tumor size of 2000 mm3 was used asa surrogate end point of survival, P < 0.001.(C) Schematic diagram showing tumor inoculation on day 1 and hydrogelimplantation 1 day later, followed by two immunizations in the therapeuticmodel. (D) Tumor growth was plotted as mean ± SEM (n = 8) as a function of days after B16-OVA tumor challenge (** indicates P < 0.01).
© Copyright Policy - editor-choice
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4195289&req=5

fig5: Two-step hybrid strategyconfers potent antitumor immunity. (A)Schematic diagram showing the immunization and tumor challenge procedurein the prophylactic model. (B) Kaplan–Meier survival plot ofmice treated with PBS (Ctrl), empty hydrogel scaffolds (Emp-gel),GM-CSF hydrogel scaffolds (GM-gel), followed by immunization withDC-LV-OVA only or with adjuvant MPL (Emp-gel + MPL, GM-gel + MPL; n = 10). A tumor size of 2000 mm3 was used asa surrogate end point of survival, P < 0.001.(C) Schematic diagram showing tumor inoculation on day 1 and hydrogelimplantation 1 day later, followed by two immunizations in the therapeuticmodel. (D) Tumor growth was plotted as mean ± SEM (n = 8) as a function of days after B16-OVA tumor challenge (** indicates P < 0.01).
Mentions: The utility of this two-step hybrid strategy (illustratedin Scheme 1) that first recruits DCs and thenprograms them within the GM-CSF hydrogel as a cancer vaccine was evaluatedin a murine melanoma model. In the prophylactic tumor model, micewere immunized with DC-LV-OVA alone or with MPL adjuvant 7 days afterinjection of hydrogels, as illustrated in Figure 5A. A total of 10 days after immunization, mice were inoculatedwith B16-OVA tumor cells, which stably express the model tumor antigenOVA. Using a tumor size of 2000 mm3 as a surrogate endpoint of survival, none of the PBS-injected (control) mice survivedfor more than 30 days (Figure 5B). Mice injectedwith empty hydrogels showed moderately improved immune protectioncompared to mice injected with PBS, suggesting that the residenceprovided by hydrogels could be beneficial to enhance antigen uptakeefficiency of APCs. However, a longer overall survival (p < 0.001) was observed in mice injected with GM-CSF hydrogelscompared to mice injected with empty hydrogels, indicating the benefitof recruiting DCs with GM-CSF. The benefit of GM-CSF-encapsulatedhydrogel was further confirmed by a significantly longer median survivaltime in GM-CSF-treated mice that received both DC-LV-OVA and MPL treatmentcompared to empty hydrogel-injected mice with the same immunizationcondition (p < 0.001).

Bottom Line: Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes.We demonstrate that GM-CSF-releasing mPEG-PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response.This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells.

View Article: PubMed Central - PubMed

Affiliation: Mork Family Department of Chemical Engineering and Materials Science, ‡Department of Biomedical Engineering, and §Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, California 90089, United States.

ABSTRACT
Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes. The development of biomaterials capable of modulating DCs in situ to enhance antigen uptake and presentation has emerged as a novel method toward developing more efficient cancer vaccines. Here, we propose a two-step hybrid strategy to produce a more robust cell-based cancer vaccine in situ. First, a significant number of DCs are recruited to an injectable thermosensitive mPEG-PLGA hydrogel through sustained release of chemoattractants, in particular, granulocyte-macrophage colony-stimulating factor (GM-CSF). Then, these resident DCs can be loaded with cancer antigens through the use of viral or nonviral vectors. We demonstrate that GM-CSF-releasing mPEG-PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response. Moreover, this two-step hybrid strategy generates a high level of tumor-specific immunity, as demonstrated in both prophylactic and therapeutic models of murine melanoma. This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells.

Show MeSH
Related in: MedlinePlus