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Biopolymer implants enhance the efficacy of adoptive T-cell therapy.

Stephan SB, Taber AM, Jileaeva I, Pegues EP, Sentman CL, Stephan MT - Nat. Biotechnol. (2014)

Bottom Line: Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities.In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect.Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

ABSTRACT
Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.

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Biomaterial carriers can deliver anticancer T cells to prevent recurrence or eliminate inoperable tumors. (a) Implementation of the approach: The top panel shows hydrating and loading the biopolymer scaffold with tumor-reactive T cells. Scale bar: 0.5 cm. In the middle panel, the loaded device is surgically implanted at a mouse 4T1 mammary tumor resection site to eradicate residual disease there: [1] resection of the tumor; [2] resection cavity with residual tumor tissue; [3–5] implantation of the scaffold; [6] sustained release of tumor-reactive T cells into the resection bed and associated lymph nodes (black circles). Scale bar: 0.5 cm. In the lower panel, a T cell/polymer scaffold is placed directly into the peritoneal cavity to treat disseminated ovarian tumor lesions that cannot be removed by surgery: [1] skin incision; [2] established mouse ID8-VEGF-Luc ovarian cancer metastases (white arrows); [3–5] implantation of T cell-loaded device; [6] dispersion and functional support of anti-tumor T cells throughout the abdominal cavity. Scale bar: 0.5 cm. (b) Schematic diagram of a T cell-loaded scaffold surgically situated at a tumor site. Stimulatory microspheres incorporated into the device trigger cell expansion and promote their egress into surrounding tissue.
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Figure 1: Biomaterial carriers can deliver anticancer T cells to prevent recurrence or eliminate inoperable tumors. (a) Implementation of the approach: The top panel shows hydrating and loading the biopolymer scaffold with tumor-reactive T cells. Scale bar: 0.5 cm. In the middle panel, the loaded device is surgically implanted at a mouse 4T1 mammary tumor resection site to eradicate residual disease there: [1] resection of the tumor; [2] resection cavity with residual tumor tissue; [3–5] implantation of the scaffold; [6] sustained release of tumor-reactive T cells into the resection bed and associated lymph nodes (black circles). Scale bar: 0.5 cm. In the lower panel, a T cell/polymer scaffold is placed directly into the peritoneal cavity to treat disseminated ovarian tumor lesions that cannot be removed by surgery: [1] skin incision; [2] established mouse ID8-VEGF-Luc ovarian cancer metastases (white arrows); [3–5] implantation of T cell-loaded device; [6] dispersion and functional support of anti-tumor T cells throughout the abdominal cavity. Scale bar: 0.5 cm. (b) Schematic diagram of a T cell-loaded scaffold surgically situated at a tumor site. Stimulatory microspheres incorporated into the device trigger cell expansion and promote their egress into surrounding tissue.

Mentions: Here we demonstrate that the anti-tumor potency of transplanted lymphocytes can be substantially improved by harboring them in bioengineered polymer matrices designed to deliver and stimulate them when placed in tumor resection sites or close to inoperable tumors (Fig. 1a). The polymer acts as an active reservoir from which the propagating cells are released as the material biodegrades (Fig. 1b).


Biopolymer implants enhance the efficacy of adoptive T-cell therapy.

Stephan SB, Taber AM, Jileaeva I, Pegues EP, Sentman CL, Stephan MT - Nat. Biotechnol. (2014)

Biomaterial carriers can deliver anticancer T cells to prevent recurrence or eliminate inoperable tumors. (a) Implementation of the approach: The top panel shows hydrating and loading the biopolymer scaffold with tumor-reactive T cells. Scale bar: 0.5 cm. In the middle panel, the loaded device is surgically implanted at a mouse 4T1 mammary tumor resection site to eradicate residual disease there: [1] resection of the tumor; [2] resection cavity with residual tumor tissue; [3–5] implantation of the scaffold; [6] sustained release of tumor-reactive T cells into the resection bed and associated lymph nodes (black circles). Scale bar: 0.5 cm. In the lower panel, a T cell/polymer scaffold is placed directly into the peritoneal cavity to treat disseminated ovarian tumor lesions that cannot be removed by surgery: [1] skin incision; [2] established mouse ID8-VEGF-Luc ovarian cancer metastases (white arrows); [3–5] implantation of T cell-loaded device; [6] dispersion and functional support of anti-tumor T cells throughout the abdominal cavity. Scale bar: 0.5 cm. (b) Schematic diagram of a T cell-loaded scaffold surgically situated at a tumor site. Stimulatory microspheres incorporated into the device trigger cell expansion and promote their egress into surrounding tissue.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4289408&req=5

Figure 1: Biomaterial carriers can deliver anticancer T cells to prevent recurrence or eliminate inoperable tumors. (a) Implementation of the approach: The top panel shows hydrating and loading the biopolymer scaffold with tumor-reactive T cells. Scale bar: 0.5 cm. In the middle panel, the loaded device is surgically implanted at a mouse 4T1 mammary tumor resection site to eradicate residual disease there: [1] resection of the tumor; [2] resection cavity with residual tumor tissue; [3–5] implantation of the scaffold; [6] sustained release of tumor-reactive T cells into the resection bed and associated lymph nodes (black circles). Scale bar: 0.5 cm. In the lower panel, a T cell/polymer scaffold is placed directly into the peritoneal cavity to treat disseminated ovarian tumor lesions that cannot be removed by surgery: [1] skin incision; [2] established mouse ID8-VEGF-Luc ovarian cancer metastases (white arrows); [3–5] implantation of T cell-loaded device; [6] dispersion and functional support of anti-tumor T cells throughout the abdominal cavity. Scale bar: 0.5 cm. (b) Schematic diagram of a T cell-loaded scaffold surgically situated at a tumor site. Stimulatory microspheres incorporated into the device trigger cell expansion and promote their egress into surrounding tissue.
Mentions: Here we demonstrate that the anti-tumor potency of transplanted lymphocytes can be substantially improved by harboring them in bioengineered polymer matrices designed to deliver and stimulate them when placed in tumor resection sites or close to inoperable tumors (Fig. 1a). The polymer acts as an active reservoir from which the propagating cells are released as the material biodegrades (Fig. 1b).

Bottom Line: Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities.In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect.Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

ABSTRACT
Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.

Show MeSH
Related in: MedlinePlus