Cell-loaded scaffold implant may improve cell therapy [PreClinical]

1. A polymer scaffold modified with stimulatory molecules promoted the growth and migration of tumor-specific immune T cells in vitro and in vivo.

2. In mouse cancer models, the T cell-loaded polymer implant prevented disease relapse following surgical tumor removal and caused regression of inoperable tumors.

Evidence Rating Level: 2 (Good)

Study Rundown: Surgical removal of solid tumors can leave behind residual cancer cells that cause relapse, or in other cases such resection is not a feasible procedure. Adoptive T cell therapy, which uses infusions of anti-tumor primed immune T cells to target cancer cells, is considered an additional or alternative treatment for solid tumors. This study sought to address one of the major limitations in adoptive T cell therapy, effective delivery of activated T cells to the tumor site. Researchers developed a scaffold of alginate, a natural polymer approved by the U.S. Food and Drug Administration that degrades in the body; the scaffold was modified with collagen-like molecules and microparticles that mimicked T cell-stimulating cells. When tumor-specific T cells were loaded into the scaffold, T cell growth and migration into surrounding tissue was increased by the scaffold modifications. In a breast cancer mouse model of relapse after surgery, the polymer implant loaded with T cells improved survival and prevented tumor relapse when compared to bolus injections of the anti-tumor T cells. In an ovarian cancer mouse model of inoperable tumors, the implant improved survival and promoted tumor regression.

This study demonstrated a technology for effective T cell delivery to a specific tumor site. Compared to current methods of systemically infusing T cells, the surgical implant was more invasive, but had the advantage of improved anti-tumor activity due to localized, prolonged release of continuously stimulated large numbers of T cells. Overall, this modified, cell-loaded implant has great potential to improve adoptive T cell therapy for treating solid tumors.

Click to read the study in Nature Biotechnology

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In-Depth [animal study]: The alginate macroporous scaffolds used in this study were functionalized with collagen-mimetic molecules, which promoted T cell migration, and with soluble-factor containing microparticles, intended to provide cell growth and activity signals. Because T cells respond to a variety of molecules that are soluble or attached to other cells, the microparticles were designed to release a form of the soluble factor interleukin 15 and have a lipid outer layer with bound signaling molecules. Over a seven-day period, tumor-specific T cells seeded onto the functionalized scaffold exhibited a 22-fold increase in proliferation and a 8.3-fold increase in migration out of the implant compared to cell activity in a scaffold lacking the microparticle modification.

Using a breast cancer mouse model, tumors were partially surgically removed with around 1% of residual tumor tissue left at the site. All animals that received the cell-loaded fully modified polymer implant survived for at least 80 days (last follow up) following the surgery with no tumor relapse. In contrast, animals receiving no treatment, intravenous T cell injection, or intracavitary T cell injection survived a median of 19, 21, and 25 days, respectively. In a separate experiment, a stage 3 ovarian carcinoma mouse system was used to model inoperable tumors. Tumor regression was observed only in the animals treated with the implant, with complete tumor eradication in 6 of 10 animals (at follow up of 80 days). Survival of animals with the implant was significantly higher than for animals receiving an injection of pre-activated T cells to the tumor site (p < 0.0001).

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Image: PD

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