Nature Sub-Journal . . . Magical metal film sendCAR-T cells directly to solid tumor

Since two CAR-T therapies were approved for blood tumors in 2017, CAR-T therapy has remained inast for the treatment of solid tumorsThis is mainly due to the fact that solid tumors (including breast, ovarian, pancreatic, etc.) have a variety of strategies to evade and fight cancer cells, and intravenous CAR-T cells can not enter the tumor, nor can they survive in the adverse microenvironment formed by the tumor lesionsso, what if the CAR-T cells were allowed to "drop" directly around the tumor?December 9, scientists at the Fred Hutchinson Cancer Research Center, in the journal Nature Biomedical Engineering, for the first time, showed that in preclinical models of ovarian cancer mice, a metal film loaded with anti-cancer immune cells not only increased the density of CAR-T cells in tumor tissue by 232 times compared to traditional intravenous injections, but also allowed 70 percent of mouse tumors to disappear completelyimage source: DrMatthias TStephan, who led the studyNature Biomedical Engineering, said: "Anti-tumor cell therapy has been a great success in treating blood cancer, but has not been effective in solid tumorsOur findings are an important step towards effective cell therapy against solid tumorsIn addition to minimizing patient side effects, our ultimate goal is to make T-cell therapy faster, cheaper and easier to treat patientsto achieve this goal, the Stephan team studied the method of "dropping" CAR-T cellsIn fact, other research teams have tried this idea, such as implanting CAR-T cells into hydrogels, fibrin matrixes, extracellular matrix components, or stents made of electro-woven polymers, and then implanting them directly around tumors, but none of these methods have been successfulStephan's team chose a film made of nickel-titanium, a near-transparent metal film made by Monarch Biosciences, which is 10 microns thick and about seven times thinner than a person's hairunder a microscope, the membrane has very little space and can be designed into different pattern structures"We need to find a thin-film pattern structure that fits T-cells," Stephan and his colleagues saidThis pattern structure needs to be small enough to ensure that the cells do not fall between the gaps, but not too small, which can make the T cells feel too crowded to movescreened and found that a linear pattern structure similar to a maze-top view was best suited for loading T-cells In this film, the researchers implanted CAR-T cells that were edited to the ovarian cancer marker ROR1, placed on both sides of the membrane, and they were absorbed into the material "It's like a slice of bread with jam on both sides The metal film is the bread, we put car-T cells on both sides of the bread, and then they soak into the middle of the bread Stephan explains image source: Nature Biomedical Engineering Considering that the goal of the experiment is not only to provide anti-tumor T cells, but also to trigger their rapid amplification at the implant site, the researchers coated the fibrin coating on the metal film and added T-cell amplification activators: CD3, CD28, and CD137 "It's not just a passive delivery device, it's a release platform that triggers the amplification of CAR-T cells to overcome tumor defenses against immune cells," Stephan said After ready for a "weapon," the researchers tested a mouse model of non-removal ovarian cancer A nickel-titanium film containing CAR-T cells is implanted into the tumor, which is easy to process and locate on the tumor lesions Once positioned, the implant promotes the rapid amplification of embedded anti-cancer lymphocytes, making CAR-T cell density in tumor tissue 232 times higher than traditional intravenous T cells in addition , 70 percent of the tumors in the treated mice were completely removed, with an average survival time of 80 days, 2.7 times higher than in the untreated control group During the experiment, the metal film was safe and reliable and there was no necrosis in the surrounding tissues or organs image source: Nature Biomedical Engineering
based on this, the researchers also developed a three-dimensional device Self-puffed tumor stents are commonly used as palliative measures to relieve malignant obstruction of the airways, gastrointestinal tract, or urethra, and the researchers hypothesized that tubular metal films with CAR-T cells can release antitumor T cells into tumors while preventing blockages in the tube cavity, thus inducing disease to subside this idea was confirmed by an in vitro experiment with a three-dimensional pancreatic tumor: the use of functional stents loaded with tumor-specific CAR-T cells does prevent blocking caused by tumor growth, suggesting that this method can be used in cancers that cause obstruction of the respiratory tract or digestive system, such as lung, pancreatic or esophageal cancers image source: Nature Biomedical Engineering finally, Stephan presents the prospect: In the current experiment, we are focused on CAR-T cells, but I can expect this approach to work with T-cell receptor therapy, natural killer cells, and other immune cells that target cancer concluded that this study confirms that the combination of nickel-titanium films with good biocompatibility and anti-tumor immune cells can effectively eliminate solid tumors that cannot be surgically removed Although the transformation of this technology into clinical application sits further experimental research, it is promising and worth looking forward to summary areas: Journal of Cancer : Nature Biomedical Engineering Highlights: Scientists at the Fred Hutchinson Cancer Research Center have designed a biocompatible, porous mesh nickel-titanium film that can efficiently load CAR-T cells and trigger their rapid amplification at the implant site In the preclinical model of ovarian cancer, this technique can effectively eliminate tumors in mice and prolong their survival In addition, tubular metal films developed on this basis are suitable for cancers that cause obstruction of the respiratory tract or digestive system related papers: Michael E Coon, et al Nitinol thin films functionally with car-t cells for the treatment of the solids Nat Biomed Eng (2019) , Oliveira, J M et al Hydrogel-based scaffolds to support intrathecal stem cell a gateway to the spinal cord: clinical needs, biomaterials, and imaging technologies NPJ Regen Med (2018) Osama, I et al In vitros on space-space-self-assembling silk hydrogels as a mesenchymal stem cell-support matrix for minimally brain application Sci Rep (2018) Snyder, T N et al A fibrin/hronic acid hydrogel for delivery of mesenchymal stem cells and potential for artalalticstedirepair J Biol Eng (2014) Machula, H et al Electrospun tropoeelastin for delivery of the therapeutic dipose-derived stem cells to full-thickness dermal wounds Adv Wound Care (2014) References: 1's Scientists show thin metal mesh loaded with T cells shrinks solid tumors