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  • br Nanoparticles can be exploited to address some of the


    Nanoparticles can be exploited to address some of the aforementioned challenges. To simplify the production of CAR T-cells, Stephan et al. developed T-cell-targeting nanoparticles delivering plasmid DNA specifically constructed against CD19 antigens that were ubiquitously expressed on B lineage leukemia cells. The surface of these nanoparticles were decorated with T-cell markers—anti-CD3e f(ab’)2 fragments on the surface, and further incorporated with peptides containing microtubule-associated sequences and nuclear localization signals to facilitate nuclear transport134. These nanoparticles were further incorporated with peptides containing microtubule-associated sequences and nuclear localization signals to facilitate nuclear transport. Upon systemic administration of these CD3-targeted nanoparticles to mice, circulating T-cells were successfully reprogrammed to leukemia-specific CAR T-cells in situ and proliferated 5.5-fold with high expression of CAR transgene by day 12. Antitumor efficacy was evaluated in mice with B-cell acute lymphoblastic leukemia. In the group treated with lymphocyte-targeting nanoparticles, seven out of ten mice survived tumor-free until the end of the study, which was 58 days longer than untreated control. This result was comparable with mice infused with ex vivo-produced CAR T-cells. This study provided proof-of-principle for the ability to reprogram the antigen-recognizing capabilities of lymphocytes with synthetic nanoparticles while achieving comparable therapeutic effect with conventional CAR-T and circumventing the complication of T-cell manufacturing. Despite the low cost, simple production, and good stability of nanoparticles, validation is needed on human T-cells before this approach can proceed to clinical translation.
    To modulate the unfavorable TME, tumor-specific T-cells were equipped with nanogels containing cytokines and targeting ligands137. Human IL-15 super-agonist complex (IL-15Sa) was
    crosslinked with disulfide-containing linkers to form nanogels (NGs) and anti-CD45 Gefitinib (<10 mol%) were further incorporated, aiming to retain NGs on the surface of T-cells without compromising TCR signaling. A small amount of poly (ethylene glyco)-b-poly(L-lysine) was adsorbed to NGs to enhance NGs loading on T-cells. These NGs could promote T-cell expansion in vivo by releasing cytokines liberated when linkers were reduced during T-cell activation. When treated with transferred T-cells tagged with NGs, tumor growth was significantly inhibited compared to those treated with T-cells and free IL-15Sa. The dose of IL-15Sa could be increased up to 8-fold without inducing dose-limited toxicity when delivered within NGs, allowing multiple administrations of this T-cell therapy. Antitumor efficacy was further evaluated in a human glioblastoma mouse model. NG-tagged EGFR-targeted CAR-T cells could eradicate tumors in 80% of mice, while CAR-T cells alone or CAR-T cells plus free IL-15Sa only achieved a marginal therapeutic effect. In another effort to attenuate immunosuppression in the TME, a selective inhibitor of PI3K kinase (PI-3065) and immunostimulant-invariant natural killer T-cell (iNKT) agonist (7DW8-5) were co-encapsulated in liposomes decorated with tumor targeting iRGD peptides138. Mice bearing 4T1 tumors were treated with these dual-drug liposomes and much less (>4-fold) immune suppressing cells, such as TAMs, monocytic MDSCs and T-regs, were found at tumor site comparing to those treated with empty liposomes. The concentration of antitumor immune effector cells, such as CD8+ T cells and iNKT cells, was significantly increased due to the treatment. Therapeutic studies have shown that liposome pretreatments could augment T-cell accumulation in tumors and thus boost the effectiveness of cell therapy. The maximized outcomes could be obtained by multiple dosing of dual-drug liposomes several weeks in advance of T-cell infusion and implementation of combined therapies pivots on their safety evaluation in clinical trials.
    5. Summary and Conclusions
    Nanomedicines are a diverse class of engineered nanoscale compounds that can be finely tuned for the targeted in vivo delivery of drugs and macromolecules to specific cell populations. Actively targeting the immune system is uniquely challenging. The process of generating signal-specific immunity is tightly regulated, often requiring the simultaneous stimulation of multiple signals. Failure to simultaneously deliver both signals is not only inefficient, but can be counterproductive by facilitating immune tolerance. Many immune-modulating cell populations also exist as competing proinflammatory and immunosuppressive cell populations and efficient stimulation of class-restricted immune responses often requires specific targeting of one population without directly affecting the other. As highlighted in this review, novel nanomedicines are in many ways ideally suited for the translation of effective cancer immunotherapies. Nanomedicines can be engineered to optimize the targeted delivery of multiple signals to specific cell types using spatiotemporal accuracy not possible with other drug delivery methods. Lessons learned with first-generation nanomedicines have been used to further optimize the engineering of advanced nanocarriers for targeted cancer immunotherapies. In the short term, we predict that NPs will primarily serve as advanced drug-delivery vectors to improve targeting of specific subpopulations and synchronous delivery of co-stimulatory signals using approaches derived from existing platforms. In our view, the strongest potential for paradigm-altering impact probably lies with truly novel nanomedicines including engineered immune-cell mimetics (like ex vivo generated CAR-T cells). However, because these will require extensive preclinical validation before entering trials in humans, it is unlikely their clinical impact is realized for several years to come.