Nanotechnological Approaches in Prostate Cancer Therapy: Integration of engineering and biology

Pancreatic cancer is one of the most lethal forms of cancer, predicted to be the second leading cause of cancer-associated death by 2025. Despite intensive research for effective treatment strategies and novel anticancer drugs over the past decade, the overall patient survival rate remains low. RNA interference (RNAi) is capable of interfering with expression of specific genes and has emerged as a promising approach for pancreatic cancer because genetic aberrations and dysregulated signaling are the drivers for tumor formation and the stromal barrier to conventional therapy. Despite its therapeutic potential, RNA-based drugs have remaining hurdles such as poor tumor delivery and susceptibility to serum degradation, which could be overcome with the incorporation of nanocarriers for clinical applications. Here we summarize the use of small interfering RNA (siRNA) and microRNA (miRNA) in pancreatic cancer therapy in preclinical reports with approaches for targeting either the tumor or tumor microenvironment (TME) using various types of nanocarriers. In these studies, inhibition of oncogene expression and induction of a tumor suppressive response in cancer cells and surrounding immune cells in TME exhibited a strong anticancer effect in pancreatic cancer models. The review discusses the remaining challenges and prospective strategies suggesting the potential of RNAi-based therapeutics for pancreatic cancer.

RNAi-Based Approaches for Pancreatic Cancer Therapy.

Feasibility study of a novel preparation strategy for anti-CD7 CAR-T cells with a recombinant anti-CD7 blocking antibody

Abstract Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development. 

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Strategies to enhance CAR-T persistence

Small interfering RNAs based therapies for intracerebral hemorrhage: challenges and progress in drug delivery systems

RNAi effectors (e.g., siRNA, shRNA, and miRNA) can efficiently trigger the silencing of specific genes, and its genomic alteration functions allowed to pursue clinical trials in distinct areas, including infectious diseases, neurodegenerative disorders, and cancer. Moreover, regarding cancer immunotherapy, RNAi therapeutics showed potential immunomodulatory ability by downregulating suppressive receptors such as PD-1 and CTLA-4, which restrict immune cell function and present challenges in cancer immunotherapy. Therefore, compared with extracellular targeting by antibodies, RNAi-mediated, cell-intrinsic disruption of inhibitory pathways in immune cells can promote an increased antitumor immune response. Along with nonviral vectors, DNA-based RNAi strategies might be a more promising method for immunomodulation to silence multiple inhibitory pathways in T cells than immune checkpoint blockade antibodies. Thus, in this review, we discuss diverse RNAi implementation strategies, with recent viral and non-viral mediated RNAi synergism to immunotherapy that augments the antitumor immunity. Finally, we provide the current progress of RNAi in clinical pipeline.

Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy.

Persistence of CAR-T cell function is associated with relapse rate after CAR-T therapy, while co-stimulatory agents are highly concerned with the persistence of CAR-T cells. In this study, we designed and constructed a series of BCMA-targeting second-generation CAR constructs containing CD28, 41BB, and OX40 molecules, respectively, to identify the costimulatory domains most favorable for persistence. The results of routine in vitro studies showed that OX40-CAR-T and 41BB-CAR-T had similar antitumor effects and were superior to CD28-CAR-T in terms of proliferation and cytotoxicity. Although difficult to distinguish by conventional functional assays, OX40-CAR-T cells exhibited greater proliferation and enhanced immune memory than 41BB-CAR-T cells with the repeated stimulation assay by BCMA-expressing target cells. In vivo studies further demonstrated that OX40-CAR-T cells had stronger proliferative activity than 41BB-CAR-T cells, which was highly consistent with the in vitro antitumor activity and proliferation results. Our study provides for the first time a scientific basis for designing OX40-CAR-T cell therapy to improve relapse in patients with MM after CAR-T treatment. 

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Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells

High interleukin 17A (IL-17A) expression in hepatocellular carcinoma (HCC) tissue promotes HCC development. This study explores a method to inhibit HCC growth by neutralizing IL-17A in the HCC microenvironment. A novel type 5 adenoviral vector (Ad5) that carries DNA sequences encoding specific neutralizing IL-17A recombinant antibody fragments was developed in this research. After locally injecting into tumor tissues, the Ad5 transduced into tumor cells. This leads to the expression of the anti-IL-17A recombinant antibody fragments in the HCC tissue and consequently to an inhibition of HCC growth by neutralizing IL-17A. The stability of the antibody fragments was optimized by different structures design. Stable HCC cell lines that secrete IL-17A continuously were constructed, which showed stronger invasion and migration ability than control HCC cell lines. In addition, the enhanced migration and invasion ability were partially reversed by applying the adenoviral vectors. These results suggest that IL-17A might promote HCC growth by enhancing the invasion and migration ability of hepatoma cells. The antibody fragments from Ad5 neutralized IL-17A locally, in turn inhibiting the growth of HCC tumors. In conclusion, the local administration of Ad5 vectors encoding IL-17A-neutralizing antibody fragments provides a new option for HCC immunotherapy.

Israth Jahan Tuhin

Papers

Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy.

Feasibility study of a novel preparation strategy for anti-CD7 CAR-T cells with a recombinant anti-CD7 blocking antibody

Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells

Gene Therapy for Hepatocellular Carcinoma Using Adenoviral Vectors Delivering a Gene Encoding IL-17A-Neutralizing Antibody Fragments.