bims-limsir 2022-09-25 papers

Viruses. 2022 Sep 16. pii: 2052. [Epub ahead of print]14(9):

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects.

Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.

Keywords: ASO; HBsAg; NAP; functional cure; immunostimulation; siRNA

DOI: https://doi.org/10.3390/v14092052

Pharmacol Res. 2022 Sep 14. pii: S1043-6618(22)00400-5. [Epub ahead of print] 106454

Nanotechnology-based chimeric antigen receptor T-cell therapy in treating solid tumor.

Yi-Han Zuo, Xiao-Ping Zhao, Xing-Xing Fan.

Chimeric Antigen Receptor (CAR) T cells have changed the therapeutic landscape of hematological malignancies with overwhelming success. The clinical success of CAR T-cell therapy in hematologic malignancies has fueled interest in exploring the technology in solid tumors. However, the treatment of solid tumors presents a unique set of challenges compared to hematological tumors. The biggest impediments to the success of CAR T cell treatment are the paucity of tumor-specific antigens that are produced selectively and uniformly and the immunosuppressive tumor microenvironment. To overcome these significant challenges, nanotechnology has been involved to improve the efficacy of CAR-T cells. In this review, we systematically introduced the components of different generation of CARs and summarized recent innovations in nano-based CAR-T cell therapy to conquer therapeutically resistant non-hematologic malignancies, including mRNA and hydrogel-based CAR T cells delivery, photothermal-remodeling, and tumor microenvironment-based CAR T cell therapy. These nanotechnologies remarkably facilitate in vivo generation of CAR T cells and hold promise as a therapeutic platform to treat solid tumor and even other diseases.

Keywords: CAR; Nanotechnology; solid tumor; tumor microenvironment

DOI: https://doi.org/10.1016/j.phrs.2022.106454

Biomark Res. 2022 Sep 19. 10(1): 70

CAR-T cell potency: from structural elements to vector backbone components.

Marzieh Mazinani, Fatemeh Rahbarizadeh.

Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own T lymphocytes are engineered to recognize and kill cancer cells, has achieved remarkable success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Once equipped with a CAR construct, T cells act as living drugs and recognize and eliminate the target tumor cells in an MHC-independent manner. In this review, we first described all structural modular of CAR in detail, focusing on more recent findings. We then pointed out behind-the-scene elements contributing to CAR expression and reviewed how CAR expression can be drastically affected by the elements embedded in the viral vector backbone.

Keywords: Cancer immunotherapy; Chimeric antigen receptor; Lentiviral vectors; Nanobody; Signal peptide; Single-chain variable fragment

DOI: https://doi.org/10.1186/s40364-022-00417-w

JCO Oncol Pract. 2022 Sep 21. OP2200315

Chimeric Antigen Receptor T-Cell Therapies: Barriers and Solutions to Access.

Joseph Mikhael, Jessica Fowler, Nina Shah.

Chimeric antigen receptor T-cell (CAR-T) therapies are relatively new treatments for patients with heavily pretreated hematologic malignancies. Although these innovative therapies can offer substantial benefit to patients with limited alternative treatment options, patient-access barriers exist. Conventional clinical trials are time-consuming and may be limited by strict patient eligibility criteria, resources, and availability of enrollment slots. Because of the complexity of the CAR-T administration process, treatment delivery can be associated with additional burden for the patient, including requiring patients to reside close to treatment centers and remain with a caregiver after infusion. Manufacturing of CAR-T cells is completed in specialized facilities and depends on the availability of reagents, manufacturing workforce, and timely transportation. CAR-T therapy is costly, and many US health plans restrict coverage of cell and gene therapies. Several of the existing challenges because of these barriers have been exacerbated during the COVID-19 pandemic. This review discusses these barriers and proposes some potential solutions to improving patient access, including innovation in clinical trial design and manufacturing, location of treatment delivery, and key stakeholder opinions regarding treatment and reimbursement. We propose a call to action for key stakeholder groups to address these barriers to CAR-T therapy to expand treatment access for patients. Future collaboration between key stakeholders, including payers, regulatory agencies, and industry/academia, will be critical to continue to address these barriers and enhance patient access to these therapies.

DOI: https://doi.org/10.1200/OP.22.00315