bims-limsir 2023-07-16 papers

on Lipophilic modified siRNAs

Issue of 2023‒07‒16
eight papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Where should siRNAs go: applicable organs for siRNA drugs.
Ongoing Clinical Trials of Nonviral siRNA Therapeutics.
Clinical Pharmacology and Translational Considerations in the Development of CRISPR-Based Therapies.
Challenges and interventions of chimeric antigen receptor-T cell therapy in solid tumors.
Chimeric Antigen Receptor T Cells in Glioblastoma-Current Concepts and Promising Future.
Chimeric Antigen Receptor (CAR) T-Cell Therapy for Patients with Lung Cancer: Current Perspectives.
High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions.
The Future of Chimeric Antigen Receptor T Cell Therapy.

Exp Mol Med. 2023 Jul 10.

Where should siRNAs go: applicable organs for siRNA drugs.

Insook Ahn, Chanhee S Kang, Jinju Han.

RNA interference mediated by small interfering RNAs (siRNAs) has been exploited for the development of therapeutics. siRNAs can be a powerful therapeutic tool because the working mechanisms of siRNAs are straightforward. siRNAs determine targets based on their sequence and specifically regulate the gene expression of the target gene. However, efficient delivery of siRNAs to the target organ has long been an issue that needs to be solved. Tremendous efforts regarding siRNA delivery have led to significant progress in siRNA drug development, and from 2018 to 2022, a total of five siRNA drugs were approved for the treatment of patients. Although all FDA-approved siRNA drugs target the hepatocytes of the liver, siRNA-based drugs targeting different organs are in clinical trials. In this review, we introduce siRNA drugs in the market and siRNA drug candidates in clinical trials that target cells in multiple organs. The liver, eye, and skin are the preferred organs targeted by siRNAs. Three or more siRNA drug candidates are in phase 2 or 3 clinical trials to suppress gene expression in these preferred organs. On the other hand, the lungs, kidneys, and brain are challenging organs with relatively few clinical trials. We discuss the characteristics of each organ related to the advantages and disadvantages of siRNA drug targeting and strategies to overcome the barriers in delivering siRNAs based on organ-specific siRNA drugs that have progressed to clinical trials.

DOI: https://doi.org/10.1038/s12276-023-00998-y
Bioconjug Chem. 2023 Jul 11.

Ongoing Clinical Trials of Nonviral siRNA Therapeutics.

Eshan A Narasipura, Rachel VanKeulen-Miller, Yutian Ma, Owen S Fenton.

Short interfering RNAs (siRNA) are a powerful class of genetic medicines whose clinical translation can be hindered by their suboptimal delivery properties in vivo. Here, we provide a clinically focused overview that summarizes ongoing siRNA clinical trials from the perspective of innovations in nonviral delivery strategies. More specifically, our review begins by highlighting the delivery barriers and physiochemical properties of siRNA that make it challenging to deliver it in vivo. We then provide commentary on specific delivery strategies, including sequence modification, siRNA ligand conjugation, and nanoparticle and exosomal packaging, each of which can be used to control the delivery of siRNA therapies in living systems. Last, we provide a summary table of ongoing siRNA clinical trials which also highlights the indication of use, target, and National Clinical Trial (NCT) number associated with each entry. In writing this review, our work aims to highlight the key challenges and strategies for effective nonviral siRNA delivery in vivo, while simultaneously summarizing information on ongoing clinical trials for siRNA therapy in humans.

DOI: https://doi.org/10.1021/acs.bioconjchem.3c00205
Clin Pharmacol Ther. 2023 Jul 10.

Clinical Pharmacology and Translational Considerations in the Development of CRISPR-Based Therapies.

Ahmed M Abdelhady, Jonathan A Phillips, Yuanxin Xu, Mark Stroh.

Genome editing holds the potential for curative treatments of human disease, however clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model-informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from Phase 1 investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR-based investigational therapies in the clinic. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/cpt.3000
Chin J Cancer Res. 2023 Jun 30. 35(3): 239-244

Challenges and interventions of chimeric antigen receptor-T cell therapy in solid tumors.

Shasha Liu, Yi Zhang.

  Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors. Remarkable clinical success has been achieved in chimeric antigen receptor (CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies. However, many challenges such as resistance, antigen heterogeneity, poor immune cell infiltration, immunosuppressive microenvironment, metabolic obstructive microenvironment, and T cell exhaustion remain as barriers to broader application especially in solid tumors. Encouragingly, the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers. Here, in this perspective, we focus on the most recent clinical advancements, challenges, and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy, to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.

Keywords:  CAR-T cell; Immunotherapy; metabolism; solid tumors

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2023.03.03
Cells. 2023 Jul 03. pii: 1770. [Epub ahead of print]12(13):

Chimeric Antigen Receptor T Cells in Glioblastoma-Current Concepts and Promising Future.

Rebecca Kringel, Katrin Lamszus, Malte Mohme.

  Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.

Keywords:  CAR-T cells; GBM; T cells; glioblastoma; glioma; immunotherapy

DOI:  https://doi.org/10.3390/cells12131770
Onco Targets Ther. 2023 ;16 515-532

Chimeric Antigen Receptor (CAR) T-Cell Therapy for Patients with Lung Cancer: Current Perspectives.

John Maher.

  Immunotherapy using chimeric antigen receptor (CAR)-engineered T-cells has achieved unprecedented efficacy in selected hematological cancers. However, solid tumors such as lung cancer impose several additional challenges to the attainment of clinical success using this emerging therapeutic modality. Lung cancer is the biggest cause of cancer-related mortality worldwide, accounting for approximately 1.8 million deaths worldwide each year. Obstacles to the development of CAR T-cell immunotherapy for lung cancer include the selection of safe tumor-selective targets, accounting for the large number of candidates that have been evaluated thus far. Tumor heterogeneity is also a key hurdle, meaning that single target-based approaches are susceptible to therapeutic failure through the emergence of antigen null cancers. There is also a need to enable CAR T-cells to traffic efficiently to sites of disease, to infiltrate tumor deposits and to operate within the hostile tumor microenvironment formed by solid tumors, resisting the onset of exhaustion. Multiple immune, metabolic, physical and chemical barriers operate at the core of malignant lesions, with potential for further heterogeneity and evolution in the face of selective therapeutic pressures. Although the extraordinarily adaptable nature of lung cancers has recently been unmasked, immunotherapy using immune checkpoint blockade can achieve long-term disease control in a small number of patients, establishing clinical proof of concept that immunotherapies can control advanced lung carcinomas. This review summarizes pre-clinical CAR T-cell research that is specifically focused on lung cancer in addition to published and ongoing clinical trial activity. A number of advanced engineering strategies are also described which are designed to bridge the gap to the attainment of meaningful efficacy using genetically engineered T-cells.

Keywords:  engineered T-cell; immunotherapy; malignancy; pulmonary

DOI:  https://doi.org/10.2147/OTT.S341179
Am Soc Clin Oncol Educ Book. 2023 Jun;43 e397912

High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions.

Edward R Scheffer Cliff, Amar H Kelkar, David A Russler-Germain, Frazer A Tessema, Adam J N Raymakers, William B Feldman, Aaron S Kesselheim.

Chimeric antigen receptor (CAR) T-cells are a cellular immunotherapy with remarkable efficacy in treating multiple hematologic malignancies but they are associated with extremely high prices that are, for many countries, prohibitively expensive. As their use increases both for hematologic malignancies and other indications, and large numbers of new cellular therapies are developed, novel approaches will be needed both to reduce the cost of therapy, and to pay for them. We review the many factors that lead to the high cost of CAR T-cells and offer proposals for reform.

DOI: https://doi.org/10.1200/EDBK_397912
Hematol Oncol Clin North Am. 2023 Jul 11. pii: S0889-8588(23)00093-X. [Epub ahead of print]

The Future of Chimeric Antigen Receptor T Cell Therapy.

Eric L Smith.

  Over the last 10 years CAR T cell therapies have been shown to be transformative for B- and plasma-cell malignancies, however the field is only beginning to realize the potential benefit to patients of such therapies. Over the next 10 years it is expected that advances will be made in durable response rates for patients with B/plasma cell malignancies; expansion to T-cell, myeloid, and solid malignancies; and in delivery and manufacturing to transform the field.

Keywords:  Adoptive cellular therapy; CAR; CAR T cell therapy; Cellular therapy; Chimeric antigen receptor

DOI:  https://doi.org/10.1016/j.hoc.2023.06.005