bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2022–06–05
six papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.
  2. CAR-T Therapy in Clinical Practice: Technical Advances and Current Challenges.
  3. Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors.
  4. Current status and perspectives of regulatory T cell-based therapy.
  5. A photoresponsive antibody-siRNA conjugate for activatable immunogene therapy of cancer.
  6. Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero?
  1. Nat Biotechnol. 2022 Jun 02.
    Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.
    Kirk M Brown, Jayaprakash K Nair, Maja M Janas, Yesseinia I Anglero-Rodriguez, Lan T H Dang, Haiyan Peng, Christopher S Theile, Elena Castellanos-Rizaldos, Christopher Brown, Donald Foster, Jeffrey Kurz, Jeffrey Allen, Rajanikanth Maganti, Jing Li, Shigeo Matsuda, Matthew Stricos, Tyler Chickering, Michelle Jung, Kelly Wassarman, Jeff Rollins, Lauren Woods, Alex Kelin, Dale C Guenther, Melissa W Mobley, John Petrulis, Robin McDougall, Timothy Racie, Jessica Bombardier, Diana Cha, Saket Agarwal, Lei Johnson, Yongfeng Jiang, Scott Lentini, Jason Gilbert, Tuyen Nguyen, Samantha Chigas, Sarah LeBlanc, Urjana Poreci, Anne Kasper, Arlin B Rogers, Saeho Chong, Wendell Davis, Jessica E Sutherland, Adam Castoreno, Stuart Milstein, Mark K Schlegel, Ivan Zlatev, Klaus Charisse, Mark Keating, Muthiah Manoharan, Kevin Fitzgerald, Jing-Tao Wu, Martin A Maier, Vasant Jadhav.
      Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer's disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.
    DOI:  https://doi.org/10.1038/s41587-022-01334-x
  2. Adv Biol (Weinh). 2022 Jun 01. e2101262
    CAR-T Therapy in Clinical Practice: Technical Advances and Current Challenges.
    Ping Ren, Chuyue Zhang, Wenping Li, Xian Wang, Aibing Liang, Guang Yang, Hongtao Xu, Peixiang Ma.
      Chimeric antigen receptors (CAR) redirect T cells to specifically recognize and eliminate tumor cells. CAR-T therapy has achieved successful clinical outcomes, and it has been transformed into commercially available products to treat acute lymphoblastic leukemia and B cell lymphoma. These breakthroughs have motivated hundreds of CAR-T clinical trials initiated each year, with ≈900 cases registered on the ClinicalTrials website till 2021. Accumulating clinical experiences have highlighted some limitations of this strategy, e.g., relapse after complete response, poor efficacy in solid tumors, on-target off-tumor toxicities, lack of persistence, and tumor resistance. These challenges limit the therapeutic application of CAR-T cells. Multidisciplinary approaches are actively investigated to address these issues. In this review, the antigens, CAR designs, and cell sources are summarized in clinical trials from 2020 to 2021. The innovative modular and programmable designs in CAR-T cells, including advances in signaling domains, antigen-recognition domains, T cell engineering, and cell resources, are further discussed. Integrative genetic and chemical engineering strategies are promising to improve the versatility, antitumor efficacy, persistence, and safety of CAR-T cells. In the future, the next generation of CAR-T cell therapies will offer more options for patients who are refractory to standard tumor therapies.
    Keywords:  CAR-T; T cell engineering; clinical trials; immunotherapy
    DOI:  https://doi.org/10.1002/adbi.202101262
  3. Antibodies (Basel). 2022 Apr 27. pii: 31. [Epub ahead of print]11(2):
    Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors.
    Christopher W Mount, Luis Nicolas Gonzalez Castro.
      Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient's own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.
    Keywords:  H3 K27M-mutant; adoptive cell therapy; chimeric antigen receptor (CAR) T-cell therapy; diffuse midline glioma; glioblastoma; primary brain tumors
    DOI:  https://doi.org/10.3390/antib11020031
  4. J Genet Genomics. 2022 May 27. pii: S1673-8527(22)00156-4. [Epub ahead of print]
    Current status and perspectives of regulatory T cell-based therapy.
    Guojun Qu, Jieqiong Chen, Yangyang Li, Yaqin Yuan, Rui Liang, Bin Li.
      The CD4+FOXP3+ regulatory T (Treg) cells are essential for maintaining immune homeostasis in healthy individuals. Results from clinical trials of Treg cell-based therapies in patients with graft-versus-host disease (GVHD), type 1 diabetes (T1D), liver transplantation and kidney transplantation have demonstrated that adoptive transfer of Treg cells is emerging as a promising strategy to promote immune tolerance. Here we provide an overview of recent progresses and current challenges of Treg cell-based therapies. We summarize the completed and ongoing clinical trials with human Treg cells. Notably, a few of chimeric antigen receptor (CAR)-Treg cell therapies are currently undergoing clinical trials. Meanwhile, we describe the new strategies of engineering Treg cells used in preclinical studies. Finally, we envision that the use of novel synthetic receptors, metabolic regulators, combined therapies, and in vivo generated antigen-specific or engineered Treg cells through the delivery of modified mRNA and CRISPR-based gene editing will further promote the advances of next-generation Treg cell therapies.
    Keywords:  CRISPR-based gene editing; Cell therapy; Chimeric antigen receptor; FOXP3; Regulatory T cell; mRNA-based therapy
    DOI:  https://doi.org/10.1016/j.jgg.2022.05.005
  5. Chem Sci. 2022 May 11. 13(18): 5345-5352
    A photoresponsive antibody-siRNA conjugate for activatable immunogene therapy of cancer.
    Xingxing Wang, Xiao Xiao, Yi Feng, Jinbo Li, Yan Zhang.
      Tumor-targeted delivery of small-interfering RNAs (siRNAs) for cancer therapy still remains a challenging task. While antibody-siRNA conjugates (ARCs) provide an alternative way to address this challenge, the uncontrollable siRNA release potentially leads to undesirable off-tumor side effects, limiting their in vivo therapeutic efficacy. Here, we report a photoresponsive ARC (PARC) for tumor-specific and photoinducible siRNA delivery as well as photoactivable immunogene therapy. PARC is composed of an anti-programmed death-ligand 1 antibody (αPD-L1) conjugated with a siRNA against intracellular PD-L1 mRNA through a photocleavable linker. After targeting cancer cells through the interaction between αPD-L1 and membrane PD-L1, PARC is internalized and it liberates siPD-L1 upon light irradiation to break the photocleavable linker. The released siPD-L1 then escapes from the lysosome into the cytoplasm to degrade intracellular PD-L1 mRNA, which combines the blockade of membrane PD-L1 by αPD-L1 to boost immune cell activity. Owing to these features, PARC causes effective cancer suppression both in vitro and in vivo. This study thus provides a useful conditional delivery platform for siRNAs and a novel means for activatable cancer immunogene therapy.
    DOI:  https://doi.org/10.1039/d2sc01672a
  6. Front Immunol. 2022 ;13 795164
    Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero?
    Pouya Safarzadeh Kozani, Pooria Safarzadeh Kozani, Milad Ahmadi Najafabadi, Fatemeh Yousefi, Seyed Mohamad Javad Mirarefin, Fatemeh Rahbarizadeh.
      Chimeric antigen receptor T-cells (CAR-Ts) are known as revolutionary living drugs that have turned the tables of conventional cancer treatments in certain hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) by achieving US Food and Drug Administration (FDA) approval based on their successful clinical outcomes. However, this type of therapy has not seen the light of victory in the fight against solid tumors because of various restricting caveats including heterogeneous tumor antigen expression and the immunosuppressive tumor microenvironments (TME) that negatively affect the tumor-site accessibility, infiltration, stimulation, activation, and persistence of CAR-Ts. In this review, we explore strategic twists including boosting vaccines and designing implementations that can support CAR-T expansion, proliferation, and tumoricidal capacity. We also step further by underscoring novel strategies for triggering endogenous antitumor responses and overcoming the limitation of poor CAR-T tumor-tissue infiltration and the lack of definitive tumor-specific antigens. Ultimately, we highlight how these approaches can address the mentioned arduous hurdles.
    Keywords:  chimeric antigen receptor; immunotherapy; infiltration; solid tumors; tumor microenvironment; vaccines
    DOI:  https://doi.org/10.3389/fimmu.2022.795164
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