bims-limsir 2022-10-02 papers

on Lipophilic modified siRNAs

Issue of 2022–10–02
ten papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Molecularly engineered siRNA conjugates for tumor-targeted RNAi therapy.
Current progress in CAR-T cell therapy for tumor treatment.
Recent advances in the production, reprogramming, and application of CAR-T cells for treating hematological malignancies.
Targeted and cellular therapies in lymphoma: Mechanisms of escape and innovative strategies.
Advances in CAR-T cell therapy for malignant solid tumors.
Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy.
Ligand-based CAR-T cell: Different strategies to drive T cells in future new treatments.
The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers.
Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy.
HIV T-cell immunogen design and delivery.

J Control Release. 2022 Sep 21. pii: S0168-3659(22)00635-6. [Epub ahead of print]

Molecularly engineered siRNA conjugates for tumor-targeted RNAi therapy.

Jong Won Lee, Jiwon Choi, Yeonho Choi, Kwangmeyung Kim, Yoosoo Yang, Sun Hwa Kim, Hong Yeol Yoon, Ick Chan Kwon.

  RNA interference (RNAi) is a major cellular mechanism regulating gene expression in which short double-stranded RNA molecules called small interfering RNA (siRNA) mediate sequence-specific mRNA degradation. RNAi technology has recently emerged as a promising therapeutic platform for the effective treatment of various diseases caused by inappropriate gene activity, such as cancer. However, the clinical translation of siRNA therapeutics has been hampered by the major hurdles associated with biological instability and limited delivery efficiency. Based on the various efforts, recent siRNA delivery strategies using cationic lipids and polymers allowed to enhance pharmacokinetics and delivery efficiency, resulting in potent and liver-targeted RNAi therapy. However, non-specific protein adsorption, high liver accumulation, and severe toxicity of cationic nanocarriers still limit the possibility of transfer of siRNA therapeutics from the laboratory to the clinic. One of the promising delivery strategies to overcome the limitations of siRNA therapeutics is carrier-free bioconjugation which is chemically modified and connected with biocompatible molecules such as lipids, peptides, antibodies, aptamers, and polymers. These molecularly engineered siRNA conjugates can be utilized for RNAi delivery to tissues beyond the liver, providing opportunities for clinical translation. This review focused on introducing the recent progress in molecularly engineered siRNA conjugates and their applications toward overcoming the limitations of siRNA for tumor-targeted delivery and therapy.

Keywords:  Gene delivery; RNA interference; Small interfering RNA; cancer therapy; siRNA conjugates

DOI:  https://doi.org/10.1016/j.jconrel.2022.09.040
Oncol Lett. 2022 Oct;24(4): 358

Current progress in CAR-T cell therapy for tumor treatment.

Lei Chen, Ting Xie, Bing Wei, Da-Lin Di.

  Chimeric antigen receptor T (CAR-T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR-T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR-T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR-T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR-T cell therapy mainly focuses on improving CAR-T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR-T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR-T cell technology to provide a reference for clinical practice and research on tumor treatment.

Keywords:  adverse reactions; chimeric antigen receptor T cells; overcoming strategies; tumor treatment

DOI:  https://doi.org/10.3892/ol.2022.13478
Life Sci. 2022 Sep 27. pii: S0024-3205(22)00716-0. [Epub ahead of print] 121016

Recent advances in the production, reprogramming, and application of CAR-T cells for treating hematological malignancies.

Somayeh Vandghanooni, Morteza Eskandani, Zohreh Sanaat, Yadollah Omidi.

  As genetically engineered cells, chimeric antigen receptor (CAR)-T cells express specific receptors on their surface to target and eliminate malignant cells. CAR proteins are equipped with elements that enhance the activity and survival of T cells. Once injected, CAR-T cells act as a "living drug" against tumor cells in the body. Up to now, CAR-T cell therapy has been demonstrated as a robust adoptive cell transfer (ACT) immunotherapeutic modality for eliminating tumor cells in refractory hematological malignancies. CAR-T cell therapy modality involves several steps, including the collecting of the blood from patients, the isolation of peripheral blood mononuclear cells (PBMCs), the enrichment of CD4+/CD8+ T cell, the genetic reprogramming, the expansion of modified T cells, and the injection of genetically engineered T cells. The production of CAR-T cells is a multi-step procedure, which needs precise and safety management systems, including good manufacturing practice (GMP), and in-line quality control and assurance. The current study describes the structure of CARs and concentrates on the next generations of CARs that are engaged in enhancing the anti-tumor responses and safety of the engineered T cells. This paper also highlights the important concerns in quality control and nonclinical research of CAR-T cells, as well as general insights into the manufacture, reprogramming, and application of CAR-T cells based on new and enhanced techniques for treating hematological malignancies. Besides, the application of the CRISPR-Cas9 genome editing technology and nanocarrier-based delivery systems containing CAR coding sequences to overcome the limitations of CAR-T cell therapy has also been explained.

Keywords:  CAR-T cell therapy; Chimeric antigen receptors; Hematological malignancies; Living medicines; Production steps

DOI:  https://doi.org/10.1016/j.lfs.2022.121016
Front Oncol. 2022 ;12 948513

Targeted and cellular therapies in lymphoma: Mechanisms of escape and innovative strategies.

Anagha Deshpande, Javier Munoz.

  The therapeutic landscape for lymphomas is quite diverse and includes active surveillance, chemotherapy, immunotherapy, radiation therapy, and even stem cell transplant. Advances in the field have led to the development of targeted therapies, agents that specifically act against a specific component within the critical molecular pathway involved in tumorigenesis. There are currently numerous targeted therapies that are currently Food and Drug Administration (FDA) approved to treat certain lymphoproliferative disorders. Of many, some of the targeted agents include rituximab, brentuximab vedotin, polatuzumab vedotin, nivolumab, pembrolizumab, mogamulizumab, vemurafenib, crizotinib, ibrutinib, cerdulatinib, idelalisib, copanlisib, venetoclax, tazemetostat, and chimeric antigen receptor (CAR) T-cells. Although these agents have shown strong efficacy in treating lymphoproliferative disorders, the complex biology of the tumors have allowed for the malignant cells to develop various mechanisms of resistance to the targeted therapies. Some of the mechanisms of resistance include downregulation of the target, antigen escape, increased PD-L1 expression and T-cell exhaustion, mutations altering the signaling pathway, and agent binding site mutations. In this manuscript, we discuss and highlight the mechanism of action of the above listed agents as well as the different mechanisms of resistance to these agents as seen in lymphoproliferative disorders.

Keywords:  CAR T-cells; cerdulatinib; lymphoma; mechanism of action; resistance; targeted therapy; tazemetostat

DOI:  https://doi.org/10.3389/fonc.2022.948513
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Apr 25. 51(2): 175-184

Advances in CAR-T cell therapy for malignant solid tumors.

Jiao Liu, Xiaoxuan Tu, Lulu Liu, Weijia Fang.

  T cells modified by chimeric antigen receptor (CAR) have the advantage of major histocompatibility complex-independent recognition of tumor-associated antigens, so can achieve efficient response to tumor targets. Chimeric antigen receptor (CAR) T cell therapy has shown a good therapeutic effect in hematological malignancies; however, its efficacy is generally not satisfactory for solid tumors. The reasons include the lack of tumor specific antigen target on solid tumors, the uncertainty of homing ability of engineered T cells and the inhibitory immune microenvironment of tumors. In clinical trials, the targets of CAR-T cell therapy for solid tumors are mainly disialoganglioside (GD2), claudin-18 isoform 2 (CLDN18.2), mesenchymal, B7 homolog 3 (B7H3), glypican (GPC) 3 and epidermal growth factor receptor variant Ш (EGFRvШ)Ⅲ. Combination of CAR-T cells with oncolytic viruses, tyrosine kinase inhibitors, and programmed death ligand-1 monoclonal antibodies may increase its efficacy. The CAR-T cell therapy for solid tumors can be optimized through gene editing to enhance the activity of CAR-T cells, adding corresponding regulatory components to make the activation of CAR-T cells safer and more controllable, and enhancing the persistence of CAR-T cells. In this article, we review the latest advances of CAR-T cell therapy in solid tumors to provide new insights for clinical application.

Keywords:  Chimeric antigen receptor T cell; Clinical trials; Immunotherapy; Malignant solid tumors; Review

DOI:  https://doi.org/10.3724/zdxbyxb-2022-0044
Theranostics. 2022 ;12(14): 6273-6290

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy.

Zaoqu Liu, Zhaokai Zhou, Qin Dang, Hui Xu, Jinxiang Lv, Huanyun Li, Xinwei Han.

  Chimeric antigen receptor (CAR)-T cell therapy represents a landmark advance in personalized cancer treatment. CAR-T strategy generally engineers T cells from a specific patient with a new antigen-specificity, which has achieved considerable success in hematological malignancies, but scarce benefits in solid tumors. Recent studies have demonstrated that tumor immune microenvironment (TIME) cast a profound impact on the immunotherapeutic response. The immunosuppressive landscape of TIME is a critical obstacle to the effector activity of CAR-T cells. Nevertheless, every cloud has a silver lining. The immunosuppressive components also shed new inspiration on reshaping a friendly TIME by targeting them with engineered CARs. Herein, we summarize recent advances in disincentives of TIME and discuss approaches and technologies to enhance CAR-T cell efficacy via addressing current hindrances. Simultaneously, we firmly believe that by parsing the immunosuppressive components of TIME, rationally manipulating the complex interactions of immunosuppressive components, and optimizing CAR-T cell therapy for each patient, the CAR-T cell immunotherapy responsiveness for solid malignancies will be substantially enhanced, and novel therapeutic targets will be revealed.

Keywords:  Tumor immune microenvironment; chimeric antigen receptor T cell; immunosuppression network; immunotherapy; solid tumors

DOI:  https://doi.org/10.7150/thno.76854
Front Immunol. 2022 ;13 932559

Ligand-based CAR-T cell: Different strategies to drive T cells in future new treatments.

Alejandro Ramírez-Chacón, Sergi Betriu-Méndez, Ariadna Bartoló-Ibars, Azucena González, Mercè Martí, Manel Juan.

  Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific evidence of the limitations of these therapies mainly due to immunogenicity issues, toxicities associated with the infusion of the product, and relapses of the tumor. As a result, novel approaches are appearing aiming to solve and/or mitigate the harmful effects of CAR-T therapies. These include strategies based on the use of ligands as binding moieties or ligand-based CAR-T cells. Several proposals are currently under development, with some undergoing clinical trials to assess their potential benefits. In addition to these, therapies such as chimeric autoantibody receptor (CAAR), B-cell receptor antigen for reverse targeting (BAR), and even chimeric human leukocyte antigen (HLA) antibody receptor (CHAR) have emerged, benefiting from the advantages of antigenic ligands as antibody-binding motifs. This review focuses on the potential role that ligands can play in current and future antitumor treatments and in other types of diseases, such as autoimmune diseases or problems associated with transplantation.

Keywords:  BAR; CAAR; T cells; antigen; chimeric antigen receptor (CAR); ligands; receptor

DOI:  https://doi.org/10.3389/fimmu.2022.932559
Front Immunol. 2022 ;13 964442

The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers.

Qing Tang, Yun Chen, Xiaojuan Li, Shunqin Long, Yao Shi, Yaya Yu, Wanyin Wu, Ling Han, Sumei Wang.

  Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.

Keywords:  PD-1/PD-L1; biomarker; clinical application; human cancers; immunecheckpoint inhibitor

DOI:  https://doi.org/10.3389/fimmu.2022.964442
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Apr 25. 51(2): 185-191

Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy.

Baixin Ye, Yongxian Hu, Mingming Zhang, He Huang.

  Chimeric antigen receptor (CAR) T cell therapy has shown significant efficacy for hematological malignancies, however, it needs to be further optimized. Recently, the lipid nanoparticle (LNP)-mRNA delivery system as a nonviral gene transfer vector has gained rapid progress in CAR-T cell therapy. The claudin-6 (CLDN6) mRNA is delivered to antigen presenting cells (APCs) through LNP system, thereby enhancing the function of CLDN6 CAR-T cells for the clearance of solid tumor cells. For treatment of acute cardiac injury, the fibroblast activation protein (FAP) CAR mRNA can be delivered to T cells through LNP system for the in vivo production of FAP CAR-T cells, thereby blocking the process of myocardial fibrosis. The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques. This article reviews the research advance in LNP-mRNA in vivo delivery system and its application in CAR-T cell therapy.

Keywords:  Chimeric antigen receptor T cell; Gene transfer vector; Lipid nanoparticle; Messenger RNA; Review; delivery system

DOI:  https://doi.org/10.3724/zdxbyxb-2022-0047
Curr Opin HIV AIDS. 2022 Nov 01. 17(6): 333-337

HIV T-cell immunogen design and delivery.

Christian Brander, Dennis Hartigan-O'Connor.

PURPOSE OF THE REVIEW: Not all T-cell responses against HIV are created equally and responses of certain epitope specificities have been associated with superior control of infection. These insights have spurred the development of a wide range of immunogen sequences, each with particular advantages and limitations.
RECENT FINDINGS: We review some of the most advanced designs that have reached or are close to reaching human clinical trials, with a special focus on T-cell immunogen developed for therapeutic use. We also touch upon the importance of how immunogens are delivered and point out the lamentable fact that there is essentially no alignment between different designs and vaccine regimens, which is a major hindrance to accelerated advances in the field.
SUMMARY: The design of an immunogen able to induce T-cell responses of adequate specificity and functionality is subject of a wide range of preclinical and clinical studies. Few designs have shown promise to date, but emerging data highlight the critical contribution of specificity to effective antiviral activity in vivo .

DOI: https://doi.org/10.1097/COH.0000000000000765