bims-limsir 2023-10-29 papers

on Lipophilic modified siRNAs

Issue of 2023–10–29
nine papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

N-acetylgalactosamine delivery systems for RNA therapeutics:a patent perspective.
CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.
Mechanistic pharmacokinetics and pharmacodynamics of GalNAc-siRNA: Translational model involving competitive receptor-mediated disposition and RISC-dependent gene silencing applied to givosiran.
CAR T-Cells in Acute Lymphoblastic Leukemia: Current Status and Future Prospects.
Hepatocellular Carcinoma: Up-regulated Circular RNAs Which Mediate Efficacy in Preclinical In Vivo Models.
Hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors.
PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.
Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients.
Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy.

Expert Opin Ther Pat. 2023 Oct 28.

N-acetylgalactosamine delivery systems for RNA therapeutics:a patent perspective.

Hai-Long Zhang, Lansuo Wang.

   INTRODUCTION: SiRNA molecules with a feature of good gene-silencing are critical for drug discovery and development based on RNA interference. GalNAc-RNA therapeutics is a rapid growing area in RNA therapeutics.
AREAS COVERED: This article provides patent landscape and modification feature of GalNAc-RNA therapeutics. The US-granted patents from January 2004 to April 2023 were retrieved and analyzed.
EXPERT OPINION: Globally, our study is first one to holistically depict a map of modifications and therapeutic applications for GalNAc-RNA therapeutics by patent data analysis. The results showed there were 8 major modifications and 5 new emerged modifications for GalNAc-RNA therapeutic agents. Especially, the study provides recent new emerged modifications in sugar, base and internucleotide linkage of GalNAc-RNA therapeutic agents, e.g. morpholino-type ring, 5-methylcytosine, and phosphorodithioates. In addition, our study systematically demonstrated major therapeutic applications for GalNAc-RNA therapeutics, including liver or gallbladder disorders, anticancer, antihyperlipidemics, and disorders of the nervous system etc.

Keywords:  GalNAc; GalNAc-RNA; N-acetylgalactosamine; RNA; patent

DOI:  https://doi.org/10.1080/13543776.2023.2277249
Biomol Biomed. 2023 Oct 24.

CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.

Kun Chen, Min-Ling Liu, Jian-Cheng Wang, Shuo Fang.

Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.

DOI: https://doi.org/10.17305/bb.2023.9675
J Pharm Sci. 2023 Oct 21. pii: S0022-3549(23)00435-5. [Epub ahead of print]

Mechanistic pharmacokinetics and pharmacodynamics of GalNAc-siRNA: Translational model involving competitive receptor-mediated disposition and RISC-dependent gene silencing applied to givosiran.

Vivaswath S Ayyar, Dawei Song.

  Triantennary N-acetyl-D galactosamine (GalNAc)3-conjugated small interfering RNA (siRNA) have majorly advanced the development of RNA-based therapeutics. Chemically stabilized GalNAc-siRNAs exhibit extensive albeit capacity-limited (nonlinear) distribution into hepatocytes with additional complexities in intracellular liver disposition and pharmacology. A mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model of GalNAc-siRNA was developed to i) quantitate ASGPR-mediated disposition and downstream RNA-induced silencing complex (RISC)-dependent pharmacology following intravenous (IV) and subcutaneous (SC) dosing, ii) assess the kinetics of formed active metabolite, iii) leverage, as an example, published experimental data for givosiran, and iv) demonstrate PK translation across two preclinical species (rat and monkey) with subsequent prediction of human plasma PK. The structural model is based on competition between parent and formed active metabolite for occupancy and uptake via ASGPR into hepatocytes, intracellular sequestration and degradation, and downstream engagement of RNA-induced silencing complex (RISC) governing target mRNA degradation. The model jointly and accurately captured available concentration-time profiles of givosiran and/or AS(N-1)3' givosiran in rat and/or monkey plasma, liver, and/or kidney following givosiran administered both IV and SC. RISC-dependent gene silencing of ALAS1 mRNA was well-characterized. The model estimated an in vivo affinity (KD) value of 27.7 nM for GalNAc-ASGPR and weight-based allometric exponents of -0.27 and -0.24 for SC absorption and intracellular (endolysosomal) degradation rate constants. The model well-predicted reported givosiran plasma PK profiles in humans. PK simulations revealed net-shifts in liver-to-kidney distribution ratios with increasing IV and SC dose. Importantly, decreases in the relative liver uptake efficiency were demonstrated following IV and, to a lesser extent, following SC dosing explained by differential ASGPR occupancy profiles over time.

Keywords:  Clinical pharmacokinetics; Hepatocyte(s); Nonlinear pharmacokinetics; Pharmacokinetic/pharmacodynamic (PK/PD) modeling; RNA interference (RNAi); Small interfering RNA (siRNA); Targeted drug delivery; Translational pharmacokinetics

DOI:  https://doi.org/10.1016/j.xphs.2023.10.026
Biomedicines. 2023 Oct 02. pii: 2693. [Epub ahead of print]11(10):

CAR T-Cells in Acute Lymphoblastic Leukemia: Current Status and Future Prospects.

Abdulrahman H Almaeen, Mohamed Abouelkheir.

  The currently available treatment for acute lymphoblastic leukemia (ALL) is mainly dependent on the combination of chemotherapy, steroids, and allogeneic stem cell transplantation. However, refractoriness and relapse (R/R) after initial complete remission may reach up to 20% in pediatrics. This percentage may even reach 60% in adults. To overcome R/R, a new therapeutic approach was developed using what is called chimeric antigen receptor-modified (CAR) T-cell therapy. The Food and Drug Administration (FDA) in the United States has so far approved four CAR T-cells for the treatment of ALL. Using this new therapeutic strategy has shown a remarkable success in treating R/R ALL. However, the use of CAR T-cells is expensive, has many imitations, and is associated with some adverse effects. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are two common examples of these adverse effects. Moreover, R/R to CAR T-cell therapy can take place during treatment. Continuous development of this therapeutic strategy is ongoing to overcome these limitations and adverse effects. The present article overviews the use of CAR T-cell in the treatment of ALL, summarizing the results of relevant clinical trials and discussing future prospects intended to improve the efficacy of this therapeutic strategy and overcome its limitations.

Keywords:  CAR T-cells; acute lymphoblastic leukemia; cytokine release syndrome; refractoriness/relapse

DOI:  https://doi.org/10.3390/biomedicines11102693
Cancer Genomics Proteomics. 2023 Nov-Dec;20(6):20(6): 500-521

Hepatocellular Carcinoma: Up-regulated Circular RNAs Which Mediate Efficacy in Preclinical In Vivo Models.

Ulrich H Weidle, Adam Nopora.

  Hepatocellular carcinoma (HCC) ranges as number two with respect to the incidence of tumors and is associated with a dismal prognosis. The therapeutic efficacy of approved multi-tyrosine kinase inhibitors and checkpoint inhibitors is modest. Therefore, the identification of new therapeutic targets and entities is of paramount importance. We searched the literature for up-regulated circular RNAs (circRNAs) which mediate efficacy in preclinical in vivo models of HCC. Our search resulted in 14 circRNAs which up-regulate plasma membrane transmembrane receptors, while 5 circRNAs induced secreted proteins. Two circRNAs facilitated replication of Hepatitis B or C viruses. Three circRNAs up-regulated high mobility group proteins. Six circRNAs regulated components of the ubiquitin system. Seven circRNAs induced GTPases of the family of ras-associated binding proteins (RABs). Three circRNAs induced redox-related proteins, eight of them up-regulated metabolic enzymes and nine circRNAs induced signaling-related proteins. The identified circRNAs up-regulate the corresponding targets by sponging microRNAs. Identified circRNAs and their targets have to be validated by standard criteria of preclinical drug development. Identified targets can potentially be inhibited by small molecules or antibody-based moieties and circRNAs can be inhibited by small-interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) for therapeutic purposes.

Keywords:  review; shRNA; short hair-pin RNA; siRNA; small interfering RNA; target vailidation; xenograft models

DOI:  https://doi.org/10.21873/cgp.20401
Cancer Res. 2023 Oct 24.

Hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors.

Xiuxiu Zhu, Jun Chen, Wuling Li, Yanmin Xu, Juanjuan Shan, Juan Hong, Yongchun Zhao, Huailong Xu, Jiabing Ma, Junjie Shen, Cheng Qian.

Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR-T cells were in a "resting" state with low CAR expression under normoxic conditions. Compared to conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T cell exhaustion and improved T cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR-T cell efficacy and safety in solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1038
J Immunother Cancer. 2023 Oct;pii: e007585. [Epub ahead of print]11(10):

PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.

Krisztian Homicsko, Panagiota Zygoura, Maxim Norkin, Stephanie Tissot, Nicholas Shakarishvili, Sanjay Popat, Alessandra Curioni-Fontecedro, Mary O'Brien, Anthony Pope, Riyaz Shah, Patricia Fisher, James Spicer, Amy Roy, David Gilligan, Sylvie Rusakiewicz, Ekaterina Fortis, Nesa Marti, Roswitha Kammler, Stephen P Finn, Georges Coukos, Urania Dafni, Solange Peters, Rolf A Stahel.

   BACKGROUND: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better.
METHODS: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals.
RESULTS: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy.
CONCLUSION: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.

Keywords:  CD8-positive T-lymphocytes; biomarkers, tumor; immunotherapy; macrophages; programmed cell death 1 receptor

DOI:  https://doi.org/10.1136/jitc-2023-007585
BMC Cancer. 2023 Oct 23. 23(1): 1019

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients.

Yuxin Zhou, Wenjing Mu, Chen Wang, Zipeng Zhuo, Yu Xin, Hongxu Li, Changsong Wang.

   BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy, a new adoptive cell therapy, has been widely used to treat lymphoma patients. Immune checkpoint blockade may improve the cytotoxicity of CAR-T cells by reducing the failure of CAR-T cells and improving antitumor activity. It has shown promising efficacy.
METHOD: We searched PubMed, the Cochrane Library, Embase and Web of Science from January 2012 to August 2022 to find data reporting the results of CAR-T cells therapy combined with PD-1 in tumor patients. An updated search was conducted in October 2023. The partial response rate (PR), complete response rate (CR), objective response rate (ORR), mortality rate, and incidence of adverse reactions were calculated.
RESULTS: We analyzed 57 lymphoma patients from 5 clinical trials. The pooled partial, complete and overall response rates were 21% (95% CI 0.06-0.39, I2 = 0.37%), 27% (95% CI 0.03-0.60, I2 = 60.43%) and 65% (95% CI 0.23-0.98, I2 = 76.31%), respectively. The pooled incidence of cytokine release syndrome, neutropenia, fever, and fatigue was estimated to be 57% (95% CI 0.08-0.99, I2 = 85.20%), 47% (95% CI 0.14-0.81, I2 = 74.17%), 59% (95% CI 0.27-0.89, I2 = 60.23%), and 50% (95% CI 0.13-0.87, I2 = 73.89%), respectively.
CONCLUSION: CAR-T-cell therapy combined with anti-PD-1 immunotherapy in the treatment of lymphoma patients has efficacy, and the most common adverse effect is fever.
REGISTRATION: The protocol was registered in prospero, with the registration number CRD42022342647.

Keywords:  Chimeric antigen receptor T cell therapy; Efficacy; Immunotherapy; Lymphoma; Programmed cell death protein-1; Safety

DOI:  https://doi.org/10.1186/s12885-023-11536-4
J Hematol Oncol. 2023 Oct 25. 16(1): 108

Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy.

Yannick Bulliard, Borje S Andersson, Mehmet A Baysal, Jason Damiano, Apostolia M Tsimberidou.

  T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies.

Keywords:  CAR-T; Differentiation; Exhaustion; Memory; T cell

DOI:  https://doi.org/10.1186/s13045-023-01504-7