bims-limsir 2022-08-28 papers

BioDrugs. 2022 Aug 23.

Therapeutic siRNA: State-of-the-Art and Future Perspectives.

The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.

DOI: https://doi.org/10.1007/s40259-022-00549-3

Biomedicines. 2022 Aug 12. pii: 1960. [Epub ahead of print]10(8):

CAR T-Based Therapies in Lymphoma: A Review of Current Practice and Perspectives.

Semira Sheikh, Denis Migliorini, Noémie Lang.

While more than half of non-Hodgkin lymphomas (NHL) can be cured with modern frontline chemoimmunotherapy regimens, outcomes of relapsed and/or refractory (r/r) disease in subsequent lines remain poor, particularly if considered ineligible for hematopoietic stem cell transplantation. Hence, r/r NHLs represent a population with a high unmet medical need. This therapeutic gap has been partially filled by adoptive immunotherapy. CD19-directed autologous chimeric antigen receptor (auto-CAR) T cells have been transformative in the treatment of patients with r/r B cell malignancies. Remarkable response rates and prolonged remissions have been achieved in this setting, leading to regulatory approval from the U.S. Food and Drug Administration (FDA) of four CAR T cell products between 2017 and 2021. This unprecedented success has created considerable enthusiasm worldwide, and autologous CAR T cells are now being moved into earlier lines of therapy in large B cell lymphoma. Herein, we summarize the current practice and the latest progress of CD19 auto-CAR T cell therapy and the management of specific toxicities and discuss the place of allogeneic CAR T development in this setting.

Keywords: cellular therapy; chimeric antigen receptor; lymphoma

DOI: https://doi.org/10.3390/biomedicines10081960

Int Immunopharmacol. 2022 Aug 17. pii: S1567-5769(22)00506-9. [Epub ahead of print]111 109022

A review of PD-1/PD-L1 siRNA delivery systems in immune T cells and cancer cells.

Mehdi Barati, Farshad Mirzavi, Mahdi Atabaki, Bahram Bibak, Mojgan Mohammadi, Mahmoud Reza Jaafari.

OBJECTIVES: Programmed cell death 1 (PD-1) is a member of the CD28/CTLA-4 family of inhibitory immunological checkpoint receptors that's also widely produced by exhausted T lymphocytes in an immunosuppressive tumor microenvironment. PD-1 binds to programmed death ligand (PD-L1) and suppresses anti-cancer activity of T lymphocytes. We examined the current literature on how siRNA delivery systems can be used to target PD-1 and PD-L1, as well as the anti-cancer mechanisms and challenges associated with siRNA molecules. We look at studies that use program death 1 siRNA or program death 1 ligand siRNA to treat cancer. Several databases have been used for this purpose, including NCBI, Scopus, and Google Scholar.
KEY FINDINGS: This study looked at several methods for delivering siRNA to immune cells and cancer cells. According to these findings, suppressing PD-1 in T cells increases T lymphocyte activity. PD-L1 suppression in DCs improves antigen presentation and co-stimulatory signals on their surface, resulting in T cell activation. Chemotherapy resistance and cancer cell suppression of T cells are reduced when PD-L1/2 is suppressed in cancer cells.
CONCLUSION: The findings of this study indicated that several strategies for siRNA transfection to immune and cancer cells have been evaluated in recent decades, some of which effectively transfect siRNA to target cells, and defined PD-1 siRNA as a promising strategy for cancer treatment.

Keywords: Cancer cells; Immune cells; Program death 1; Small interfering RNA

DOI: https://doi.org/10.1016/j.intimp.2022.109022

Oncoimmunology. 2022 ;11(1): 2111904

CAR-T Engager proteins optimize anti-CD19 CAR-T cell therapies for lymphoma.

Lihe Su, Lan Wu, Roy R Lobb, Paul D Rennert, Christine Ambrose.

B cell lymphoma therapy has been transformed by CD19-targeting cellular therapeutics that induce high clinical response rates and impressive remissions in relapsed and refractory patients. However, approximately half of all patients who respond to CD19-directed cell therapy relapse, the majority within 6 months. One characteristic of relapse is loss or reduction of CD19 expression on malignant B cells. We designed a unique therapeutic to prevent and reverse relapses due to lost or reduced CD19 expression. This novel biologic, a CAR T Engager, binds CD20 and displays the CD19 extracellular domain. This approach increases the apparent CD19 antigen density on CD19-positive/CD20-positive lymphoma cells, and prevents antigen-loss induced relapse, as CD19 bound to CD20 remains present on the cell surface. We demonstrate that this novel therapeutic prevents and reverses lymphoma relapse in vitro and prevents CD19-negative lymphoma growth and relapse in vivo.

Keywords: CAR T cells; CD19; CD20; Engager protein; lymphoma; relapse

DOI: https://doi.org/10.1080/2162402X.2022.2111904