bims-limsir 2022-10-09 papers

Nat Commun. 2022 Oct 03. 13(1): 5802

Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models.

Faith Conroy, Rachael Miller, Julia F Alterman, Matthew R Hassler, Dimas Echeverria, Bruno M D C Godinho, Emily G Knox, Ellen Sapp, Jaquelyn Sousa, Ken Yamada, Farah Mahmood, Adel Boudi, Kimberly Kegel-Gleason, Marian DiFiglia, Neil Aronin, Anastasia Khvorova, Edith L Pfister.

Small interfering RNAs are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing of gene expression in vivo. We recently demonstrated that siRNA chemical architectures can be optimized to provide efficient delivery to the CNS, enabling development of CNS-targeted therapeutics. Many genetically-defined neurodegenerative disorders are dominant, favoring selective silencing of the mutant allele. In some cases, successfully targeting the mutant allele requires targeting single nucleotide polymorphism (SNP) heterozygosities. Here, we use Huntington's disease (HD) as a model. The optimized compound exhibits selective silencing of mutant huntingtin protein in patient-derived cells and throughout the HD mouse brain, demonstrating SNP-based allele-specific RNAi silencing of gene expression in vivo in the CNS. Targeting a disease-causing allele using RNAi-based therapies could be helpful in a range of dominant CNS disorders where maintaining wild-type expression is essential.

DOI: https://doi.org/10.1038/s41467-022-33061-x

Int Rev Immunol. 2022 Oct 03. 1-19

Clinical utility of CAR T cell therapy in brain tumors: Lessons learned from the past, current evidence and the future stakes.

Abhishek Chatterjee, Sweety Asija, Sandhya Yadav, Rahul Purwar, Jayant S Goda.

The unprecedented clinical success of Chimeric Antigen Receptor (CAR) T cell therapy in hematological malignancies has led researchers to study its role in solid tumors. Although, its utility in solid tumors especially in neuroblastoma has begun to emerge, preclinical studies of its efficacy in other solid tumors like osteosarcomas or gliomas has caught the attention of oncologist to be tried in clinical trials. Malignant high-grade brain tumors like glioblastomas or midline gliomas in children represent some of the most difficult malignancies to be managed with conventionally available therapeutics, while relapsed gliomas continue to have the most dismal prognosis due to limited therapeutic options. Innovative therapies such as CAR T cells could give an additional leverage to the treating oncologists by potentially improving outcomes and ameliorating the toxicity of the currently available therapies. Moreover, CAR T cell therapy has the potential to be integrated into the therapeutic paradigm for aggressive gliomas in the near future. In this review we discuss the challenges in using CAR T cell therapy in brain tumors, enumerate the completed and ongoing clinical trials of different types of CAR T cell therapy for different brain tumors with special emphasis on glioblastoma and also discuss the future role of CAR T cells in Brain tumors.

Keywords: Brain tumors; CAR T therapy; challenges; clinical trials; opportunities

DOI: https://doi.org/10.1080/08830185.2022.2125963

Cancer Treat Res Commun. 2022 Sep 22. pii: S2468-2942(22)00129-0. [Epub ahead of print] 100638

Universal chimeric antigen receptor T cell therapy - The future of cell therapy: A review providing clinical evidence.

Wenxuan Sun, Zehui Jiang, Wen Jiang, Rui Yang.

Autologous CAR-T therapy has shown promising outcomes in the treatment of tumors, particularly hematological malignancies over the past years. However, the application of autologous CAR-T therapy is limited, due to undesirable patient and/or peripheral blood characteristics, the high cost and long time period of manufacturing, and other challenges. Universal CAR-T therapy could overcome major limitations of autologous CAR-T therapy. In this review, we described the research and development status of universal CAR-T therapy for hematological malignancies. In addition, we also summarized the challenges had been encountered and the current solutions.

Keywords: Allogeneic CAR-T; B-ALL; Hematological malignancies; Immunotherapy; Universal chimeric antigen receptor T cell therapy

DOI: https://doi.org/10.1016/j.ctarc.2022.100638

Front Immunol. 2022 ;13 1016208

New insights into CAR T cell-mediated killing of tumor cells.

David Espie, Emmanuel Donnadieu.

Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, CAR T-cell efficacy has been very limited in most solid tumors. In this context, it is of paramount importance to understand the determinants that condition CAR T-cell success versus failure. To control tumor growth, CAR T cells need to form conjugates with their targets via the assembly of an immunological synapse. Here, we review recent advances showing that the adhesion between CAR T cells and cancer cells from solid tumors strengthens over time in an IFNγ- and ICAM-1-dependent manner, resulting in CAR T cell-mediated killing. We discuss how these findings can be exploited to increase the efficacy of the CAR T-cell strategy against solid tumors.

Keywords: CAR (chimeric antigen receptor) T cells; adhesion; cytotoxicity; immune synapse; interferon gama (IFNγ); tumor cell

DOI: https://doi.org/10.3389/fimmu.2022.1016208