bims-limsir 2022-06-12 papers

Clin Transl Sci. 2022 Jun 08.

Recent Advances and Clinical Pharmacology Aspects of Chimeric Antigen Receptor (CAR) T-Cellular Therapy Development.

Johannes Kast, Saeideh Nozohouri, Di Zhou, Marc R Yago, Po-Wei Chen, Malidi Ahamadi, Sandeep Dutta, Vijay V Upreti.

Advances in immuno-oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno-therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non-solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno-therapies, especially CAR-T cells. Here, we summarize the current knowledge of TCR and CAR-T cell immunotherapy with particular focus on the structure of CAR-T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR-T cell therapies are described.

DOI: https://doi.org/10.1111/cts.13349

Front Immunol. 2022 ;13 886546

Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation.

Aalia N Khan, Ambalika Chowdhury, Atharva Karulkar, Ankesh Kumar Jaiswal, Ankit Banik, Sweety Asija, Rahul Purwar.

Chimeric antigen receptor T cell (CAR-T) therapy demonstrated remarkable success in long-term remission of cancers and other autoimmune diseases. Currently, six products (Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykti) are approved by the US-FDA for treatment of a few hematological malignancies. All the six products are autologous CAR-T cell therapies, where delivery of CAR, which comprises of scFv (single-chain variable fragment) derived from monoclonal antibodies for tumor target antigen recognition is through a lentiviral vector. Although available CAR-T therapies yielded impressive response rates in a large number of patients in comparison to conventional treatment strategies, there are potential challenges in the field which limit their efficacy. One of the major challenges is the induction of humoral and/or cellular immune response in patients elicited due to scFv domain of CAR construct, which is of non-human origin in majority of the commercially available products. Generation of anti-CAR antibodies may lead to the clearance of the therapeutic CAR-T cells, increasing the likelihood of tumor relapse and lower the CAR-T cells efficacy upon reinfusion. These immune responses influence CAR-T cell expansion and persistence, that might affect the overall clinical response. In this review, we will discuss the impact of immunogenicity of the CAR transgene on treatment outcomes. Finally, this review will highlight the mitigation strategies to limit the immunogenic potential of CARs and improve the therapeutic outcome.

Keywords: anti-CAR antibodies; cellular immunity; chimeric antigen receptor; immunogenicity; monoclonal antibodies; persistence; scFv

DOI: https://doi.org/10.3389/fimmu.2022.886546

J Pharmacol Exp Ther. 2022 Jun 09. pii: JPET-MR-2022-001234. [Epub ahead of print]

RNAi Based Therapeutics and Novel RNA Bioengineering Technologies.

Gavin M Traber, Ai-Ming Yu.

RNA interference (RNAi) provides researchers with a versicle means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNA) and exogenous small interfering RNAs (siRNA), converge into RNA-induced silencing complexes to achieve post-transcriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the United States Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biological activity away from their natural equivalents. Novel technologies in development today seek to utilize intact cells to yield true biological RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiological and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran), as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biological RNAi agents for research and development. Significance Statement In our review, we summarize the major concepts of RNA interreference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of FDA-approved RNAi medications and those siRNAs and miRNA-based therapeutics entered the clinical investigations. Novel approaches to producing new true biological RNAi molecules for research and development are highlighted.

Keywords: MicroRNA; RNA/siRNA; Regulation - post-transcriptional; cancer; gene regulation; gene therapy; neurodegeneration

DOI: https://doi.org/10.1124/jpet.122.001234