The landscape of CAR T-cell therapy in the United States and China: A comparative analysis.

The clinical trials of CAR T-cell therapy are growing fast in recent years, and most of the trials are initiated by sponsors from the United States and China. Exhibiting the distinctions between the clinical trials in the two countries is of great value for understanding the panorama of CAR T-cell clinical trials and forecasting the future of this promising therapy. We analyzed the critical elements of 289 clinical trials posted on the clinicaltrials.gov website by sponsors from the two countries and evaluated the efficacy data in available 50 published CAR T-cell studies. Our analysis shows that China has become the country with the largest number of CAR-T cell clinical trials by the end of 2017, while overall subject sample size and study center numbers are still larger, and the design of the clinical trials is more cautious in the United States. There are obvious differences between the two countries in CAR-targeted antigens in solid tumors and genetic modifications besides CARs for enhancing the potency of CAR T-cells. Although the currently available response rates are promising in both countries, it is inexpedient to conclude that the clinical efficacy is comparable between the two countries considering the smaller patient sample sizes and discrete distribution of median cell doses in China. And finally, the flexible regulatory regime of cell therapy in China, which expedites the bursting of CAR T-cell therapy, is also firstly introduced in our study.

Banxia Xiexin Decoction Alleviated Cerebral Glucose Metabolism Disorder by Regulating Intestinal Microbiota in APP/PS1 Mice.

OBJECTIVE: To identify whether Banxia Xiexin Decoction (BXD) alleviates cerebral glucose metabolism disorder by intestinal microbiota regulation in APP/PS1 mice. METHODS: Forty-five 3-month-old male APP/PS1 mice were divided into 3 groups using a random number table (n=15 per group), including a model group (MG), a liraglutide group (LG) and a BXD group (BG). Fifteen 3-month-old male C57BL/6J wild-type mice were used as the control group (CG). Mice in the BG were administered BXD granules by gavage at a dose of 6 g/(kg•d) for 3 months, while mice in the LG were injected intraperitoneally once daily with Liraglutide Injection (25 nmol/kg) for 3 months. Firstly, liquid chromatography with tandem-mass spectrometry was used to analyze the active components of BXD granules and the medicated serum of BXD. Then, the cognitive deficits, Aß pathological change and synaptic plasticity markers, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), were measured in APP/PS1 mice. Brain glucose uptake was detected by micropositron emission tomography. Intestinal microbial constituents were detected by 16S rRNA sequencing. The levels of intestinal glucagon-like peptide 1 (GLP-1) and cerebral GLP-1 receptor (GLP-1R), as well as the phosphoinositide-3-kinase/protein kinase B/glycogen synthase kinase-3ß (PI3K/Akt/GSK3ß) insulin signaling pathway were determined by immunohistochemical (IHC) staining and Western blot analysis, respectively. RESULTS: BXD ameliorated cognitive deficits and Aß pathological features (P<0.01). The expressions of SYP and PSD95 in the BG were higher than those in the MG (P<0.01). Brain glucose uptake in the BG was higher than that in the MG (P<0.01). The intestinal microbial composition in the BG was partially reversed. The levels of intestinal GLP-1 in the BG were higher than those in the MG (P<0.01). Compared with the MG, the expression levels of hippocampal GLP-1R, Akt, PI3K and p-PI3K in the BG were significantly increased (P<0.01), while the levels of GSK3ß were reduced (P<0.01). CONCLUSION: BXD exhibited protective effects against Alzheimer's disease by regulating the gut microbiota/GLP-1/GLP-1R, enhancing PI3K/Akt/GSK3ß insulin signaling pathway, and improving brain glucose metabolism.

Development and regulation of stem cell-based therapies in China.

BACKGROUND: Clinical researches of stem cell-based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies. METHODS: This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell-based products, as well as the clinical review concerns of stem cell-based products in China. MAIN FINDINGS: The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued "Administrative Measures on Stem Cell Clinical Research" (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell-based products are supervised by Drug Administration Law (DAL). CONCLUSION: The regulatory framework of stem cell-based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well-designed and patient-focused clinical trial is required for commercially developed stem cell-based products, and definite clinical benefit evidence is crucial to obtain marketing authorization.

Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro.

BACKGROUND: Shen-Zhi-Ling oral liquid (SZL) is an herbal formula known for its efficacy of nourishing "heart and spleen", and is used for the treatment and prevention of middle- and early-stage dementia. This study investigated the effects of SZL on amelioration of AD, and examined whether the underlying mechanisms from the perspective of neuroprotection are related to brain glucose metabolism. METHODS: Firstly, LC-MS/MS was used to analysis the SZL mainly enters the blood component. Then, the effects of SZL on cognitive and behavioral ability of APP/PS1 double transgenic mice and amyloid protein characteristic pathological changes were investigated by behavioral study and morphological observation. The effects of SZL on the ultrastructure of mitochondria, astrocytes, and micrangium related to cerebral glucose metabolism were observed using transmission electron microscopy. Then, micro-PET was also used to observe the effects of SZL on glucose uptake. Furthermore, the effects of SZL on insulin signaling pathway InR/PI3K/Akt and glucose transporters (GLUT1 and GLUT3) were observed by immunohistochemistry, Western-blot and RT-qPCR. Finally, the effects of SZL on brain glucose metabolism and key enzyme were observed. In vitro, the use of PI3K and/or GSK3ß inhibitor to observe the effects of SZL drug-containing serum on GLUT1 and GLUT3. RESULTS: In vivo, SZL could significantly ameliorate cognitive deficits, retarded the pathological damage, including neuronal degeneration, Aß peptide aggregation, and ultrastructural damage of hippocampal neurons, improve the glucose uptake, transporters and glucolysis. Beyond that, SZL regulates the insulin signal transduction pathway the insulin signal transduction pathway InR/PI3K/Akt. Furthermore, 15% SZL drug-containing serum increased Aß42-induced insulin signal transduction-pathway related indicators and GLUT1 and GLUT3 expression in SH-SY5Y cells. The improvement of GLUT1 and GLUT3 in the downstream PI3K/Akt/GSK3ß signaling pathway was reversed by the use of PI3K and/or GSK3ß inhibitor. CONCLUSIONS: In summary, our results demonstrated that improving glucose uptake, transport, and glycolysis in the brain may underlie the neuroprotective effects of SZL, and its potential molecular mechanism may be related to regulate the insulin signal transduction pathway.

Considerations for Clinical Review of Cellular Therapy Products: Perspectives of the China Food and Drug Administration Center for Drug Evaluation.

With increasing numbers of technical developments and clinical studies, pioneering cellular/gene therapies are now available that could cure life-threatening disease. Cellular/gene therapy products are broad-ranging and complicated, and thereby bring challenges for clinical review by regulatory agencies. This review discusses principles for the clinical review of cellular therapy products, including protection of clinical trial populations, pharmacodynamics, pharmacokinetics, dose evaluation, clinical efficacy, clinical safety, and risk-management plans. Based on these principles, key points in the clinical review of chimeric antigen receptor T-cell therapy are also discussed.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.

Severalconsiderationsontherelatedissuesofclinicaltrialdesignofchimericantigen receptorT lymphocytes in the treatment of lymphohematopoietic malignancies / 中国肿瘤生物治疗杂志

@# Chimeric antigen receptor (CAR) T lymphocyte has shown attractive prospects in the treatment of lymphohematopoietic malignancies including B-cell lymphoblastic leukemia, B-cell lymphoma and multiple myeloma. Many applicants have submitted investigational new drug (IND) applications to Center for Drug Evaluation of National Medical Products Ggency, however, many of the INDs have problems in patient selection, prognostic indicators and risk management, etc, which might hinder the evaluation of the safety and efficacy of CAR-T cells. Thus, we made some suggestions on the above-mentioned problems through summarizing clinical experience and communicating with domestic clinical experts, which the sponsors and researchers can refer to when conducting CAR-T cell clinical trials for registration.