Quality Control and Nonclinical Research on CAR-T Cell Products: General Principles and Key Issues

Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products;however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products.

Nonclinical safety, tolerance and pharmacodynamics evaluation for meplazumab treating chloroquine-resistant Plasmodium falciparum

Meplazumab is an anti-CD147 humanized IgG2 antibody.The purpose of this study was to characterize the nonclinical safety,tolerance and efficacy evaluation of meplazumab treating chloroquine resistant Plasmodium falciparum.Meplazumab was well tolerated in repeat-dose toxicology studies in cynomolgus monkeys.No observed adverse effect level was 12 mg/kg.No difference between genders in the primary toxicokinetic parameters after repeat intravenous injection of meplazumab.No increased levels of drug exposure and drug accumulation were observed in different gender and dose groups.Meplazumab had a low cross-reactivity rate in various tissues and did not cause hemolysis or aggregation of red blood cells.The biodistribution and excretion results indicated that meplazumab was mainly distributed in the plasma,whole blood,and hemocytes,and excreted in the urine.Moreover,meplazumab effectively inhibited the parasites from invading erythrocytes in humanized mice in a time-dependent manner and the efficacy is superior to that of chloroquine.All these studies suggested that meplazumab is safe and well tolerated in cynomolgus monkeys,and effectively inhibits P.falciparum from invading into human red blood cells.These nonclinical data facilitated the initiation of an ongoing clinical trial of meplazumab for antimalarial therapy.

Integrating traditional Chinese (herbal) medicines into risk based regulation-With focus on non-clinical requirements to demonstrate safety

Within the public health sector of Hong Kong(China),there is a consensus around the important role of traditional Chinese medicines.For Hong Kong(China)to play a bridging role to bring Chinese medicines to the global market requires a concerted effort from the government,academic institutes and industries.The release of the final version of the European Medicines Agencies guidance document,which details the acceptance of minimum requirements to nonclinical package in bibliographical applications,grants the opportunity for well-established and traditional herbal medicines to demonstrate an‘acceptable safe’status for registration in the European Union.It is anticipated that this minimum nonclinical package can be applied to demonstrate the safe use of many traditional Chinese medicines regardless of their eligibility to be registered under the simplified procedure within the European Union.This paper conceptualizes an integration of a simplified evaluation route for eligible proprietary Chinese medicines(pCm)with long history of use into the existing drug regulatory framework in Hong Kong(China).Such integration utilizing the minimum nonclinical package,based on bibliographical data or expert report,as proof of evidence to demonstrate safety for pCm with long history of use requires less demand in scientific resources.With Hong Kong(China)conducting‘first hand’review for eligible pCm,it provides an option for overseas and local pharmaceutical companies to register their products in Hong Kong(China)without the need to rely on issuance of Certificate of Pharmaceutical Product from other countries.This could bring eligible pCm with long history of use to reach international risk-based standard and to be marketed globally as‘medicines’to reach their full therapeutic potential.An important process to positioning Hong Kong(China)to compete with other countries in promoting importation and exportation of pCm to better serve the global health.