A Brief Introduction of CD19 CAR-T Therapy

The CD19 chimeric antigen receptors (CARs) are fusion proteins expressed on the surface of T
cells by gene recombination technology, which combines a hinge region, a transmembrane
domain, and one or more intracellular T cells that will specifically recognize the single-chain
variable region and the extracellular domain of antibodies of CD19 by stimulating or co-
stimulatory molecules. The first generation of CARs includes only one T cell stimulatory
molecule (usually CD3), and the second or third generation CARs usually have one or more
costimulatory molecules (eg, 4-1BB, CD28) in addition to CD3.

When the gene sequences constituting the CARs molecule are transferred into T cells by genetic
modification, the expression of CD19 CARs in T cells alters the specificity of the T cells to
directly act on the target cells expressing CD19. Normally, CD19 CAR-T cells are delivered to
patients after chemotherapeutic treatment with lymphocytic clearance in vivo, and the clinical
effect of CD19-positive tumor cell lysis occurs when CAR-T cells are accumulated in large
amounts in vivo for 2-3 weeks. This treatment may cause the patient to develop cytokine release
syndrome (CRS). The main clinical manifestations of CRS include fever, hypotension, capillary
exudation, coagulopathy, organ failure, and neurotoxicity. The main cause of CRS is the increase
in serum cytokine concentrations such as IL-6 and gamma interferon. Cellular immunotherapy of
CD19 CAR-T has shown very promising results in relapsed B-cell acute lymphoblastic leukemia
and has also shown encouraging results in the treatment of B-cell non-Hodgkin lymphoma and
chronic lymphocytic leukemia.

Although CD19 CAR T immunotherapy is still immature, many research centers have begun to
accumulate and report on the important experience of CAR-T cells in the treatment of B-cell
malignancies related to production and effective delivery of CAR-T cells. We hope to find out the
main influencing factors affecting the outcome of CAR-T cell immunotherapy by comparing
different clinical trial data. It should be noted that the production strategy including the separation
and stimulation of T cells, the design of CAR structures, the transduction of CAR T gene, and the
composition of cells and the number of amplifications to be prepared for input into patients are all
different in different research centers. Because many production details receive patent protection,
this also leads to certain difficulties in conducting comparative studies on different studies. In
addition, the selection of chemotherapy regimens for lymphocyte depletion, the input dose of
CAR-T cells and the time of entry, post-treatment assessment, and methods for re-segmentation
were used in different trials because of the subject's and admission criteria. Although the relevant
experimental data and the results of the analysis of clinical trial results have emerged and have
guided the development of this field, we still need to carefully analyze the differences when
comparing different clinical studies of different CAR-T cell products.

Numerous preclinical studies of CAR-T cell therapy have demonstrated that the design of CAR T
cell structure, the selection of single-chain variable domains, the length and composition of
extracellular hinge regions, and the selection of intracellular co-stimulatory molecular sequences
as a model system for CAR produce a very important influence on the clinical effect of CAR T.
Current relevant clinical trials have shown that CAR-T containing a CD28 or 4-1BB co-
stimulatory molecular structure is more efficient than CAR-T alone with a CD3ζ T cell activating
structure. Compared to two CAR-T cell therapy clinical trials with CD28 CAR structure, two
CAR-T cells containing a 4-1BB CAR structure showed more advantages in a complete remission
rate negative for minimal residual disease and the extension of CAR-T cell survival period.
However, these tests differ in the cost of the co-stimulatory molecules, the differences between
antibody single-chain variable regions, the hinge region and the transmembrane domain, the
production of CAR-T cells, clinical entry criteria, lymphocyte clearance protocols, treatment
procedures, and the different choices of post-relapse treatment all present a certain degree of
difficulty in summarizing the optimal choice of CAR-T cell therapy. Test data in NHL patients
indicate that there is no significant difference in the treatment effect of CD28 or 4-1BB.

Obviously, in addition to the production and delivery of CAR-T cells, various factors such as co-
stimulatory molecules or inhibitory molecules on the surface of tumor cells will affect their
therapeutic outcome, and thus the choice of costimulatory molecules will be different in different
clinical contexts.

Author Bio
As a global company, Creative Biolabs has more than 200 talented and well-trained scientists
located in different continents working closely with partners from the entire world to develop and
produce medicines of tomorrow. Specifically, we are the established leading expert in TCR and
CAR T&NK cell immune therapy development, as we offer the one-stop custom services that
cover the entire new drug development pipeline. Additionally, we also offer an exclusive line of
ready-to-use TCR and CAR T&NK cell construction products, such as virus packaging,
purification, expansion and titer determination kits. Furthermore, we have built up a unique
unparalleled CAR construction and production platform for all four CAR generations.