Analysis of CD19 CAR-T Cell Therapy Clinical Trials

Analysis of CD19 CAR-T Cell Therapy Clinical Trials
In the transduction of CARs molecular gene sequences, CAR-T, which is currently used clinically, is mainly used for
transfection of CAR T gene by retroviruses. The methods of gamma retrovirus and lentivirus are used on average. Due to the
confounding effects, there is currently no clear data indicating which transfection distribution is more advantageous. Currently,
4-1BB transfection uses a lentivirus in the clinic, and a gamma retrovirus in CD28. In addition, considering the economic
factors and ease of use, the non-viral transfection process has also received widespread attention. Some transduction
strategies such as mRNA transposon-transposon enzyme are also underway, but there is still a lack of sufficient In vitro study
data.
One of the difficulties in the optimization of the CD19 CAR-T clinical trial is the lack of homogeneity of the imported CAR-T
cells. The results of the xenogeneic model suggest that different T cell subsets in CAR-T cells have distinct effects on B-cell
lymphoma. Therefore, The initial T cell species before T cell transformation has an important influence on the therapeutic
effect of T cells, which is particularly important for patients with T cell subpopulations that constitute a highly diverse group of
B cell malignancies. Researchers at the Fred Hutchinson Cancer Research Center (FHCRC) returned to the patient by
separating CD4+ and CD8+ T cells from T cells and then composing the final therapeutic CAR-T cells in a certain proportion,
although the process was more complicated but improved. The homogeneity of the input cells simultaneously enhances the
predictability of the dose and toxicity of imported CAR-T cells and the CRS response in the eye between biomarkers.
Patients with B-ALL were treated by using CAR-T cells containing CD4-positive T cells together with central memory CD8-positive T
cells or host CD8-positive T cells. The test results showed that these two types of CAR-T cells were almost complete remissio in the
treated patients, and a similar high rate of complete remission also occurred in the CAR-T treatment group containing the host T cells
and CD4-positive T cells. In the clinical trial of CAR-T treatment after autologous peripheral blood stem cell transplantation in patients
with non-Hodgkin's lymphoma, the two groups of different therapeutic CAR-T cells were composed of central memory CD8-positive T
cells and large central Memory CD8 positive T cells. Due to the small number of trials, it is not possible to compare the differences
between the two treatment groups. More tests are required in the fashion to demonstrate whether CAR-T cells formed by different T
cell subtype ratios affect the survival time of CAR-T cells or reduce the recurrence rate.
A major challenge in cell delivery in CAR-T cell therapy is the production of sufficient CAR-T cells from patients who have
undergone lymphopenia after chemotherapy treatment. Researchers at FHCRC have found that stimulation of CARtransformed
T cells with CD19-bearing antigen-presenting cells alone can maintain the proliferation of CAR-T cells in vitro.
This finding can ensure that patients with severe lymphopenia can enter clinical trials. CAR-T cells produced by allogeneic
donors can also be applied to patients with severe lymphocytopenia, although allogeneic peripheral blood stem cell
transplantation is clinically applied as a feasible solution to patients, however, heterologous CAR-T cell transplantation is not
applicable. The role of transplant patients is not clear.
Preclinical studies have shown that limiting the differentiation of CAR-T cells during in vitro culture can improve their clinical
outcome after international reinfusion. Limiting cell differentiation may be achieved by, for example, supplementing different
cytokines (using IL-7 and IL-15 instead of IL-2) or altering the signaling pathway of the culture process. There are different
production methods for different clinical CAR-T products, such as stimulation of polyclonal T cells before reinfusion,
concentration of IL-2 during culture, or in vitro antigen stimulation to enable the input of CAR-T cells to patients. Different
differentiation states thus affect the therapeutic effect. However, specific clinical data related to the above factors do not yet
have more open information.
Finally, the choice of pre-treatment patient lymphocyte depletion strategy also affects the expansion and survival of CAR-T
cells in patients. This is mainly due to the widespread use of IL-7 and IL-15 in CAR-T cell culture before reinfusion. A clinical

study showed that patients with B-ALL who received both cyclophosphamide and fludarabine for T-cell clearance had better T
cell proliferation and survival than patients who received cyclophosphamide only. This may be caused by the fact that CD8-
positive T cells immunoreact with antigenic epitopes present in the mouse single-chain variable region, and that the same
immune response is also triggered by CD4-positive T cells. All current CD19 CARs include the CAR T scFv and fusion sites
that are immunogenic in humans. Therefore, comparison of the maintenance of CAR-T cells in different clinical trials must first
consider the lymphocyte clearance protocol. Although the addition of fludarabine increases the in vivo expansion and
maintenance of CAR-T cells, the degree of lymphocyte depletion optimization and the importance of lymphocyte depletion are
different in different patients. For patients at risk of an anti-CAR immune response, a more aggressive clearance of
lymphocytes is required, and for other patients, such as patients who have undergone myelosuppression prior to undergoing
autologous peripheral blood stem cell transplantation, due to the elimination of available antigens in vivo. Instead, it will impair
the role of CAR-T cells.
At present, the successful clinical application of CD19 CAR-T cells is based on numerous preclinical and clinical studies.
Although the differences in CAR T design development, production strategies, and clinical delivery make it difficult to compare
the results of different clinical trials, we have begun to look for some key models to guide the optimization of future CAR-T cell
immunotherapy protocols.
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 in vivo animal testing, 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.