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Last year, the FDA approved two CAR-T products to be marketed, namely Kymriah of Novartis and Yescarta of Gilead. Although both products are capable of targeting CD19, there are significant differences in their CAR design. The co-stimulation zone of Kymriah uses 4-1BB, while the co-stimulation zone of Yescarta’s CAR structure uses CD28.

There was no co-stimulation zone in the first generation of CAR design, but in the 1990s the researchers found that the first generation of CAR-T cells were very inactive and the cell survival time in the body was very short.

Around 2002, Michel Sadelain Labs attempted to insert the CD28 costimulatory region into the structure of the CAR. Almost at the same time, Dario Campana of St. Jude Children’s Research Hospital attempted to insert 4-1BB into the CAR structure, forming a second generation of CAR-T cells.

The second generation of CAR-T cells played a crucial role in the development of the CAR-T field. The two products that were listed later also used two co-stimulation zones.

The selection of antigens (targets) has been the focus of research in the CAR-T field, but there is now some evidence that, in addition to the extracellular regions of the CAR structure, the co-stimulatory regions can also be active on CAR-T cells. And the final efficacy and toxicity have a greater impact.

Company Product Target Co-stimulation zone
Novartis Kymriah CD19 4-1BB
Gilead Yescarta CD19 CD28
Celgene/Juno JCAR017 CD19 4-1BB
JCAR014 CD19 4-1BB
Celgene/Bluebird bb2121 BCMA 4-1BB
bb21217 BCMA 4-1BB
Nanjing Legend LACR-B38M BCMA/CD38 4-1BB

 

Science Signaling on Tuesday launched an article examining the differences between CAR-T cells containing two different costimulatory regions, CD28 and 4-1BB.

Although the authors were very careful in this study and did not explicitly say which co-stimulation zone is better, in vitro studies found that CAR-T cells containing the CD28 co-stimulation zone were more co-stimulated than the 4-1BB co-stimulation zone. Cells attack tumor cells faster and more intensely.

Although both types of CAR-T cells were activated by a similar signaling pathway, the phosphorylation process by mass spectrometry revealed that CD28/CD3 zeta CAR-T cells were phosphorylated faster and more strongly.

In the mouse model of lymphoma, they found that 4-1BB CAR-T cells were able to clear tumor cells more effectively. 4-1BB/CD3 zeta CAR-T cells also highly express T cell memory-related genes, allowing T cells to survive for a longer period of time to maintain their anti-tumor activity.

A more rapid mode of action of CD28 CAR-T cells may be a very important factor in causing severe cytokine release storms in patients (Yescarta and Kymriah may have this potentially fatal toxicity).

The effect of 4-1BB CAR-T cells on tumor cells is slower and longer lasting. Better than some patients will still have recurrence after treatment, the persistence of this effect may have certain advantages for the control of the patient’s recurrence.

 

However, this study only studies in vitro and animal model levels, and does not indicate that CD28 CAR-T cells are more effective and less toxic than 4-1BB CAR-T cells in humans.

In fact, in addition to the study of in vitro and animal model levels, there are some evidence related to clinical trials. A summary presented by the company at the ASCO Annual Meeting this year showed that in a clinical trial they conducted, 36 patients with B-cell-associated acute lymphoblastic leukemia were enrolled, including 18 in the CD28 and 4-1BB groups. people.

All patients receiving 4-1BB CAR-T cell therapy produced an objective response, while 15 of 17 patients receiving CD28 CAR-T cell therapy developed an objective response. Moreover, patients receiving 4-1BB CAR-T cells had more CAR-T cells in their blood than CD28 patients, suggesting that 4-1BB CAR-T may survive longer in vivo.

A cytokine release storm occurred in almost all patients, but the most severe 5 patients were in the CD28 group. Yimei Shenzhou concluded that 4-1BB CAR-T cells can show better safety and effectiveness.

However, it should be noted that the study still does not directly compare the effectiveness of Yescarta and Kymriah, and so far there has been no peer-reviewed review article to compare the advantages and disadvantages of the two products.

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