Professor Zhang Xi: How to combine CAR-T cell therapy with clinical needs

Professor Zhang Xi, director of the Hematology Medical Center of Xinqiao Hospital of Army Military Medical University and director of the Chinese People's Liberation Army Hematology Center, gave a wonderful sharing on "How CAR-T can be integrated with clinical needs" at the 2021 Leukemia and Lymphoma Summit Forum.

The editor is organized as follows for readers.

In recent years, Chimeric Antigen Receptor (CAR) T cell therapy has had significant effects in the treatment of acute leukemia and non-Hodgkin’s lymphoma, and is considered to be one of the most promising tumor treatments, especially CD19-CAR -CAR-T technology represented by T cells brings new hope for the treatment and survival of relapsed and refractory acute B-lymphocytic leukemia (B-ALL).

However, how to expand the indications of CAR-T cell therapy, obtain better safety, and organically combine CAR-T cell therapy with existing clinical methods to better meet clinical needs is still a problem that needs to be further explored.

In addition, the current CAR-T treatment research and development model is basically the development of new CAR-T products by biological companies, which are registered by clinicians to carry out clinical research.

Therefore, how to balance the needs of the development company and the clinic and better serve the clinic is also an urgent problem to be solved.

Professor Zhang Xi took the team's development history of CAR-T cell research and development in recent years as an example, and vividly demonstrated their efforts in combining CAR-T with clinical needs.

Professor Zhang Xi’s team started CAR-T research and development 3 years ago, and discussed clinical needs with biological companies.
The design not only meets clinical needs, guarantees safety, reduces risk values, but also takes into account the company’s products.
The final research content is locked in CD19.
Fast-CAR-T cell treatment of B-ALL and CD7 CAR-T cell treatment of refractory and relapsed acute T-lymphocytic leukemia (T-ALL).

After the R&D direction was determined, the clinical situation was focused on to prepare for technological innovation.

"Can it be faster?" In our country, patients usually start to seek CAR-T treatment after repeated relapses in the later stage of treatment.
At this time, patients are often in a state of low immunity and high tumor burden after the previous multi-line treatment.
Losing the best time for treatment, and receiving CAR-T cell therapy at this time is not safe, so it is more "fast" to buy time for the patient.

Through the unremitting efforts of the team, the preparation process of CAR-T cells has been continuously optimized, reducing the time from blood collection to infusion to 8 days from the previous 3-4 weeks, of which the preparation time is only 1 day.

By mutating in vitro expansion into in vivo expansion, it not only shortens the preparation time, but also surprises everyone that the expansion ability of Fast-CAR-T cells in vivo is stronger than in vitro, and it has a longer duration and stronger Lethality.

The study enrolled 26 patients with B-ALL who were treated with CD19 Fast-CAR-T cells.
Among them, 23 were evaluable.
The CR rate reached 100% at 28 days after enrollment.
However, there was a higher cytokine release syndrome (CRS).
) Incidence rate (92.
31%).
Early intervention treatments such as tocilizumab and hormones have effectively reduced the incidence of CRS.

"Can you just use it?" At that time, there were still many obstacles to be broken in the application of universal CAR-T cells.

On the one hand, you can choose to find general-purpose CAR-T cells with low immunogenicity.
This general-purpose CAR-T cell enters the body and is not easily destroyed by the patient's immune system, so that it can survive longer.
However, the total amount of cells is very high.
It is difficult to reach a therapeutic amount; on the other hand, genetic modification can be used to knock out the identified genes.

After repeated deliberation, the team finally chose the second idea, through genetic modification, using CD7 universal CAR-T cells to treat refractory and relapsed T-ALL.

In the initial preliminary test, after the patient was infused with CD7 universal CAR-T cells, no universal CAR-T cells were found to survive in the body.

So is there a problem with the pre-processing program? Combining the experience in transplantation, the team innovatively proposed the use of autologous transplantation pretreatment program.
In this way, in the first batch of 5 patients, not only the general-purpose CAR-T cells survived well in the body, but also the results It was shown that the rate of MRD-negative CR reached 80% (4/5) after 1 month of enrollment, but higher cytotoxicity followed.
After realizing this problem, the team negotiated with the biological company many times and continuously improved To improve, the second-generation CD7 universal CAR-T cells currently developed are about to enter the clinical research stage.
It is expected that while ensuring the efficacy, the toxic and side effects will be minimized.

How to combine CAR-T with existing clinical methods? Professor Zhang mainly introduced the combination of CAR-T and hematopoietic stem cell transplantation.

CAR-T therapy before transplantation is still controversial at home and abroad, and the combination of CAR-T therapy during and after transplantation is still a current research hotspot.

Professor Zhang shared a case of transplantation combined with CAR-T in the treatment of B-ALL patients, a 12-year-old girl failed after multi-line treatment, malignant cells still proliferate rapidly after chemotherapy, try autologous CAR-T treatment, due to tumor burden Gao was unable to collect enough T cells, and finally used transplantation combined with allogeneic CAR-T treatment, and CR was achieved after the operation, and there has been no recurrence so far.
Therefore, combined CAR-T treatment in transplantation can be considered for patients with extensive drug resistance.

In terms of combined CAR-T treatment after transplantation, Professor Zhang shared a national multi-center retrospective study of donor CAR-T treatment of relapsed B-ALL after transplantation.
The results showed that CR reached 79.
07%, and the incidence of GVHD was only 2%, but Recurrence reached 43% after 1 year, and the incidence of CRS reached 88%.
Further research and improvement are still needed.

Comparing multiple clinical studies on recurrence after transplantation, it is found that the combined CAR-T treatment after transplantation is basically the same as the second transplantation, and it is far superior to donor lymphocyte infusion (DLI) treatment.

In addition, for patients with a high recurrence rate after transplantation, preventive infusion of CAR-T cells after transplantation is also a future research direction.

Combining CAR-T therapy with clinical needs to benefit more patients is still the direction of the hematological oncology community.
We look forward to more breakthroughs and advances in CAR-T therapy in the future. Professor Zhang Xi, Chief Physician, Doctor (Post) Supervisor, Director of the Hematology Medical Center, Xinqiao Hospital, Army Military Medical University, Changjiang Scholar Distinguished Professor, Standing Committee Member of the Chinese Medical Association Hematology Branch, Standing Committee Member of the Chinese Medical Association Hematology Branch, Chinese Anti-Cancer Association Hematology Oncology Specialty Standing Committee Member of the Chinese Medical Association Hematopoietic Stem Cell Application Group, Deputy Leader of the Hematopoietic Stem Cell Application Group, stamp "read the original", we will make progress together