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CAR-T cell therapy is an epoch-making breakthrough technology in the field of hematological tumors in recent years, bringing hope for cure to patients with relapsed/refractory (R/R)
lymphoma.
However, CAR-T also has certain limitations – it is expensive, the treatment is risky, and not all patients can achieve long-term remission
.
On the occasion of the "7th Anti-Leukemia and Lymphoma International Summit Forum and CSCO Leukemia & Lymphoma Expert Committee Tour - Harbin Station", Yimaitong is honored to invite Professor Ying Zhitao of Peking University Cancer Hospital to be interviewed to introduce the current status of CAR-T cell therapy in lymphoma treatment, and talk about the achievements and future exploration directions
of the lymphoma department of Peking University Cancer Hospital (Beiwei).
In the past ten years, CAR-T cell therapy has made rapid progress, and commercial CAR-T cell therapy has been marketed at home and abroad, and most of the CAR-T cell therapy indications are lymphoma
.
Can you briefly talk about the changes that CAR-T therapy has brought to the treatment of lymphoma?
Taking diffuse large B-cell lymphoma (DLBCL) as an example, the traditional treatment regimen for R/R DLBCL has an effective rate of only 26%, a complete response (CR) rate of only 7%, and a median overall survival (OS) of only 6.
3 months
.
Compared with traditional treatment options, CAR-T cell therapy significantly improves the efficacy of R/R DLCL, with an effective rate of up to 80%, a CR rate of up to 50%, a 5-year OS rate of 40%, and about 35%-40% of patients can achieve clinical cure
.
The efficacy of CAR-T in R/R follicular lymphoma (FL) is also good, and the best effective rate can reach 100% and the CR rate can reach more than 90% in the registered clinical study led by Beiwei, but the long-term survival data of R/R FL still needs to be improved by longer follow-up
。 At present, China's R/R MCL related CAR-T test data is not perfect, from the foreign relevant test data, CAR-T in R/R MCL patients has a good effect, the total effective rate can reach more than 90%, the CR rate can be close to 70%, and according to the latest 3-year follow-up data, patients with R/R MCL who receive CAR-T treatment have a good
survival.
Yimaitong: Although CAR-T brings hope for a cure for lymphoma patients, there are still some patients who have drug resistance/recurrence after CAR-T treatment, how to choose a coping strategy for these patients?
For patients who develop resistance/relapse after CAR-T therapy, the mechanism of
resistance/recurrence should be focused on first.
The mechanism of CAR-T resistance/recurrence is more complex
than conventional drugs.
CAR-T cells are "live" drugs that expand in large quantities when they enter the patient's body, causing immune-related responses
while taking effect.
There are four main mechanisms of drug resistance/recurrence after CAR-T treatment
.
The first is related to CAR-T cells themselves, and there are differences in T cell phenotype, T cell subtype ratio or expansion ability of CAR-T cells, resulting in differences in their efficacy, and relevant mechanisms are currently being studied
.
The second is related to the patient's clinical factors, such as a large number of previous treatment lines, a high tumor burden (especially large masses), and different lymphoma subtypes, which can affect the efficacy
of CAR-T cells.
The third is related to the tumor cells themselves, such as some tumor cells that lose target antigens during treatment, resulting in antigen-negative recurrence
.
The fourth is related to the tumor microenvironment (TME), which contains a large number of immune cells, such as bone marrow-derived suppressor cells (MDSCs), regulatory T cells (Treg), etc.
, whose structure is very complex, and the cellular and non-cellular components in TME can participate in the regulation of many tumor-related signaling pathways
.
Although CAR-T cells can be expanded well in patients, some specific TMEs can lead to poor efficacy of CAR-T
.
For different resistance/recurrence mechanisms, different treatment regimens can be used to improve efficacy
。 At present, there are three main treatment options available in clinical practice, the first is combination drug therapy, such as combination with BTK inhibitor, lenalidomide, PD-1/L1 monoclonal antibody to improve the efficacy; The second is to adjust the pretreatment regimen, such as adjusting the pretreatment regimen to the pretreatment regimen of autologous hematopoietic stem cell transplantation, which may improve the efficacy to some extent; The third use of dual-target CAR-T shows the prospect of improving the efficacy; The fourth is to improve TME or intervene in the CAR-T cell culture process to make CAR-T cells have stronger expansion ability and tumor cell killing ability, but this method is currently
less clinically used.
Yimaitong: Current CAR-T cells are self-derived and relatively expensive
.
Is it possible to achieve mass production of allogeneic CAR-T cells in the future? What are the advantages and disadvantages of allogeneic CAR-T cells?
Although autologous CAR-T has good efficacy, it also has certain disadvantages, such as high price, long production cycle of autologous cell collection and certain risk
of preparation failure.
Allogeneic CAR-T cells, also known as general-purpose CAR-T cells, are one of the research directions in the field of
CAR-T.
The advantage of universal CAR-T is that it can reduce the cost of treatment and shorten the treatment time, and the exploration of universal CAR-T cells is ongoing, but there is no clear research data to support the efficacy or safety of universal CAR-T cells over autologous CAR-T cells
.
The research on universal CAR-T is still in the clinical trial stage, and some small clinical data show that the short-term efficacy of universal CAR-T is good, which can benefit some patients with R/R
lymphoma.
At present, general-purpose CAR-T has entered phase II clinical trials, which means that general-purpose CAR-T has gradually entered the clinical application stage
.
However, general-purpose CAR-T also has certain disadvantages, such as general-purpose CAR-T needs to use a larger intensity pretreatment scheme to remove as many lymphocytes as possible in the body to play a better immunosuppressive role, so that the imported general-purpose CAR-T cells can better exert their curative effects
.
At the same time, however, a stronger conditioning regimen can cause a more severe reaction
.
In addition, universal CAR-T needs to reduce the rejection response of patients to general-purpose CAR-T cells as much as possible through gene editing, so that general-purpose CAR-T cells can expand normally in vivo, but this method will weaken the tumor cell killing ability
of general-purpose CAR-T to a certain extent.
Even though rejection is mitigated by gene editing, general-purpose CAR-T cells have poorer survival in patients than autologous CAR-T cells
.
Yimaitong: Could you please introduce the efforts and explorations made by the Department of Lymphoma of Peking University Cancer Hospital in the treatment of lymphoma CAR-T? And what are the future directions for exploration?
The Department of Northern Lymphoma began to carry out clinical trials of lymphoma CAR-T in 2013, which has been
9 years ago.
So far, the Department of Northern Lymphoma has completed CAR T cell therapy
for nearly 300 lymphoma patients.
There are three main CAR-T-related explorations carried out by the Department of Northern Lymphoma in recent years, one of which is the study of CAR structural modification, in which we modified the transmembrane and hinge region structures of CAR, so that CAR-T reduced toxic side effects on the basis of retaining the efficacy, and no patients developed severe cytokine release syndrome (CRS) and severe neurotoxicity, the results of the study were published in Nature MEDICINE in 2019
.
The second item compares the efficacy and safety of CAR-T cells in two different CAR-T co-stimulation domains, 4-1BB and CD28, and the results show that CAR-T with CD28 as the co-stimulation domain and CAR-T with 4-1BB as the co-stimulation domain have the same efficacy, but the toxicity and side reactions caused by CAR-T with CD28 as the co-stimulation domain are more serious, and the results are more consistent
with the current clinical data.
The third is a key registration clinical study led by the Department of Northern Lymphoma - relmacel for the treatment of relapsed/refractory large B-cell lymphoma and FL, of which the pivotal registration clinical trial data of the R/R FL cohort has been officially published
.
At present, relmacel has been approved by the National Medical Products Administration for the treatment of R/R large B-cell lymphoma after ≥ 2 lines and treatment and R/R FL
with ≥ 2 lines or relapse within 24 months.
In addition to the above three studies, other CAR-T-related registered clinical trials and investigator-initiated clinical trials are currently underway
in the Department of Northern Lymphoma.
For the future exploration direction, there are mainly 4.
The first is to improve the efficacy of CAR-T, such as the exploration of dual-target CAR-T and CAR-T combination therapy regimens, and the exploration of the molecular mechanism related to the efficacy of CAR-T
.
The second is the application of CAR-T in the treatment of CAR-T in T-cell lymphoma, due to the lack of specific CAR-T target antigen and other reasons, the efficacy of CAR-T in T-cell lymphoma is not ideal
.
The third is the exploration
of general-purpose CAR-T.
The fourth is the exploration of CAR-NK, unlike T cells, NK cells do not produce rejection when
used for allogeneic therapy.
It is believed that through the joint efforts of the majority of peers, it is just around the corner to improve the efficacy of CAR-T and solve the dilemma of CAR-T cell therapy
.
Professor Ying Zhitao
- Chief physician of Peking University Cancer Hospital
- Vice Chairman of the Cell Immunotherapy Professional Committee of the Chinese Health Science and Technology Promotion Association
- Youth member of Hematological Oncology Committee of Chinese Anti-Cancer Association
- Member of Chinese Geriatric Hematology Lymphoma Group
- Member of the Young Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
- The 11th Youth Committee Member of the Oncology Branch of the Chinese Medical Association
- Member of the Drug Clinical Research and Evaluation Professional Committee of the Chinese Geriatric Health Care Association
- Young Associate Editor of JCO-Blood Chinese Cell and Immunotherapy
- Member of the editorial board of Blood and Genomics magazine
- His main research interests are standardized diagnosis and treatment of lymphoma and the application of cellular immunotherapy in lymphoma
- He has participated in the compilation of many oncology books and published more than 30 papers
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