Application of CAR-T cell therapy in lymphoma
August 15, 2018 Source: Oncology
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];In recent years, although targeted immunotherapy has significantly improved the survival of lymphoma patients, some patients still show relapse or refractory disease. The mechanism of chimeric antigen receptor T cell immunotherapy (CAR-T) is different from that of existing therapeutic systems—that is, by genetically engineering a patient's T cells, the antigen on the surface of the tumor cell can be specifically recognized by it, and Activation of T cells in an MHC-independent manner and stimulation of an effective cytotoxic response can therefore be a useful method for the resolution of refractory clones.
The scope and results of CAR-T cell therapy
In 2012, 2015, and 2017, Kochenderfer reported the successful treatment of multiple types of relapsed and refractory non-Hodgkin's lymphoma (NHL), including diffuse, using second-generation CAR-T cells with CD28 as a costimulatory molecule. Large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL), and splenic marginal lymphoma (SMZL), total response The rate (ORR) is 73-100% and the complete response (CR) rate is 0-56%.
At the 59th annual ASH conference in 2017, the latest data from the Phase II clinical trial of the Novy Kymriah, called JULIET, showed that 81 patients with relapsed or refractory (r / r) DLBCL were at an earlier follow-up. The ORR was 53%, the CR was 40%, and the partial response rate (PR) was 14%. After 3 months of Kymriah infusion, the ORR was 38% and the CR was 32%, consistent with the sixth month (30% CR, 7% PR). The probability of recurrence at 6 months after the first response was 74% (95% CI, 52%-87%), the duration of median remission had not been reached, and the median overall survival (OS) had not yet reached (95% CI). : 6.5 months - not estimated), the median time from infusion to data cutoff was 5.6 months.
Based on this, in May 2018, the FDA approved Kymriah's second indication for the treatment of relapsed or relapsed B-cell acute lymphoblastic leukemia, an adult patient for the treatment of relapsed or refractory large B-cell lymphoma. (Previously received two or more systemic therapies), including the most common form of non-Hodgkin's lymphoma, DLBCL, and high-grade B-cell lymphoma and DLBCL transformed from FL.
So, can CAR-T cells be used for the treatment of Hodgkin's lymphoma (HL) or T-cell lymphoma (TCL)? Since HL does not express B cell surface-associated markers and uniformly expresses CD30, clinical studies of HL with CAR-T cells targeting CD30 are also underway. In addition, although neoplastic HL Reed-Sternberg (HRS) cells are negative for CD19, CD19-positive clonal HRS precursor cells and CD19-positive cells are present in the HL tumor microenvironment, which indicates the use in HL. The possibility of targeting CD19 for CAR-T cell therapy. In the case of T-cell lymphoma, CAR-T cells are most difficult to treat in TCL because of the need to find a target for the expression of tumor cells that is not expressed by CAR-T cells. Studies have shown that one epitope of CD7 in CD3-positive CAR-T cells can be cleaved with CRISPR/cas9, so that it can no longer express CD7, which can avoid autophagy of CAR-T cells, thus treating CD7. Positive T cell lymphoma. In addition, CAR-NK cells are also a solution.
Hematopoietic stem cell transplantation and CAR-T cell therapy
In simple CAR-T cell therapy, the survival time of CAR-T cells in vivo is relatively short, and it is difficult to maintain the risk of long-term disease-free survival and easy recurrence. Therefore, patients with relapsed/refractory disease who are relieved by CAR-T treatment can bridge the transplant during the remission period, reduce the recurrence rate of the primary disease, and prolong the disease-free survival of the patient.
In addition, because CAR-T cells have specific killing ability to tumor tissues, we can also combine CAR-T cell therapy after hematopoietic stem cell transplantation to reduce the recurrence rate after transplantation.
Drug resistance in CAR-T cell therapy
Loss of CD19 and overexpression of PD-L1 in tumor cells is often considered a possible mechanism of resistance to CAR-T treatment. In some patients, after the treatment of CD19-CAR-T cells for a period of time, the tumor relapses, and the CD19 is often negative. In this case, even if CAR-T is strongly active in the body, the disease will progress. In order to solve the problem of tumor cell antigen loss after CD19-CAR-T cell therapy, B-cell lymphoma can be treated with a novel target CD22. The high expression of PD-L1 in tumor cells can inhibit the activation of T cells by PD-L1 binding to PD-1 on T cells, and cause immune escape of tumor cells. Although the application of anti-PD-1 antibody can partially restore the effect of CAR-T cells, some patients still relapse after stopping the antibody. Therefore, Liu et al. applied genetic engineering technology to transform CAR-T cells to make T cells in cells. The outer domain simultaneously expresses the CAR structure and PD-1. The PD-1 binds to PD-L1 and transmits an activation signal through intracellular CD28, thereby avoiding the immune escape of the tumor and avoiding other immune related factors caused by PD-1 inhibitor. complication.
Research Trends in CAR-T Cell Therapy
Loss of CD19 after CAR-T cell therapy is likely to lead to tumor recurrence. It may be possible to prevent this by sequential infusion of anti-CD19-CAR-T and anti-CD22-CAR-T cells; CAR-T cells often The occurrence of cytokine release syndrome (CRS), how to better reduce its severity is also something we need to think about, such as the choice of pretreatment protocol, the number of imported CAR-T cells. In addition, IL-7 can also be transferred into CAR-T cells together with the CCL-19 gene, and IL-7 and CCL-19 can efficiently recruit peripheral T cells and DC cells to tumor tissues to kill tumors together. In addition, some patients with refractory/relapsed lymphoma progress faster, and it takes at least one month to recover from collecting cells to CAR-T cells. Therefore, the development of universal CAR-T (UCART) can effectively solve this problem. problem.
In conclusion, the emergence of CAR-T cell therapy and its combination with existing treatments have brought new hopes for patients with refractory/recurrent lymphoma, but there are still many problems that we need to discover and solve.
Fingerprint Safe,Biometric Fingerprint Safe,Portable Fingerprint Safe,Fingerprint Lock Safe Box
Ningbo Reliance Security Technology CO.,Ltd , https://www.reliancesafes.com