New target CD99 CAR-T for T-ALL releases research data

Recent popular reports from Yimaike ★The first cancer immunotherapy for adjuvant treatment of NSCLC was approved, reducing the risk of early lung cancer recurrence by 34% ★Wu Zhiwei/Liu Yalan team jointly developed inhaled new nanoantibodies to effectively inhibit new coronavirus infections October 26, 2021/Doctor EMedClub News/--Recently, Professor Zhang Tongcun of Wuhan Polytech Biosciences published a titled "CAR T cells targeting CD99 as" in the international authoritative journal "Journal of Hematology & Oncology" (IF 17.
388).
an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity" research paper
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The author innovatively uses CD99, a broad-spectrum antigen on the tumor cell membrane surface, to optimize CAR-T cell therapy for T-ALL treatment
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▲ Image source: Journal of Hematology & Oncology CAR-T cell therapy is currently one of the most commonly used immunotherapy methods
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After years of research, CAR-T therapy has achieved great clinical success, especially in the treatment of hematological tumors, and many products have been approved for marketing
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The CAR-T therapies currently on the market are summarized as follows: T-ALL recurrence rate and mortality rate after combined chemotherapy are high.
Although there are continuous successes in the field of CAR-T treatment of tumors, the current CAR-T cell treatment of tumors is still facing tumors.
The off-target caused by high heterogeneity and the singularity of the target lead to problems such as poor therapeutic effect
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Among them, the high degree of heterogeneity of tumor cells directly leads to the limitations of CAR-T therapy in the treatment process, and the singularity of the target limits the broad spectrum of treatment
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Therefore, the selection of membrane surface markers that are specifically expressed in tumor cells and have broad-spectrum expression in different tumors has become a crucial step for the effectiveness of CAR-T therapy
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T-ALL (T-Lineage Acute Lymphoblastic Leukemia) is a type of malignant tumor of the lymphatic system, accounting for approximately 15-25% of all patients
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CAR-T cells and malignant T-cell tumors have similar antigens.
There are technical obstacles such as cannibalism or T cell hypoplasia in the process of CAR-T cell preparation, which has led to the progress of CAR-T cell therapy in T-cell leukemia/lymphoma.
Slow
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Combination chemotherapy is a common therapy for clinical treatment of T-ALL in recent years.
Although the effect is significant, a relatively high proportion of patients are still at risk of recurrence and death
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Therefore, the development of new T-ALL treatment strategies, especially for patients with relapsed and refractory T-ALL, has very important clinical significance
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▲ Image source: Internet CAR-T therapy for T-ALL is currently in the research and exploration stage.
The mainstream solution is to use CRISPR/Cas9 gene editing technology to excise the CD7 or CD2 antigen gene on the surface of CAR-T cells to prepare allogeneic CAR- T cells can circumvent the suicidal effect of CAR-T cells, thereby achieving the goal of effective treatment of T-ALL
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Wugen's WU-CART-007 and WU-CART-002 are candidate products developed on this basis.
Among them, WU-CART-007 is undergoing a clinical proof of concept in preparation for the launch
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▲ Image source: Recommended reading on the Internet: Breakthrough: The world's first universal CART treatment of T-ALL has completed an exploratory study, and data shows clinical feasibilityYi Mai Meng broke the news 2020 CSCOProfessor Zhang Mingzhi: CD7 CAR-T cell therapy for refractory and relapsed T -ALL/LBL, early clinical studies with excellent curative effect and significant CD99 new target CD99 protein is a glycosylated protein encoded by the gene MIC2 (MIC2X, MIC2Y) located on the cell membrane
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It is mainly expressed in normal tissue cells such as thymic epidermal cells, pancreatic islet cells, ovarian granulosa cells and testicular supporting cells
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According to previous studies, more than 50% of samples from a variety of tumor tissues are positive for CD99
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In particular, the CD99 positive of Ewing's sarcoma samples is almost 100%, and it is clinically used as a diagnostic marker for Ewing's sarcoma
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For T-cell acute lymphoblastic leukemia (T-ALL), CD99 is not only highly expressed in tumors at the initial stage, but the expression of CD99 is also used for the detection of immune minimal residual cells after chemotherapy and the basis for the diagnosis of T-ALL recurrence
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Aiming at CD99, Poruida designed a unique chimeric antigen receptor (CAR), which sequentially splices signal peptides, single-chain antibody ScFv, streptII, CD8 hinge, CD28 transmembrane region, and CD28 from N-terminal to C-terminal.
Intracellular domain, intracellular costimulatory domain 4-1BB, and CD3ζ chain; and at the C-terminus of CD3ζ chain, F2A peptide, IL-7, F2A peptide and CCL19 are spliced
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The lentiviral vector with PTK881-EF1α vector as the backbone is used as a recombinant chimeric antigen receptor gene vector to transduce T cells to prepare CAR-T cell preparations
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▲ Picture source: In the recombinant chimeric antigen receptor of the State Intellectual Property Office, the single-chain antibody ScFv is one of the most important parts for recognizing CD99
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In response, Professor Zhang’s team screened out the low-affinity antibody 12E7 mAb, which can specifically recognize the CD99 antigen on the surface of tumor cells without having an immune response to normal hematopoietic cells
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The results of the study showed that the anti-CD99 CAR-T cells prepared based on 12E7 ScFv showed better expansion ability
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In addition, the CAR-T cell preparation has selective killing properties, can effectively inhibit the proliferation of tumor cells in vitro and in vivo and guide their apoptosis, and at the same time does not exhibit cytotoxicity to normal cells
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In addition, Professor Zhang's team also used this CAR-T cell preparation to explore the treatment of AML and a variety of solid tumors, and obtained good results, which is the follow-up expansion of anti-CD99 CAR-T cell preparations.
Research provides positive ideas
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▲ Picture source: Journal of Hematology & Oncology wheat summarizes the new research results of this time.
The past subtraction idea of ​​removing CAR-T cell surface targets through gene editing has been transformed into a new idea of ​​finding strong expression targets of cancerous T cells.
The treatment of T-ALL disease is a landmark
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There have been pioneers who have illuminated the way forward and followed the clear road.
I believe that T-ALL will also be overcome in the near future.
Even with the efforts of CAR-T researchers, solid tumors will become CAR-T cell therapy.
A member of the list
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Reference: 1.
https:? //Mp.
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https: //jhoonline.
biomedcentral.
com/articles/10.
1186 /s13045-021-01178-z3.
http://pss-system.
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gov.
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