This year, the general public was discussing1.2000 dose of CAR-T (the second paragraph1.2900), and the most intractable disease was poverty. Professionals are more discussing the therapeutic spectrum of CAR-T, and discussing the shortcomings and prospects of CAR-T.
CAR-T therapy has become a well-known immunotherapy for hematological tumors in the industry, but solid tumors are the most difficult thing in the industry. According to statistics, 90% of cancers in the world are solid tumors, and only 10% are cancers of the blood system. Undoubtedly, CAR-T's helplessness in treating solid tumors has brought TCR-T to the forefront of overcoming solid tumors.
At the ASCO meeting on 20021,Adaptimmune announced that their second-phase open trial of TCR-T cell therapy was used to treat 29 patients with advanced synovial sarcoma, with a total remission rate of 4 1.4%(n= 12/29), of which 2 cases were in complete remission (CR),/kloc-. The company announced that this drug is expected to go on the market next year.
In 20021and1October, Immatics announced that their TCR-T cell therapy showed anti-cancer activity with the increase of dose in the early stage of clinical trials. Including non-small cell lung cancer, head and neck cancer, melanoma, ovarian cancer and synovial sarcoma. Among 16 patients, 15 patients (94%) achieved disease control, and 14 patients (88%) observed tumor shrinkage. The researchers also observed that all patients had stable T cell implantation, and TCR-T cells also had tumor infiltration in patients who underwent biopsy during treatment.
In 2020, the International Congress of Hepatology (ILC) was the first anti-liver cancer TCR-T therapy. Among 9 patients with liver cancer, 1 CR (complete remission), the AFP level of all patients decreased!
At the ASCO meeting in 2020, The University of Texas MD Anderson Cancer Center announced a new type of adoptive T cell therapy for 38 patients with extremely advanced stage, including synovial sarcoma, ovarian cancer, head and neck cancer, gastric cancer, myxoid/round cell liposarcoma, non-small cell lung cancer, bladder cancer, esophageal cancer and melanoma. The experimental results show that these patients have a strong reaction after receiving cell therapy. Nine patients (23.7%) had remission or tumor shrinkage, and 18 patients (47.4%) had stable condition.
In particular, a 67-year-old male patient with advanced synovial sarcoma received 12 weeks of cell therapy, and the largest tumor focus (155mm) was reduced by 45%. After further treatment, the tumor shrank by 765438 0%.
As two very important directions of adoptive T cell therapy, CAR-T and TCR-T have obvious differences.
TCR is a T cell-specific receptor, which recognizes antigens through naturally occurring T cells, while CAR is an artificial chimeric receptor, which combines antigen binding and T cell activation. The typical difference between the two is that TCR needs MHC expressions, but CAR doesn't.
But CAR only binds to cell surface antigen, while TCR can recognize all kinds of tumor-specific proteins, including CEA, Her-2, CD 19, GP 100, MART- 1, MAGA-A3, NY-ESO- 1 and so on, which are all cells.
For example, CAR-T replaced the mace of T cells with a sword, and directly replaced the "head" of TCR on T cells with a specific antibody. This allows T cells to directly attack cancer cells under the guidance of antibodies. Then TCR-T is to arm the original mace and make it sharper, harder and sharper. Let the softened mace recombine and kill cancer cells through genetic modification.
Compared with CAR-T therapy, TCR-T therapy has more advantages in the field of solid tumor treatment. In the treatment of solid tumor, TCR-T has achieved better therapeutic effect than CAR-T. When TCR-T and CAR-T attack solid tumor at the same time, CAR-T usually adheres to the outer layer of tumor without infiltrating into it, and the effective rate is low. TCR-T is naturally expressed in human body, completely humanized and will not cause immune rejection. At the same time, TCR-T cells have immune memory function and can survive in the body for a long time. As far as CAR-T is concerned, some artificial genetic modification will objectively shorten the survival time of CAR-T and affect the treatment results. It is expected to further promote the growth of TCR-T therapy market.
Among the 1007 clinical trials of immune cells registered by NIH, there are 774 cases of CAR-T therapy and 53 cases of TCR-T/kloc-0, and there are more than 80 trials such as CIK cells (cytokine-induced killer cells) and NK cells (natural killer cells).
T cells are the most important cells in our cellular immunity, so they are called T cells because their maturation and differentiation are completed in the thymus.
T cells are very much like the "discipline inspection commission" of our bodies. When they patrol the body, they constantly make "intimate" contact with various cells to check whether the cells are normal.
This kind of contact and inspection work is mainly carried out through a kind of "T cell receptor", TCR is the English abbreviation of T cell receptor.
If T cells find mutated protein fragments, they may attack the cells and destroy the mutated cells. This is the main reason why our immune system can keep a cancer-free life for a long time.
The occurrence of cancer shows that our T cells have lost the ability to recognize cancer cells and destroy them. The key to improve T cell recognition ability is to improve "T cell receptor".
TCR-T therapy means that by transducing chimeric antigen receptors into T cells, the affinity of TCR that specifically recognizes tumor-associated antigens and the combat effectiveness of immune cells are improved, so that T lymphocytes can re-recognize target cells with high efficiency and play a powerful anti-tumor immune role in vivo.
TCR-T therapy can not only kill tumor as quickly as chemotherapy, but also avoid the delayed effect of vaccine and T lymphocyte checkpoint therapy.
The earliest clinical study of TCR-T has been registered as a clinical trial since 2004, but there are many obstacles. In the middle of 2009, the TCR-T test of colorectal cancer failed, and the TCR-T of 201solid tumor failed twice for MAGE-A3.
As far as registered clinical trials are concerned, all registered TCR-T clinical studies are in phase I or II, mainly for solid tumors, not hematological tumors. The most common is melanoma (13%), followed by gastrointestinal cancer (13%), lung cancer (8%) and almost all other solid tumors.
The most common targets of TCR-T are CTA(47%) and other TAA(25%), and cancer virus antigen accounts for 16% (9 cases of human papillomavirus, 4 cases of HBV, EBV, MCV 1 case).
As mentioned above, TCR-T has made some progress in solid tumors, but we still can't ignore the practical difficulties of TCR-T. Only by breaking through these obstacles can we have more hope for conquering tumors in the future.
Target selection and optimization: this is the eternal challenge of TCR treatment, that is, to solve the affinity of TCR to tumor targets, TCR- T needs more blood transfusion.
Tumor escape and inhibition of T cell activation: The activation of TCR-T depends on MHC-I molecules to present tumor antigen to TCR-T, but in tumor cells, MHC expression is often down-regulated or completely lost, so TCR-T is powerless, and tumors can also inhibit T cell activation, which is also a problem that TCR-T must solve to improve clinical efficacy.
Individualization: Due to the diversity of MHC in the population and the need for MHC molecules for TCR-T to kill tumor cells, TCR-T therapy can not develop a universal TCR-T, and the patient's cost will be higher, which will also limit the use of TCR-T.
At present, scientists are trying various new development strategies to enhance the persistence and expansion of adoptive transfer T cells, thus enhancing the therapeutic effect of TCR-T, including improving in vitro culture conditions, genetic modification of T cells, patient pretreatment and cooperative treatment.
At present, the CAR-T clinical trial initiated by China has surpassed that of the United States, while the TCR-T field is catching up, as shown in the following figure.
Cancer Express announced that the cancer prevalence rate in China in previous years was 556/65438+ 10,000. Based on the cost of RMB 300,000 and the treatment ratio of 10%, the potential market space of CAR-T/TCR-T therapy in China exceeds RMB 200 billion.
For TCR-T therapy, several companies at home and abroad have laid out research and development, and the leading foreign company is adaptive immunity. Immuncore, Medigene, Lion TCR, TCR2 Therapeutics, RootPath, Kite Pharma. Domestic leading enterprises include Xiangxue Pharmaceutical (Xiangxue Precision), Hengrui Jacky, Youruike, Yao Mingjunuo, Shenzhen Innolux, Shenzhen Binde Bio, Ke Rui Bio, etc.
In a word, TCR-T cell therapy has developed rapidly and has become a promising strategy for treating various cancers, especially solid tumors.
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