A noble therapy that can cure , which will eventually be civilian.
The CAR-T currently approved for listing is all self-T.The plan can reduce production costs by about 90%, and the preparation cycle is shortened from about 3 weeks to stand.
To wear the crown first.In May 2022, the star company Caribou universal CAR-T therapy CB-010 was alarming in the phase I clinical trial, with a total relief rate of 100%, but the cheers have not disappeared. Six subjects in subsequent studies have 3 recurrenceEssenceCompared with the clinical data of BCMA CAR-T in recurrence or refractory multi-myeloma, Allogenes universal CAR-T therapy Allo-715 relieves the duration of 8.3 months (3.2x108 dose group), while autologous CAR-T.The therapy CARVYKTI (Legendary Biology) and Zevor – Cel (Koji Pharmaceutical) relieved the duration of 21.8 months and 26.0 months, respectively.
The persistence of efficacy is a hurdle that the universal CAR-T needs to cross.When an exogenous general-purpose CAR-T cells are infused into the patients body, it will cause the host to resist the relocation (HVGR), causing the general-purpose CAR-T cells to be rejected by the immune system.
On November 5th, the 2024 ASH annual meeting was announced, the general CAR-T0590 of Koji Pharmaceutical targeted BCMAs first-time Human Test data showed that a total of 5Example subjects, the median follow-up time is 16.6 months, and 3 cases have reached an objective relief. One case reaches an unsatisfactory objective relief (because of the reason for COVID-19, it cannot be evaluated in time), and two of which have reached strict and completely alleviated(SCR).Among the two subjects who reached SCR, 1 patient with multiple recurrence of multiple osteoma (RRMM) patients at the time of data deadline (DOR) exceeded 23 months (still continued to be relieved, and it has reached.The autologous BCMA CAR-T is quite alleviated), and 1 case of recurrence of primary plasma cell leukemia (PPCL) patients DOR is 20 months.The efficacy of its PCL is far exceeding the efficacy of the autologous BCMA CAR-T of the previous report (the previously reported autologous BCMA CAR-T to treat PCL, and the patients efficacy duration is less than 10 months).
This not only means that the CT0590 initially reflects the durability of the curative effect, but also is likely to be the first common CAR-T in the public document data to treat hemoma-T is equivalent.
The dawn finally follows the reality.
01
Passor
Autologous CAR-T is a high-end customized therapy. Doctors need to obtain T cells from the patients body. In vitro, in vitro through genetic engineering on the surface of the T cell surfaceIn the patients body, the preparation cycle is about 3 weeks. There are problems with difficulty in production, high cost, and long waiting time for patients, and restrict large -scale clinical use.
Some patients may be due to the influence of autoimmune inhibition or chemotherapy, which will cause autologous T cells to exhaust, aging and function defects. In the endSuccessful preparation or affecting clinical efficacy; some patients also developed rapidly because of the disease, and they could not wait for the preparation of autologous CAR-T cell production, which could not benefit from this breakthrough technology.For example, in CARVYKTIs Cartitude-1 clinical trial, the total number of people in the group is 113, and the number of Carvykti infusal of the release standard is only 80, accounting for 71%of the total number of people.
In addition, in order to wait for the production of autologous CAR-T, a large number of patients also need to receive bridge treatment. 75%of patients in the Cartitude-1 test received bridge treatment.
Other products also have similar situations. For example, according to the product manual of Kymriah, the open labels of children and young people who have recurrence/difficulty cure B -cell metal cell leukemia, young peopleMulti -center single -arm test (Eliana, NCT02435849), a total of 88 patients were entered, and only 68 patients (77%) were finally treated.
General-purpose CAR-T can crack all these pain points.
Use T cells from Healthy Volunteers to produce CAR-T cells. General-purpose CAR-T head company Allogne said that cells obtained from a healthy supply can be madeCAR-T cell therapy products for the treatment of 100 cancer patients.
It can reduce production costs through industrial production and large-scale manufacturing technology, and can produce a batch of frozen CAR-T cells. Patients doCalled the spot CAR-T.
According to the medical consultation, the universal CAR-T can reduce the total cost of consumables from $ 60,000 to $ 2,000, and reduce the cost of QC from $ 30,000 to $ 1,000, thereby leavingThe production cost was reduced from $ 95780 of the autologous CAR-T to $ 4,460.
However, the universal CAR-T landing commercial use still needs to solve the pseudo-jumping block.
According to the Huinhuang drug, the general-purpose CAR-T as an exogenous cell, there is a serious rejection response between the patients immune system. This immune recognition is expressed by the surface of the T cellThe interaction of T cell receptors (TCR) and 1 tissue composite composite (MHC-I or HLA-I) is mediated.
MHC-I expression on the surface of all cells in the human body. T cells determine whether cells are "alien" by identifying MHCI.When the exogenous universal CAR-T cells are infused to the patients body, the TCR on the general-purpose CAR-T will identify the patients MHC-I and attack the patients normal tissue, which will cause (GVHD).Similarly, the T cells in the patient will identify HLA-I on the general-purpose CAR-T cells, causing the host to resist the transplanting plant response (HVGR), which hinders the extension of the general-purpose CAR-T cells, and the effect is poor.
According to a report by Nature Reviews Clinical Oncology, the peak of the extension (CMAX) of General CAR-T in the subject is often significantly lower than the autologous CAR-T, and its duration timeIt is often shorter. Since the infusal of CAR-T is infused, the median survival time is 168 days, and 21 subjects who accept the general-purpose CAR-T are detected in 42 days, only 1 case in 120 days later, 120 days laterThere is still a universal CAR-T in the body.
The general-purpose CAR-T head enterprise Caribou, Allogene, Crispr, and Precision have all been expanded or endured.
Take the universal BCMA CAR-T Allo-715 of AlLogene as an example. The median CAR-T in the 24 patients of the 3.2x108 dose group is only 6419 copies/UG GDNA.It is significantly lower than the 202543 copy of the 47806 copy/UG GDNA and ZEVOR-CEL (Sai Kaize) of the autologous BCMA CAMA CAR-T product Carvykti.
02
Breakout point
How to solve the HVGR problem more thoroughly is the key to whether the universal CAR-T can succeed.not->Koji Pharmaceuticals expressed a total of a general-purpose CAR-T cells of TRAC and B2M gene knockout (HLA-I defect) expressed a kind of recognition of NK cell surface protein-NKG2A CARIn order to block the attack of the host NK cells, and knock on NKG2A at the same time to further enhance the efficacy of CAR-T cells. This is THANK (Target to Hinder the Attack of NK Cell) -UCAR technology.Data show that in the case of NK cells, the THANK-UCAR® T cells can better survive and amplify than trac/B2M double knocks.
CT0590 is a universal CAR-T that targets BCMA and NKG2A. Triors of TRAC/B2M/NKG2A are knocked out to avoid GVHD and HVGR.Pre-clinical studies have shown that in the case of NK cells, the expression of NKG2A-CAR has promoted the amplification, persistence and efficacy of the CT0590.
In the first phase II study of CT0590, a total of 5 patients were admitted to the group (4 patients with RRMM and 1 patient with primary plane cell leukemia PPCL), averageAt the age of 54 and received an average of 3 lines of treatment.
The median follow -up time is 16.6 months. Three subjects have responded, and 2 subjects have reached a strict sense (SCR) and 1 subject.Obtain partial relief (PR).Among the two subjects who received SCR, 1 RRMM subject had DOR for more than 23 months during the deadline for data, and the DOR of 1 PPCL subject was 20 months.In addition to these three patients who have reached objective relief, another subject reached PR after the second infusion, but did not be confirmed due to COVID-19.Among the two SCR subjects, the expansion of CAR-T cells exceeded 280000 Copies/UG GDNA, which was significantly higher than Allo-715, which was equivalent to autologous BCMA CAR-T.
The preliminary results show that the general-purpose CAR-T therapy of Koji Pharmaceutical has controllable safety, and at the same time, it is equivalent to autologous CAR-T or even better efficacy durability.In addition to the persistence of this curative effect, it may be because THNAK-UCars design for T cells and NK cells immunotherapy may also be partially derived from the design of NKG2A at the same time, and knockout NKG2A is considered a means to enhance the efficacy of immune cells.Early research samples are small, and Koji Pharmaceutical is conducting more clinical trials, not only multiple bone marrow tumors. It is reported that Koji will also start universal CAR-T such in common leukemia and lymphoma such as acute marrow leukemia and lymphoma.Clinical trials.
The current CAR-T has three major development directions.Slow diseases such as diseases.
The general-purpose CAR-T sets three directions.UCAR T development pioneer Allogene targeting the Allo-316 of CD70 is expected to open up the treatment boundary between hemomators and physical tumors, becoming the first cross-border UCAR T therapy, and the company has reached cooperation with Zhang Feng to develop self-use CAR-T.
Slow disease is more sensitive to the burden of treatment. General-purpose CAR-T has cost advantages. Not only that, universal CAR-T is the only way for cell therapy to change from sky-high price.Make aristocratic medicines into ordinary peoples homes like traditional drugs.
The market space of nearly 100 billion US dollars will be released.According to Precepts, the global CAR-T cell therapy market will reach US $ 3.827 billion in 2022, and it is expected to reach US $ 88.528 billion by 2032, with a compound annual growth rate of 29.8%.
Domestic CAR-T manufacturers represented by Koji Pharmaceuticals technical breakthrough will make this day early.
