Breaking through the traditional CD19 car-t therapy "black horse" enterprise treatment all won the title of FDA orphan drug

Recently, Autolus Therapeutics, a biopharmaceutical company committed to developing the next generation of programmed T cell therapy for cancer treatment, announced that the US FDA has awarded it the title of orphan drug of CD19 CAR-T product (AUTO1) for the treatment of patients with acute lymphoblastic leukemia (ALL) Dr Christian itin, chairman and chief executive officer of autolus, said: "we are pleased that auto1 has been assigned orphan drugs for AML From the data reported in our ongoing study, we have seen a strong remission rate and excellent car-t cell expansion and persistence, without inducing high-level CRS (cytokine release syndrome), which is a serious adverse event, affecting a large number of patients currently available for car t treatment We look forward to submitting data on auto1 to ash by the end of this year " Acute lymphocytic leukemia (ALL) is a kind of malignant tumor disease that B or T cells originated from lymphocyte are abnormal hyperplasia in bone marrow B cells are the most common This fast-growing B-cell malignant tumor of blood has relatively high tumor load, if not treated in time, it may be fatal within a few months By 2019, 5930 new cases and 1500 related deaths are expected, according to the National Cancer Institute of the National Institutes of health The patients are mainly children, but also affect adults About 60% of cases occur under the age of 20 Although the response rate of induced chemotherapy is very high, only 30 - 40% of adult patients can get long-term remission Similarly, children respond well to first-line treatment (combined chemotherapy), but 10-20% of the patients relapse of chemotherapy-resistant diseases, resulting in high-risk relapse or refractory all CD19 is a specific cell surface antigen expressed in various stages of B-cell differentiation Most B-cell-derived malignant tumors include B-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia and non Hodgkin's lymphoma cells At present, the two car-t therapies listed on the market are also targeted at CD19, namely, kymeriah (tisagenlecleucel, ctl019) of Novartis, which is used to treat patients under 25 years old with refractory relapsed B-cell precursor acute lymphoblastic leukemia (all), and yescarta (axicabagene ciloleucel) of kit Pharma, which is used for adult relapsed / refractory B-cell non Hodgkin's lymphoma The efficacy of CD19 car-t cells in the treatment of leukemia and lymphoma depends on the implantation and expansion of car-t cells However, the rapid activation and expansion of car-t cells can lead to CRS, which may be life-threatening in some cases, especially for elderly patients and patients with high tumor load and poor tolerance In addition, over activation of car-t cells may lead to cell depletion and limit its persistence Auto1 is a car-t cell therapy with CD19 as the target It is designed as CD19 with fast binding kinetics, which allows car-t cells to effectively identify cancer cells, inject cytotoxic proteins to start the process of cell self destruction, rapid dissociation, and then to combine with the next cancer cell This process is also known as "serial killer" Compared with the traditional anti-CD19 car-t cell therapy, auto1 has the same binding rate and faster dissociation rate, avoiding long-term residence on the target cells to avoid over activation of car-t cells, and reducing toxicity and car-t cell failure This allows auto1 to maintain a similar level of efficacy, at the same time, with a higher safety Autolus signed a license agreement with UCL business (uclb) in 2018 to obtain the global development and commercialization rights of auto1 for the treatment of B-cell malignant tumors Auto1 is currently being evaluated in two phase I studies, one in all for children and one in all for adults On February 19, 2019, the bone marrow transplantation of gosh and Professor persis amorlia of UCL's Research Institute for children's health of greater Ormond Street presented the latest data of the first phase of carpall test that autolus therapeutics is carrying out Auto1 has achieved positive results in safety and efficacy Compared with foreign countries, domestic car-t technology started late, but it has developed rapidly in recent years Both domestic independent R & D and foreign pharmaceutical enterprises have gradually formed a fierce competition pattern in the development of domestic car-t therapy Among them, CD19 is the most mature target of R & D, and car-t development aiming at it is particularly fierce On October 30, Novartis' car-t therapy kymriah applied for tacit permission in China's clinical trials, and China ushered in the 10th enterprise to obtain CD19 car-t clinical approval documents; and the total number of enterprises that received ind for car-t products in China is more than 20, with nearly half of enterprises targeting CD19 In 2016, autolus raised more than $100 million for the development of a new generation of car-t therapy, which gradually entered the public view; in June 2018, the IPO raised $160.4 million to be listed on NASDAQ It is one of the 11 most promising Biopharmaceutical Enterprises of endpoints news in 2018, and one of the top 10 tumor immune start-ups selected by Gen in March 2019 It is a "black horse" among car-t R & D enterprises Autolus aims to develop a safer and more effective new generation of car-t therapy for hematoma and solid tumor than car-t therapy which is now on the market or in the application stage The company uses proprietary and modular T-cell programming technology to design precisely targeted, controllable and highly active T-cell therapies designed to better identify cancer cells, break down their defense mechanisms and eliminate them At present, the company has 10 car-t cell products under research, of which 5 car-t candidate products have entered the clinical trial stage A car-t cell therapy targeting BCMA and perforin activator or TACI at the same time, in which BCMA is the antigen expressed on the surface of malignant plasma cells in most patients with multiple myeloma, while in the same cancer cells, in addition to targeting BCMA, targeting TACI at the same time will make more patients benefit from car-t therapy Patients with decreased or lost BCMA expression are not at risk of cancer recurrence In general, TACI, another receptor of TNF, is rarely expressed in myeloma cells However, due to the heterogenous characteristics of multiple myeloma diseases, some myeloma cells still express TACI more than BCMA In this regard, TACI has the potential to solve the problem of antigen escape In addition, auto2 also carries the rqr8 safety switch, allowing T cells to be eliminated with a single high dose of rituximab In September 2017, autolus announced that its first dual targeted car-t cell therapy for mm (multiple myeloma) has completed the first dose cohort study in a 1 / 2-phase clinical trial Auto3, the first dual target T-cell therapy for recurrent or refractory diffuse large B-cell lymphoma (DLBCL) and childhood all, contains two independent cars targeting B-cell antigens CD19 and CD22 For the two indications mentioned above, the company has started to carry out phase 1 / 2 clinical trials of auto3 alone in the third quarter of 2017 Among them, the first part of the clinical study is to determine the maximum tolerance dose of auto3 in children with all and adults with DLBCL and establish the recommended dose The second part is the expansion phase to further evaluate the safety, tolerability and clinical activity at this recommended dose At the end of March this year, autolus released the latest positive results of the I / II Amelia trial of autoo3 in pediatric all patients In addition to monotherapy, the researchers also evaluated the short-term efficacy of AUTO3 in combination with checkpoint inhibitors in the ALEXANDER (for DLBCL) study In April this year, the FDA granted auto3 orphan drug qualification for all treatment, which may have the potential to become the best in class therapy for all in children Trbc1 targeted T-cell therapy for peripheral T-cell lymphoma Prior to this, anti-trbc1 car-t was published in the authoritative academic journal Nature Medicine, which described in detail the unique targeting strategies for T-cell lymphoma patients The results of preclinical studies showed that it recognized and killed both normal and malignant trbc1 cells but not trbc2 T cells in the mouse model of T-cell lymphoma Different from the non selective method targeting the whole T cell population, this method eradicates some T cells containing malignant tumors, while retaining healthy T cell subsets to maintain normal cellular immune function Auto6 is a T-cell therapy targeting gD2, which is used to treat neuroblastoma The phase 1 clinical trial of auto6 was sponsored and carried out by the UK cancer research center (CRUK) Preliminary data show that auto6 has antitumor activity in this solid tumor indication On the basis of auto6, the company has developed its next generation candidate product auto6 ng, which contains additional programming modules to enhance its function by prolonging the durability and making the modified T cells resist immunosuppression Auto6 ng may be suitable for the treatment of solid tumors expressing gD2, including neuroblastoma, osteosarcoma, melanoma, small cell lung cancer, soft tissue sarcoma, etc Phase 1 / 2 clinical trials of auto6 ng are expected to start in 2020 At the 34th Annual Meeting of cancer immunotherapy Association (SITC) held from November 6 to 10, 2019, autolus therapeutics will display the preclinical data of aut06 ng, and the poster display will highlight the preclinical data of the feasibility, safety and effectiveness of auto6 ng in solid tumor indications Tumor immunotherapy has changed the way of cancer treatment Based on the curative effect and market prospect of car-t therapy, its development and layout has always been the place for all pharmaceutical companies to fight for The two car-ts that have been listed have opened up the market of this kind of therapy, and also pointed out the direction of improvement and breakthrough in the follow-up research and development to some extent Endpoints news has commented that autolus is at the forefront of the second round of innovation in car-t therapy At present, the company has two car-t products awarded the title of orphan drug (auto1 and auto3) by FDA for all Whether it can stand out in the future remains to be seen! Reference source: 1.https://www.biospace.com/article/releases/autolus-therapeutics-receives-fda-orphan-drug-designation-for-auto1-for-treatment-of-acute-lymphoblastic-leukemia/ 2.https://www.biospace.com/article/releases/autolus-therapeutics-to-present-preclinical-data-on-aut06ng-at-the-sitc-annual-meetingposter-presentation-will-highlight-preclinical-data-regarding-feasibility-safety-and-efficacy-for-auto6ng-in-solid-tumor-indication/ 3.https://www.genengnews.com/a-lists/top-10-immuno-oncology-startups/ 4.https://endpts.com/autolus-engineers-a-100m-plus-ipo-for-itself-as-it-blueprints-a-new-generation-of-better-safer-cell-therapies/