Ash to review what breakthroughs might change the existing treatment model?
Last Update: 2020-06-19
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"When people think back to this annual meeting of ash, they may remember that this is the annual meeting that bispecific antibodies really threaten car-t therapy"This is the description of this ash annual meeting on vantage websiteCar-t therapy was approved to treat blood cancer for the first time in 2017, which stimulated the development upsurge of car-t therapy around the worldAt the annual meeting of ASH, the latest clinical results of several CAR-T therapies fully showed its excellent efficacy in the treatment of patients with refractory blood diseasesHowever, the complex and long production process of car-t therapy, as well as the potentially fatal side effects, are still important factors limiting its wide application< br / > bispecific antibody therapy is another way to kill tumor by using T cells in patients' immune systemAt one end, they can bind to the antigen on the surface of cancer cells, and at the other end, they can bind to the T cell receptor (usually CD3) on the surface of T cells to collect T cells near cancer cells and activate the killing of T cells on cancer cellsThe clinical trials of a number of bispecific antibodies at this ash annual meeting show that they can produce good results in the treatment of refractory blood diseases, even in the patients with resistance to car-t therapy< br / > let's take a look at the latest progress of these two kinds of therapies at the annual meeting of ash: < br / > car-t therapy: many kinds of in-process therapies are close to being listed, and Chinese companies are emerging < br / > after the approval of kymriah and yescarta of kit Pharma of Novartis in 2017, no new car-t therapy has been approved by FDA in recent two yearsThis situation is expected to change next year, from the end of this year to the middle of next year, there may be four car-t therapies to submit biological product licensing application (BLA) to the FDAIf they are all approved, the number of approved car-t treatments will be increased by 200%< br / > four car-t therapies that are expected to come into market in the near futureIn terms of safety, the severe (grade 3 or above) cytokine release syndrome (CRS) produced by this car-t therapy only occurs in 2% of patients, and only 10% of patients have severe neurotoxicity of grade 3 or aboveBMS plans to submit BLA to FDA by the end of this year< br / > in the critical phase 2 clinical trials of relapsed refractory multiple myeloma (R / RMM), the car-t therapy, which was developed by BMS and Bluebird bio, targeting B cell mature antigen (BCMA), also reached 73.4% Orr and 31.3% CRThis car-t therapy is expected to be delivered to BLA early next year< br / > kte-x19, a CD19 targeted car-t therapy developed by kit Pharma, a subsidiary of Gilead Sciences, has achieved 93% Orr and 67% Cr in the critical phase 2 clinical trials for R / r-cell lymphoma (MCL) patients In terms of safety, the proportion of patients with CRS above level 3 and neurotoxicity was 15% and 31%, respectively Gilead science has submitted the BLA of kte-x19 to the US FDA today It is expected to be the first car-t therapy for MCL < br / > on the first day of ash opening, jnj-4528 (also known as lcar-b38m) jointly developed by Janssen and Nanjing legend Co., Ltd came on stage The car-t therapy, which carries two antibody protein domains targeting BCMA, achieved 100% Orr and 69% Cr in the cartitude-1 clinical trial for R / RMM patients The car-t treatment is expected to be delivered to BLA later next year < br / > several Chinese companies have announced the clinical progress of car-t therapy < br / > a few days ago, the cancer immunotherapy review published in Nature Reviews Drug Discovery found that the number of cell-based therapies in the research of cancer immunotherapy in China is as high as 367, accounting for 61% of cancer immunotherapy In addition to the Nanjing legend mentioned above, car-t therapy developed by a number of Chinese pharmaceutical companies appeared in ash They include jwcar029, jwcar029, car-t therapy targeted at CD19, c-car008 targeted at BCMA by sibyman biotechnology group, car-t therapy targeted at BCMA jointly developed by Cinda biology and caribou medical, and car-t therapy targeted at BCMA These car-t therapies have achieved positive results in early clinical trials for R / R MM patients < br / > in addition, Gemini announced the latest clinical trial progress of three candidate products fastcar-19, dual car-19-22 and dual car-bcma-19 at the ash annual meeting In a phase 1 clinical trial conducted jointly by Huazhong University of science and technology and cellyan therapeutics in Wuhan, China, double target car-t therapy targeting BCMA and CD38 also showed excellent early efficacy < br / > in the design of car-t therapy, many Chinese companies have used car-t design of double antibody protein domain, which is used to target a unified antigen and may improve the accuracy of antigenic binding (such as jnj-4582); if different antigens are targeted, it may help overcome the drug resistance of cancer cells and reduce the side effects of car-t therapy (such as dual car-12-22 of Gemini, Dual car-bcma-19, and double target car-t therapy targeting BCMA and CD38) Chinese companies are playing an important role in improving the research of car-t therapy On the first day of the opening ceremony of < br / > bispecific antibody therapy < br / > ash, Roche released the latest clinical trial results of two cd20-cd3 bispecific antibodies Mosunetuzumab and CD20 TCB are two T-cell connectors (TCE) with different structures They are currently in clinical trials as single drug therapy or combination therapy for inert or invasive non-Hodgkin's lymphoma (NHL) < br / > mosunetuzumab achieved 62.7% Orr and 43.3% Cr in patients with inert NHL, 43.3% and 19.4% in patients with invasive NHL, respectively < br / > when CD20 TCB was combined with anti-CD20 antibody gazyva (obinutuzumab), 54% of Orr and 46% of Cr were achieved in the clinical trials of R / R B cell NHL patients < br / > in addition to car-t therapy, BMS has also developed a T cell combiner called cc-93269 This is a bispecific antibody targeting BCMA and CD3, which has two antibody protein domains binding to BCMA < br / > in the phase 1 clinical trial of R / R MM patients, high-dose cc-93269 can achieve 88.9% Orr and 44.4% CR In terms of safety, only 3.3% of patients had grade 3 or above CSR < br / > regeneron company announced the clinical test results of two bispecific antibodies at ash annual meeting Among them, the cd20-cd3 bispecific antibody regn 1979 showed a good effect in the treatment of a variety of B-cell NHL patients For example, 95% of Orr and 77% of Cr were achieved in patients with follicular lymphoma (FL), and 50% of Orr and 25% of Cr were achieved in patients with diffuse large B-cell lymphoma treated with car-t < br / > the bcma-cd3 bispecific antibody regn5458 developed by the company also showed good efficacy in the treatment of R / RMM patients < br / > in addition, xmab 13676, a cd20-cd3 bispecific antibody from xencor, showed a promising antitumor activity in the treatment of R / R DLBCL patients, and genmab's gen3013, a cd20-cd3 bispecific antibody, showed a promising antitumor activity in the treatment of R / R B cell NHL patients < br / > these excellent results show that bispecific antibody is expected to become an important immunotherapy mode besides car-t therapy in the treatment of blood cancer < br / > breakthrough of changing the existing treatment mode < br / > at the annual meeting of ash, several biotechnology companies introduced their breakthrough progress Although these studies are at an early stage, if successful, they will change the treatment of blood cancer or disease Here are two breakthrough studies < br / > fate therapeutics: Although car-t therapy has excellent effect in the treatment of blood cancer, it needs to obtain T cells from patients, carry out gene engineering transformation and expansion in vitro, and then transfuse them back to patients Some patients are unable to provide enough T cells for a variety of reasons to benefit from this treatment Moreover, the manufacturing process of car-t therapy is complex and long Therefore, the development of "ready to use" car-t therapy is an important direction to solve the application bottleneck of car-t therapy < br / > the strategy of "ready to use" car-t therapy developed by fate therapeutics is to screen and preserve IPSC cell lines that can be expanded and differentiated into T cells and natural killer (NK) cells by genetically engineering the induced pluripotent stem cells (IPSC) These IPSC cell lines have been genetically engineered The differentiated T cells or NK cells will not lead to the immune rejection of patients, and they can express various therapeutic proteins Then, when needed, they can be expanded and differentiated into "ready to use" T-cells or NK cell therapies < br / > at the ash annual meeting, fate therapeutics released the results of phase 1 clinical trials of NK cell therapy FT500 and ft516 differentiated from IPSC cells According to the company's press release, this is the world's first generic "ready to use" IPSC differentiated NK therapy FT500 is a NK cell therapy formed by IPSC cell differentiation Based on FT500, ft516 expresses CD16 receptor which can not be cut on cell surface, thus optimizing antibody mediated cytotoxicity (ADCC) < br / > preliminary results showed that 12 solid tumor patients receiving FT500 did not show dose limited toxicity and serious adverse events related to FT500 The FT500 cells injected into the patient's body did not stimulate the immune system's rejection of them < br / > at present, most "ready to use" cell therapies still need to rely on healthy donors to provide T cells, while using IPSC cells can avoid the limitations of using donors to provide cells This research is still in the early stage, if successful, it will bring revolutionary changes to cell therapy < br / > forty seven: change the treatment paradigm of hematopoietic stem cell transplantation In the phase 1b trial of MDS and AML patients, this antibody targeting "don't eat me" signal is superior to the single drug therapy of azacitidine However, the application of magrolimab is not limited to killing cancer cells It may become an important means to change the paradigm of hematopoietic stem cell transplantation < br / > hematopoietic stem cell transplantation is an important method to treat or even cure many kinds of blood cancer However, before hematopoietic stem cell transplantation, patients need to receive chemotherapy or radiotherapy to remove the existing hematopoietic stem cells This treatment is very toxic Many patients can't receive chemotherapy or radiotherapy due to physical reasons, so they can't accept hematopoietic stem cell transplantation, and miss the chance to cure the disease < br / > forty seven's strategy to solve this problem is not to use chemotherapy or radiotherapy, but to use antibodies to specifically eliminate hematopoietic stem cells in the body The company has developed a humanized monoclonal antibody targeting ckit It can induce macrophages to engulf hematopoietic stem cells when combined with the CDIt antigen expressed on the surface of hematopoietic stem cells CD47 is a "don't eat me" signal expressed on the cell surface, which can inhibit the phagocytosis of macrophages The combination of anti-CD47 antibody and anti dependent ckit antibody can enhance the phagocytosis ability of macrophages to hematopoietic stem cells, so as to achieve the effect of eliminating hematopoietic stem cells in vivo < br / > in the non-human primate model, the company's humanized anti-ckit antibody fsi-174, combined with anti-CD47 antibody magrolimab, can significantly eliminate the hematopoietic stem cells in animals.
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