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The world’s fifth marketed CAR-T drug: targeting BCMA
The world’s fifth marketed CAR-T drug: targeting BCMA. On March 26, 2021, the US Food and Drug Administration (FDA) approved Idecabtagene Vicleucel (trade name Abecma) for the first time after 4-line treatment (including immunomodulators, proteasome inhibitors and anti-CD38 monoclonal antibodies) Adult patients with relapsed or refractory multiple myeloma (Relapsed or Refractory multiple myeloma, RRMM).
Idecabtagene Vicleucel is a CAR-T therapy targeting B cell maturation antigen (BCMA). Previously, the drug was awarded Breakthrough Drug Designation (BTD) and Priority Drug Designation (PRIME) in the United States and the European Union. Developed jointly by BMS and Bluebird.
Multiple myeloma is a blood cancer, after Hodgkin’s lymphoma, MM is the second most common blood cancer and the 14th most common cancer. In the past half century, the treatment of MM has made remarkable progress. Beginning in the mid-1960s, alkylating agents, mainly melphalan and cyclophosphamide, usually accompanied by corticosteroids, were considered the standard treatment for the disease, and this treatment lasted for 30 years.
Since the discovery of the immunomodulatory effect of thalidomide in the late 1990s, the treatment model for MM has undergone tremendous changes. This drug has significant anti-myeloma properties. Subsequently, lenalidomide and pomalidomide of the same mechanism were discovered in 2005 and 2013. In addition, in 2003, it was discovered that the proteasome inhibitor bortezomib (bortezomib) has anti-myeloma activity, and then carfilzomib and ixazomib were discovered, which provided a substantial supplement to the treatment of this disease.
In 2015, the FDA approved two monoclonal antibody drugs Daratumab and elotuzumab for the treatment of MM. The targets of the two antibodies are located on the surface of MM cells, namely CD38 and SLAMF7. Another anti-CD38 monoclonal antibody, isatuximab, was approved by the FDA in 2020. The current FDA-approved treatments for MM also include panobinostat (2015), a pan-histone deacetylase inhibitor, and linesor (2019), a nuclear export inhibitor. In the past 40 years, the success of these treatment advances has more than doubled the five-year survival rate for the disease, from 24.5% in 1975-77 to 55.1% in 2010-2016.
BCMA (CD269; TNFRSF17) is a member of the tumor necrosis factor receptor superfamily and was first discovered in the early 1990s. This 184 amino acid glycoprotein plays a major role in the maturation and differentiation of B cells into plasma cells. Structurally, BCMA consists of three main domains: extracellular segment (amino acids 1-54, connected by disulfide bonds at positions 8-21, 24-37, and 28-41), transmembrane region (amino acids 55- 77) and the intracellular segment (amino acids 78-184).
In normal human tissues, BCMA protein and mRNA are almost only found on plasma cells, and they are selectively overexpressed during the malignant transformation of plasma cells to promote tumor cell growth, survival and drug resistance, mainly by activating NFκB, AKT, phosphatidylinositol 3 kinase (PI3K), STAT3, and MAPK intracellular signal transduction cascade. Whether it is cell lines or patient samples, the consistency and uniqueness of BCMA on the surface of MM cells makes BCMA an attractive target for MM drug discovery and development.
Since Idecabbtagene vicellel was designated as a breakthrough therapy by the FDA in 2017, it has been included in a series of phased trials, named KarMMa-1 to KarMMa-4 (NCT03361748, NCT03601078, NCT03651128 and NCT04196491). Data from the top 33 RR myeloma patients (NCT02658929) in KarMMa-1 showed an ORR of 85%, including 15 patients in complete remission, although 6 of them subsequently relapsed. The average PFS for this study was 11.8 months. In addition, in this study, 100% (16/16) of the evaluable responders partially showed negative MRD.
Adverse reactions were reported as hematology grade 3 or 4 (mainly neutropenia) and neurotoxicity (42%). CRS occurred in 76% of patients. Data from the KarMMa-2 trial showed that 128 evaluable RRMM patients had an average PFS of 8.6 months, with toxicity characteristics similar to those reported earlier. Based on these data, the FDA approved the marketing application of Idecabbtagene vicellel.
In addition, there are a series of other players on the BCMA CAR-T therapy circuit, including:
bb21217 uses the same lentiviral design as bb2121, but adds an additional PI3K inhibitor domain during in vitro culture. This production improvement has been proven to significantly enhance CAR T cell-based immunotherapy by enriching the final memory-like T cell population, thereby enhancing the durability and effectiveness of T cells. Currently, bb21217 is in the Phase I dose escalation trial for RRMM patients (NCT03274219). So far, in this trial, 22 patients have reported adverse event data. Among them, 13 patients developed CRS and 5 patients developed neurotoxicity. Both toxicities have been resolved. Of the 18 evaluable patients, a clinical response was observed in 15 cases, although there were subsequent relapses in 6 cases. Of the 8 patients evaluated at 6 months, 6 patients had detected CAR-T cell persistence, and 2 patients had CAR-T cell levels detected 18 months later.
JNJ-68284528 (LCAR-B38M; JNJ-4528) is unique in BCMA targeted T cell therapy. It targets two BCMA epitopes (VH1 and VH2) to increase the affinity for BCMA expressing cells. In the LEGEND-2 phase 1 trial of JNJ-68284528 (NCT03090659), 57 patients who had received three treatments had an ORR of 88% and a PFS of 15 months. CRS occurred in 83% of subjects, mainly grade 1 or 2. The results of 21 evaluable RRMM patients in the CARTITUDE-1 phase Ib/II trial (NCT03548207) were similar to those in the LEGEND-2 study (ORR of 91%, no PFS, and CRS of 88%).
P-BCMA-101 obtained FDA orphan drug certification in 2019. It is a fully humanized anti-BCMA CAR T cell product, in which the CD3ζ/4-1BB signal domain is fused with the non-immunoglobulin Centyrin® scaffold. In contrast, this structure is smaller than that on immunoglobulins, has a higher binding affinity, improves stability, reduces immunogenicity, and reduces production costs. These qualities are attributable to the use of piggy-BAC®-based technology in the manufacturing process, rather than viral vectors. A phase I trial of P-BCMA-101 (NCT03288493; PRIME) conducted on 12 severely preconditioned RRMM patients showed that the ORR of 6 patients under evaluation was 83%, and 1 of them experienced grade 2 CRS.
JCARH125 and FCARH143 are two fully human svFv bicistronic structures, containing a 4-1BB costimulatory domain. Both CAR-Ts use lentiviral vectors, but the production methods are different. Related to this is MCARH171, a gamma retroviral engineered product with a truncated EGFR safety system, which can be activated by cetuximab when it is necessary to reduce CAR-T cytotoxicity.
CT053 and CT103A are BCMA-targeted CAR-T cell structures based on lentiviral vectors. They contain a fully human single-chain antibody, CD8α hinge and transmembrane domain, 4-1BB costimulation and CD3ζ activation domains. They are currently developed by CARSgen Therapeutics. In the first phase of CT103A trial in China (ChiCTR1800018137), the ORR of the first 16 patients was 100%.
Other BCMA targeting CAR-T cell platforms that have recently entered the RRMM trial include Arcelix’s CART-ddBCMA, in which the single-chain antibody binding domain is replaced by a proprietary soluble protein antigen receptor X-linker (sparX) (NCT04155749); Descartes- 08. A CD8+ T cell preparation whose costimulatory domain has not yet been published (NCT03448978); another product of CD3-4-1BB is called CART-BCMA (NCT02546167).
FHVH-BCMA-T (FHVH33-CD8BBZ) contains a fully human pure heavy chain binding domain (FHVH33). This structure, by eliminating the light chain attached to the linker, is thought to reduce the risk of the receptor’s immune response. The preliminary results of a trial of the drug in 12 patients (NCT03602612) showed that there were objective responses in 10 subjects. Although 11 of 12 patients developed CRS, only 1 case was considered grade 3, which has been resolved by tocilizumab.
The short survival period, coupled with the high risk of CRS and other dose-limiting adverse reactions, is still one of the shortcomings of autologous BCMA targeting CAR-T cells in MM. To alleviate these problems, some CAR-T cell researchers have turned their attention to the potential development of “off-the-shelf” allogeneic products using T cells from healthy donors. One such example is ALLO-715, whose production process uses a patented transcriptional activator-like effector nuclease (TALENTM) for site-specific BCMA gene editing technology to limit T cell receptors in the final product Mediated immune response. ALLO-715 has now advanced to a phase one trial (NCT04093596). Another allogeneic BCMA targeting CAR-T cell candidate being developed for RRMM is PBCAR269A, which is a product of Precision BioSciences’ proprietary ARCUS® nuclease gene editing platform. It has also entered phase I clinical trials (NCT04171843)
(source:internet, reference only)