ASH Spotlight: CAR-T as First-Line Therapy for Multiple Myeloma Gains Momentum – Key Advances from Chinese Biotechs
Gracell
Cell and Gene Therapy Developer
Recently, the World Cup has reached a fever pitch, with top teams showcasing their distinct styles and strengths on the field, striving to stand out through unique techniques or advantages. Across the ocean, the 64th Annual Meeting of the American Society of Hematology (ASH) is being held in a grand hybrid format, both online and offline. Multinational pharmaceutical companies and innovative biotechnology firms focused on hematological diseases are once again “competing side by side” and “soaring together,” but in this arena, the common adversary they strive to defeat is “blood diseases.” Over the course of four days, thousands of scientific abstracts will be presented, showcasing the latest research findings to renowned global experts in hematology and oncology.
In the past two years, therapeutic innovations for hematologic malignancies have advanced rapidly worldwide. Autologous CAR-T technology has gradually matured, while off-the-shelf (universal) CAR-T has garnered significant attention. As a next-generation cell therapy, CAR-NK holds great promise for treating both hematologic and solid tumors. Meanwhile, companies are actively exploring other innovative modalities, such as bispecific antibodies and PROTACs.
In China, CAR-T therapy remains at the forefront of hematologic malignancy treatment. Although it still faces the challenge of high costs, positive developments in R&D continue to emerge. Legend Biotech’s CAR-T therapy, Carvykti, developed in collaboration with Johnson & Johnson, successfully entered international markets earlier this year; following closely behind, star CAR-T companies such as Gracell and Carsgen Therapeutics are actively focusing onDifferentiated Layout, Accelerating R&D Pace. Judging from Carvykti’s currently strong overseas sales, as long asThe product’s efficacy is inherently robust., still possessesSignificantCommercialization Prospects。
Artery New Medicine continues to closely monitor the hematologic oncology sector. Leveraging the highlights from this year’s ASH Annual Meeting, let us take a direct look at the key innovations and latest trends showcased at the conference:
Focus: Differentiated Competition in Multiple Myeloma, First-Line Treatment Emerges as a New Trend
Among hematologic malignancies, multiple myeloma (MM) has been a major focus of attention. This year’s ASH Annual Meeting featured numerous latest research advances in this disease area. According to incomplete statistics, this year’s annual meetingThere are more than 40 research reports on MM., with indications covering relapsed/refractory multiple myeloma (RRMM), andNewly Diagnosed Multiple Myeloma (NDMM). CAR-T, monoclonal antibodies, bispecific antibodies, protein degraders, CAR-NK, and various combination therapies are making their competitive debut.
In the treatment of multiple myeloma (MM), B-cell maturation antigen (BCMA) is an unavoidable topic. At this year’s American Society of Hematology (ASH) Annual Meeting, representative companies across various therapeutic modalities presented their latest advancements, attracting widespread attention. A notable trend is that while many BCMA-targeted therapies continue to focus on relapsed/refractory multiple myeloma (RRMM) as their indication, keenly perceptive companies areNDMM (First-Line Treatment)breakthroughs have been achieved in the layout. Leading the charge isGracellofFasTCAR-T GC012F。
GC012F is aBCMA/CD19 Dual-TargetAutologous CAR-T product. According to the latest clinical data disclosed by Gracell, 16 transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) have received GC012F, and all patients exhibitedMultiple High-Risk Features。
Notably, compared to the data through July presented in the prior ASH abstract, Gracell Biopharma’s latestOral Presentationform, further disclosingLatest Follow-up Data as of October 14. The median follow-up time for the 16 evaluable patients was 8 months (range: 1.3–15.4 months). In terms of efficacy,ORR as high as 100%，sCR was 87.5%(14/16), in all dose groups100%of evaluable patients achievedMRD-Negative; based on the previous work by Munshi NC's team inBlood Advances1 published in a large meta-analysis demonstrated that,MRD negativity has become an indicator of better survival outcomes.。
Furthermore,100%of CAR-T cells observed in patients' bodiesRobust Amplification，Excellent Durability, also heralding a moreDeep and Enduringefficacy. Additionally, it is worth noting that GC012F'sSafety Performance Achieves Another Breakthrough. For comparison, the previously announced GC012F treatment at EHARRMMData show that,93%of patients experienced grade 0-2 CRS, the proportion of grade >3 CRSOnly 7%, already possesses advantages over similar therapies; and this treatmentNDMMthe data is even more impressive—75% of patients did not experience any grade of CRS，Only 25%of patients experienced Grade 1–2 CRS, and no ICANS or other neurotoxicity of any grade was observed. This challenges the industry’s conventional perception that CAR-T therapies offer “potent efficacy but limited safety,” achievingBalancing Efficacy and Safety, further enhancing the accessibility of CAR-T therapy.
The above data validate GC012F from multiple perspectives.Excellent Clinical Therapeutic Potential and Reliable Safety Profile, significantly reducing the recurrence rate of the condition, and also clarifying itsProgressively Deepening Response, potentially enabling patients to achieve fundamental benefits. Compared with other CAR-T therapies, GC012F'sAdverse EventsExtremely Low Incidence，Minimal side effects, which has allowed the industry to see autologous CAR-T therapy becomeFirst-line therapy for MMthe hope that it could break the current paradigm in which CAR-T therapy is limited to treating later-line hematologic malignancies.
In fact, as a product with robust capabilities, GC012F has previously demonstrated impressive preliminary clinical data in trials for the treatment of RRMM and B-NHL, which were presented at academic conferences such as EHA and ASCO in 2022.
VCBeat has noted that bispecific antibodies were also a key focus at this year’s ASH Annual Meeting. In the field of hematologic malignancies, Roche, Johnson & Johnson, AbbVie, and Pfizer all presented the latest clinical data on their respective bispecific antibody products. Notably, Johnson & Johnson’s recently approved teclistamab also targets the multiple myeloma (MM) segment.
Just one month after its approval, multiple clinical datasets for teclistamab were presented at the ASH Annual Meeting, including analyses from the pivotal registration study (MajesTEC-1, Abstract 97) and updates on studies in newly diagnosed patients (Abstracts 3242 and 4558). Its positive clinical results have positioned it as a leading bispecific antibody therapy for relapsed/refractory multiple myeloma (RRMM). Pfizer, Regeneron, and Bristol Myers Squibb (BMS) also disclosed clinical data for their BCMA/CD3 bispecific antibodies. Among them, Pfizer, with the most advanced clinical progress, is poised to emerge as a strong contender in this therapeutic area following Johnson & Johnson.
Compared with CAR-T therapy, the use of bispecific antibodies for treating RRMM still requires further exploration and breakthroughs. In terms of pricing, Johnson & Johnson’s teclistamab has a total cost of $355,000–$395,000 for a 9- to 10-month course, which is comparable to BMS’s Abecma at $410,000 or Legend Biotech’s Carvykti at $465,000, offering no significant price advantage.
In terms of efficacy, bispecific antibodies still have room for improvement. VCBeat New Medicine extracted the latest clinical data on bispecific antibodies and CAR-T products for a brief comparison. Based on current progress, the clinical efficacy of CAR-T is significantly superior to that of bispecific antibody products; however, the latter offers patients more treatment options, such as advantages in administration convenience.
Data sources: official websites of respective companies, Asymchem Pharmaceutical News
Breaking the Impasse in CAR-T Therapy
From this ASHAt the annual conference, VCBeat observed thatCAR-TTherapies are increasingly becoming the treatmentMMthe top priority.
At this year’s annual conference, there were as many as 27 reports on CAR-T therapy, including 8 clinical reports on BCMA-targeted CAR-T therapies, all for the treatment of multiple myeloma (MM).
Among them, the majority of Chinese biotech companies’ R&D pipelines focus on autologous CAR-T therapies. Apart from Gracell’s GC012F, Legend Biotech and Carsgen Therapeutics, among others, unveiled new data on their respective products. In contrast, overseas companies such as Cellectis and Allogene Therapeutics are concentrating on universal (off-the-shelf) CAR-T therapies.
CAR-T therapy holds broad prospects, yet many bottlenecks remain. The high cost speaks for itself, with prices exceeding one million yuan per dose both domestically and internationally; the reimbursement pathway for domestic products has not been smooth.
However, its primary issue remains inPreparation Cycleabove. CAR-T therapy requires patients to wait at least 4 weeks for preparation to be completed, during which time they need to receive bridging therapy,Increased Medical Risk, resulting in suboptimal prognosis even after patients ultimately receive CAR-T therapy, with rapid disease progression that compromises the efficacy of CAR-T treatment.
This outcome is closely associated with the suboptimal quality of patient-derived cells. Currently marketed CAR-T products are primarily indicated for heavily pretreated patients in later lines of therapy. Furthermore, patients receiving chemotherapy as a bridge to CAR-T cell manufacturing often have poor baseline health status, resulting in a limited yield and inferior quality of T cells isolated from peripheral blood. Regardless, this represents a pressing practical challenge that urgently needs to be addressed.
In response to these challenges, the ASH Annual Meeting showcased solutions from various companies: some focused on target optimization, others delved into universal CAR-T therapies, and still others continuously iterated their related technology platforms.
On the target,Dual-Targeting Is Emerging as a Breakthrough Strategy for CAR-T Therapy. In addition to Gracell’s GC012F, a dual-target therapy against BCMA and CD19, Hesyuan Biopharmaceuticals, Ucar-T Biotherapeutics, and Wuhan Si’an have all made innovations in dual-target approaches.
Among universal CAR-T products, gene-editing giant CRISPR Therapeutics and Allogene, the pioneer in universal CAR-T therapy, made prominent appearances, while in China, BeiHeng Biotechnology and Bund BioMed presented their Phase I clinical trial results.
In addition to designing more complex dual-target CAR-T,GracellAlso fromProcess TechnologyFrom a novel perspective, we independently developed groundbreakingFasTCAR Next-Day Manufacturing Technology Platform。
GC012F is the core candidate product developed based on the FasTCAR platform. Traditional CAR-T cell manufacturing requires steps such as T-cell activation, transduction, and ex vivo expansion, whereas the FasTCAR platform differs in that it canSimultaneous Activation and TransductionResting T cells, which exhibit enhanced expansion and tumor cell clearance activity after transduction, can be manufactured by the next day, eliminating the need for in vitro expansion steps.
Preclinical studies have demonstrated that CAR-T cells produced via the FasTCAR technology platform exhibit a younger phenotype and reduced exhaustion, along with enhanced expansion capacity, persistence, bone marrow migration capability, and tumor cell clearance activity. Leveraging"Production Completed the Next Day"Advantages: The FasTCAR platform technology can not only significantly improve cell production efficiency,Enhance T Cell Health, withFaster Speedprovided to patients to reduce medical risks; it can alsoSignificantly Reduce Production Costs, thereby alleviating the financial burden on patients.
Chinese Biotech Companies Take Root on the International Stage
This year, selected for the ASH Annual MeetingNumber of Biotech Reports in Chinahas reached as high as362articles, among which there are35 studies shortlisted for the oral session, with 327 studies selected for the poster session. Chinese pharmaceutical companies are making rapid progress, and their voice on the international academic stage is gradually growing louder.
Since the Chinese biopharmaceutical industry entered its golden age of development, domestic biotech companies have been actively participating in international clinical academic conferences. In particular, after Legend Biotech stood out at the ASCO conference in 2017 with the outstanding clinical results of Cilta-cel, the industry has been eager to see more solid Chinese innovative drug companies make their mark on the world stage.
In recent years, Gracell has not only focused on innovation but also committed to showcasing its clinical achievements on the international stage. Since presenting the clinical progress of its universal CAR-T product, GC027, at the AACR Annual Meeting in 2020, Gracell has annually disclosed its latest data and delivered multiple oral presentations at major international clinical academic conferences, including ASCO, EHA, ASH, and AACR.
It is precisely for this reason that Gracell has garnered attention from media outlets both domestically and internationally. For instance, the company has recently received multiple accolades, including an award in China presented by the China National Pharmaceutical Industry Information Center【2022 Golden Bud Award for Biopharmaceutical Innovation】, the award recognized its high-value R&D pipeline and the immense potential of its technology platform; furthermore, it earned acclaim overseas with its FasTCAR technology platform.Fierce Life Sciences Annual Innovation Awards: “Biotechnology Innovation Award”(Biotech Innovation). The companies shortlisted alongside Gracell have all achieved outstanding results in their respective fields, including DNA Script, a leader in enzymatic DNA synthesis; Genalyte, which specializes in providing blood testing services to users using chip technology; and Senda Biosciences, founded with investment from Flagship Pioneering and dedicated to programming human cells through natural code to provide patients with targeted, effective, and tunable therapies. All of these are emerging players poised to potentially bring significant impact to the pharmaceutical industry.
As a biotech company deeply rooted in China with a global perspective, Gracell has establishedGlobalizationcorporate image, steadily advancing in both China and the United StatesEarly-Stage Research, Clinical Development, and Manufacturing Processesa deeply integrated layout.
In the first quarter of this year, Gracell’s innovative R&D center in the United States was officially launched in San Diego, California. As a key component of its globalization strategy, the center will enhance its internal capabilities in drug discovery, preclinical research, and translation. On the product development front, the company’s first-in-class donor-derived allogeneic CAR-T therapy, GC007g, has entered clinical trials in China.Phase II Pivotal Clinical Stage; GC012F targetsThree Different IndicationsThe clinical development has also advanced on three fronts simultaneously, with dual Investigational New Drug (IND) applications filed in both China and the United States for the relapsed/refractory multiple myeloma (RRMM) indication; the Center for Drug Evaluation (CDE) website currently shows the application as accepted.
With continuous iteration of innovation capabilities and the gradual emergence of innovative achievements, Gracell is leading the transformative path of next-generation cell therapies, making it a company to watch.
References:
1. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma | Blood Advances | American Society of Hematology (ashpublications.org)