CAR-T cells are a high-profile treatment method in the new era. With the continuous display of their therapeutic potential, the industry is constantly expanding the therapeutic range of CAR-T therapy, including tumors, infectious diseases, autoimmune diseases, etc. Among them, self-free disease is the most popular exploration and treatment field of CAR-T, and a number of domestic and foreign companies have promoted their products into clinical practice in this direction. Recently, several self-exempt CAR-T head companies released updated clinical data at the 2024 European Annual Meeting of Rheumatology (EULAR 2024).
Kyverna Therapeutics CD19 CAR-T cell KYV-101 is one of the earliest self-free CAR-T products to enter the clinic; its recently updated clinical data covers 30 patients and is one of the largest published clinical data sets of CAR-T treatment for self-free diseases.
▲ CAR constructs of KYV-101 (Photo Source: Reference 2)
According to the report, of 30 patients with self-free disease (including myasthenia gravis, lupus nephritis, and multiple sclerosis) treated with KYV-101:21 patients were able to discontinue immune disease drugs completely and 9 patients failed to discontinue; 28 patients had reduced activity and only 1 patient receiving a lower dose of lupus relapsed. In terms of safety, no patient experienced grade 3 or higher grade CRS, and three patients developed low-grade neurotoxicity. Recently, KYV-101 has also made a breakthrough in rigid human syndrome (SPS). A report in the Proceedings of the National Academy of Sciences (PNAS) describes a significant improvement in walking distance and a 40% reduction in GABAergic drug use after KYV-101 to treat a patient with refractory SPS, while demonstrating good safety and tolerability. Based on the results, KYV-101 was designated by Germany as part of the treatment regimen for critical SPS patients who had failed conventional therapy. In addition, in an investor briefing released by Kyverna in June, the company disclosed data from the first 20 patients who received KYV-101, comparing the safety data of other CD19 CAR-T cells in tumor treatment, and the data showed that KYV-101 had a good safety profile.
▲ Data of 20 patients for KYV-101 (Photo Source: Reference 2)
Kyverna The company has high hopes for KYV-101 in the treatment of lupus nephritis. According to the preliminary clinical results of clinical studies on KYSA-1 and KYSA-3, it can clear CD19 B cells well and show signs of improved disease activity.
▲ Clinical data of lupus nephritis in KYV-101 (Photo credit: Reference 2)
Improvement in symptoms and increased mobility were observed in the first myasthenia gravis patient within 60 days of KYV-101 infusion. The detailed data was published in the Lancet Neurology.
▲ Clinical data on myasthenia gravis for KYV-101 (Photo source: Reference 2)
KYV-101 also showed a positive safety profile for MS.
▲ Multiple sclerosis data for KYV-101 (Photo source: Reference 2)
Read on: CD19 CAR-T for lupus nephritis FDA approved IND application for CD19 CAR-T for lupus nephritis
Cabaletta The CD3 / 4-1BB design
Cabaletta Bio Designed a fully human CD19 CAR-T cell CABA-201 using 4-1BB as a costimulatory domain to enhance its durability to provide long-term remission to patients after depletion of CD19-positive B cells after a one-time infusion.
▲ CAR constructs of CABA-201 (Photo Source: Reference 3)
Cabaletta Company is advancing four phase 1 / 2 clinical studies evaluating CABA-201 in a total of 10 cohorts with six patients each. All cohorts used the same dose of 1x106 cells / kg, following the pretreatment protocol of fludarabine and cyclophosphamide, without dose escalation requirements.
▲ Baseline data for two patients (Photo source: Reference 3)
In the latest published clinical data, two patients, one with immune-mediated necrotizing myopathy (IMNM) and one with systemic lupus erythematosus (SLE), were follow-up for 3 months and 1 month, respectively. Complete B cell depletion was observed 15 days after CABA-201 infusion, and both developed early, transient leukopenia as expected; both reached peak CAR T cell expansion on day 15, the magnitude consistent with academic experience with similar 4-1BB CD19-CART constructs.
▲ CABA-201-mediated depletion of B cells (Photo Source: Reference 3)
At week 12 of follow-up for IMNM patients, the data showed that creatinine kinase decreased from 617 at baseline to 308 with a total improvement score (TIS) of 30.
At week 4 of SLE visit, the data showed that the SLEDAI-2K (SLE Disease Activity Index) score improved from 26 at baseline to 10 at baseline. Importantly, at week 8, flow cytometry detected an immature, naive B cell phenotype, indicating that the underlying immune system was resetting and undergoing confirmatory analysis.
▲ B cell reconstruction (Photo credit: Reference 3)
In terms of safety and tolerability, CABA-201 was administered per protocol during the four-day hospitalization and was generally well tolerated, with no serious adverse events reported in any patient during the follow-up period. During the follow-up, no evidence of CRS or ICANS was observed, both patients used Tocilizumab; infection; prolonged maintenance therapy or combination was discontinued in all patients except for prednisone tapering in SLE.
The CD19 CAR-T of pharmacminjuol
On May 30,2024, the low-dose clinical data of CD19 CAR T cell injection in Chinese adults with active systemic lupus erythematosus (SLE) was published at the European Conference of Rheumatology 2024 (EULAR2024). Data Cutoff 18 December 2023, a total of three active SLE adult females in the 2510 ^ 6 (25M) dose group received a single CAR T cell infusion and completed a minimum of 4-month follow-up. After infusion, these 3 subjects showed continued improvement in signs and symptoms, SELENA-SLEDAI scores decreased from baseline 8 to 14 to 0 or 1, all 3 subjects achieved SLE response index 4 (SRI-4), and two subjects achieved a more severe lupus low disease activity (LLDAS). As of the data deadline, the 3 subjects were not using SLE drugs such as hormones and immunosuppressants. PK / PD data also confirm that rekeolensel can expand and deeply deplete peripheral B cells in vivo. In addition, the regeorgolense shows good safety. Two subjects had CRS, including 1 grade 1,1 grade 3; no neurotoxicity (NT); two subjects had cytopenias and one subject with infection, macrophage activation syndrome (MAS), and serosal effusion. After treatment, they recovered completely around day 60. The above three patients are still in the study and follow-up. Up to now, the follow-up time is more than 6 months, and the patients' disease activity and clinical symptoms are still improving. The data show that even at a very low dose compared with the blood tumor indication, a single infusion of rekeolenssay injection can still achieve a relatively deep and lasting disease remission in patients with moderate to severe lupus erythematosus, with good safety. In addition, in the data summarized by this IIT, 100% of patients in 1 least 3 months reached the SRI-4 index until 6 months follow-up and still 100% reached the SRI-4 index; among all patients (12), 11 patients (91.67%) discontinued traditional hormones, immunosuppressive agents, and other drugs after transfusion.
The BCMA / CD19 CAR-T of the iCell
In May 2024, iCell Gene Therapeutics published the positive results of its investigator-initiated clinical trial (IIT) for cell therapy with BCMA and CD19 targeted complex chimeric antigen receptor-T (BCMA-CD19 cCAR-T) cells. The results are published in the journal Annals of the Rheumatic Diseases. The results showed that 12 patients received an initial dose of 3x106 cCAR-T cells / kg. At 3 months after treatment, all autoantibodies (including antibodies from long-lived plasma cells) were negative and complement returned to normal levels. All achieved asymptomatic and no drug remission at 46 months of follow-up. Patients achieved complete B cell recovery within 2 – 6 months of their cCAR-T treatment. In addition, patients also decreased from a mean of 10.6 on SLE disease activity index 2000 to 2.7; 10 patients with LN significantly improved renal function within 90 days of cCAR-T. Based on the positive data presented above, iCell plans to file an investigational New Drug application (IND) in China and the United States this year.
brief summary
While Kyverna's KYV-101 and Cabaletta's CABA-201 were relatively positive, in the capital markets, the two companies continued to fall in the two days, down more than 10%. According to reports, there are more than 30 ongoing clinical trials, and with the advancement of clinical trials and more clinical data, it gradually shows the potential of CAR T cell therapy in self-free disease. However, in the self-exemption CAR-T program, there is also a potential phenomenon of a cluster of indications, including systemic lupus erythematosus and lupus nephritis.
reference documentation:
1.https://endpts.com/autoimmune-car-t-data-dump-kyverna-cabaletta-shares-fall-after-unveiling-early-stage-results/
2.https://ir.kyvernatx.com/static-files/348ee07d-e52c-423c-9a99-bf5f4637e682
3.https://www.cabalettabio.com/news-media/press-releases/detail/112/cabaletta-bio-reports-positive-initial-clinical-data-from
4. JW Therapeutics Preliminary Clinical Data of Rekeolenssay Injection for the Treatment of active systemic lupus erythematosus in China released at the European Conference of Rheumatology 2024
5.https://www.businesswire.com/news/home/20240523089601/en/iCell-Gene-Therapeutics-Announces-Positive-Clinical-Data-from-Investigator-Initiated-Phase-1-Trial-Evaluating-BCMA-CD19-Compound-CAR-in-Patients-with-Systemic-Lupus-ErythematosusLupus-Nephritis-Published-in-Annals-of-the-Rheumatic-Diseases
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