General MM,   Relapsed/refractory patients

CAR T-cell therapies in clinical development in China

During the 2nd European CAR T Meeting, Sitges, ES, Jianxiang Wang from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking, CN gave a presentation on current chimeric antigen receptor (CAR) T cell trial activities in China.1 He described intensified efforts of Chinese researchers to study various CAR T therapies targeting a variety of tumor proteins, including CD19, CD22, and B-cell maturation antigen (BCMA). The number of CAR T-cell therapies in clinical development has rocketed in recent years. Currently, in China, there are over 200 ongoing clinical trials in hematologic malignancies as well as solid tumors. The speaker then moved onto describing examples of successful clinical trials in different therapy areas.1

CAR T-cell therapy in multiple myeloma (MM)

The LEGEND-2 trial (NCT03090659) is an open-label phase I study investigating LCAR-B38M, an anti-BCMA CAR T-cell therapy, in patients with relapsed or refractory (R/R) MM.2 The treatment has resulted in the median progression-free survival (PFS) of 15 months and overall response rate (ORR) of 88%, including complete response (CR) in 68% and partial response (PR) in 14% of patients. Read more about the clinical trial and results in this article on the Multiple Myeloma Hub.

Another briefly discussed CAR T therapy was a combination of humanized anti-CD19 and anti-BCMA CAR T-cells. The safety and efficacy of the products are being evaluated in phase II clinical trial in patients with R/R MM (ChiCTR-OIC-17011272).3 After lymphodepletion with fludarabine and cyclophosphamide, patients were infused with humanized anti-CD19 CAR T cells (1×106 cells/kg) and murine anti-BCMA CAR T-cells (1×106 cells/kg). At the data cut-off, follow-up was available for 21 out of 22 patients who received the CAR T therapy. One patient was excluded due to rapid disease progression and three other patients discontinued treatment (two died and one progressed and subsequently received salvage therapy). The results of the CAR T-cell combination were promising:

  • At a median follow-up of 179 days, the regimen induced ORR of 95%, with stringent CR (sCR) rate of 43%, CR rate of 14%, very good PR (VGPR) rate of 24%, and PR rate of 14%
  • The safety profile was consistent with other reported for CAR T-cell therapies
  • There were no deaths recorded as treatment-related, cytokine release syndrome was the most common adverse event (90% of patients, the majority had grade 1 or 2), and hematological toxicities were the most common serious adverse events (95% of patients)

A phase I clinical trial of a bispecific CAR T-cell therapy against BCMA and CD38 in patients with R/R MM was also presented.4 Out of 16 patients who had received treatment at data cut-off, 87.5% responded to treatment and achieved measurable residual disease (MRD) status in the bone marrow, including 50% with sCR, 12.5% with a VGPR, and 25% with a PR. The PFS at nine months was 75% and extramedullary lesions were eliminated in all five patients with extramedullary disease.4

The fourth cellular therapy discussed by the speaker for MM was CT103A, a second-generation fully human CAR T product targeting BCMA. The product, based on the positive data from the clinical study (ChiCTR1800018137), has been granted approval by the National Medical Products Administration (NMPA) in China for the treatment of R/R MM.5 Read more about the approval here.

  • Key inclusion criteria were:
  • Refractory disease to a proteasome inhibitor and immunomodulatory imide drugs 
  • BCMA positive
  • ≥ 3 prior lines of therapy
  • Eastern Cooperative Oncology Group performance status < 2
  • After lymphodepletion with cyclophosphamide and fludarabine, patients were infused with escalating doses of the CAR T product (1×106cells/kg, 3×106 cells/kg, and 6×106 cells/kg)
  • At the data cut-off on 28th November 2019:
    • Median age was 53.5 years (38–66)
    • Median time since diagnosis was 32 months (8–92)
    • 8% of patients had high-risk cytogenetics
    • Patients received a median of four prior lines of therapy (3–6), including 38.9% with prior autologous hematopoietic stem cell transplant (auto-HSCT), and 22.2% with prior BCMA CAR T; all patients were previously exposed to bortezomib and lenalidomide
  • All patients responded to CT103A therapy:
    • sCR/CR rate of 70%
    • ≥VGPR rate of 22.2%
  • In 10 out of 14 patients the construct was present for over 100 days after infusion
CAR T-cell therapy in AML6

Phase I dose-escalation study of first-in-human CLL1-CD33 compound CAR (cCAR) T-cell therapy. Patients with R/R acute myeloid leukemia (AML) after leukapheresis and lymphodepletion with cyclophosphamide/fludarabine, received an infusion of CLL1-CD33 cCAR T-cell therapy at one of three doses: 1×106/kg, 3×106/kg, or 9×106/kg. Patients’ bone marrow biopsy was then taken and tested for the presence of residual disease. The treatment induced complete remission in refractory AML patients, including a case of CR within 19 days.

CAR T-cell therapy in non-Hodgkin lymphoma (NHL)

An open-label, non-randomized, dose-escalation, phase I study (NCT04232826) to determine the safety and efficacy of CNCT19 in adult patients with R/R diffuse NHL showed a response in 13 out of 16 patients treated with the product.1

Auto-HSCT sequential CAR T therapy for patients with high-risk R/R B-cell NHL (N = 30) was also mentioned. It induced CR in 26 patients, PR in one patient, and progressive disease (PD) in two. In patients with TP53 aberrations, 11 out of 14 patients achieved CR and two had PD.1

Conclusion

The speaker concluded with a summary of novel CAR T targets for the 14 investigational new drugs currently in development in China. The majority of them target CD19 (n = 10) evaluated in R/R acute lymphoblastic leukemia (n = 3), R/R NHL (n = 7), R/R MM (n = 3), and solid tumors (n = 1). Other CAR T targets in evaluation include anti-BCMA (n = 3) and anti-GPC3 (n = 1).

References
  1. Jianxiang Wang. Current CAR T-cell trial activities in China. The 2nd European CAR T therapy, Sitges, ES. Oral presentation
  2. Zhao WH. et al., A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018 Dec 20;11(1):141. DOI:10.1186/s13045-018-0681-6
  3. Yan Z. et al., A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019 Oct;6(10):e521-e529. DOI:10.1016/S2352-3026(19)30115-2
  4. Li C. et al. A bispecific CAR-T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Blood. 2019; 134 (Supplement_1):930. DOI: https://doi.org/10.1182/blood-2019-130340
  5. Business Wire. NMPA Approves IND Application for CT103A, a Fully-human BCMA CAR-T for the Treatment of Relapsed/Refractory Multiple Myeloma Co-developed by IASO BIO and Innovent Biologics. https://www.businesswire.com/news/home/20191002005214/en. Published; October 02 2019, [Accessed: Feb 05 2020]
  6. Liu F. et al., First-in-Human CLL1-CD33 Compound CAR T Cell Therapy Induces Complete Remission in Patients with Refractory Acute Myeloid Leukemia: Update on Phase 1 Clinical Trial. Blood. 2018; 132 (Supplement 1):901. DOI: https://doi.org/10.1182/blood-2018-99-110579
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