Recently, the Phase I clinical trial study led by Professor Li Jian, the director of the Department of Hematology at Peking Union Medical College Hospital, titled "Evaluation of the Safety, Tolerance, Preliminary Efficacy and Pharmacokinetic Characteristics of KQ-2003 CAR-T Cell Injection in POEMS Syndrome Patients" (CTR20242409), which was initiated in September 2024, has made significant progress. The first patient's initial assessment showed remarkable efficacy, achieving complete remission of VEGF (CRv) and complete hematological remission (CRH) on the 28th day, while demonstrating excellent safety features.
It is reported that the first enrolled patient (55 years old, male) was first diagnosed with POEMS syndrome in January 2019 and relapsed after third-line treatment (lenalidomide, bortezomib, etc.). At the time of enrollment in the clinical trial, the ECOG score was 1. Physical examination revealed darkened skin all over the body, white nails, muscle strength of grade V in both upper limbs, grade IV in both lower limbs, and mild limitation of dorsiflexion of both feet. The patient also presented with peripheral neuropathy, subclinical hypothyroidism, gonadal involvement, and sclerotic bone disease. The baseline VEGF was 4119.11 ng/L, and there were measurable extramedullary lesions. After receiving KQ-2003 cell infusion, VEGF dropped to 1666.36 ng/L on day 14 (a 59.5% reduction from the baseline), achieving partial response (PRv) in VEGF. On day 28, VEGF further decreased to 225.49 ng/L (a 94.5% reduction from the baseline), achieving complete response (CRv) in VEGF and complete response (CRH) in hematological efficacy. No grade 3 or higher cytokine release syndrome or neurotoxicity events occurred during the treatment, and the safety profile was good. This is also the world's first POEMS syndrome patient to receive CAR-T cell therapy in a registered clinical trial.
As Novatim's clinical research in multiple myeloma, POEMS syndrome and other fields continues to deepen, this individualized and precise treatment strategy is also expected to bring new treatment hope to patients with various relapsed/refractory diseases including autoimmune diseases, and also provides a "Chinese solution" for global plasma cell disease research.
POEMS Syndrome
POEMS syndrome is a paraneoplastic syndrome caused by abnormal proliferation of monoclonal plasma cells, mainly characterized by demyelinating peripheral neuropathy and multi-system involvement. Clinically, it is mainly manifested as polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinemia and skin changes. Other important features include papilledema, increased extravascular fluid volume, sclerotic bone lesions, thrombocytosis, erythrocytosis, increased vascular endothelial growth factor (VEGF) levels, thrombophilia and abnormal lung function [1][2]. This disease has been included in the first batch of rare disease list in China [3].
There is no unified standard treatment plan for POEMS syndrome. Clinically, hormone therapy and anti-plasma cell system treatment are mainly adopted. Common anti-plasma cell treatments include melphalan combined with dexamethasone (MD regimen), lenalidomide combined with dexamethasone (RD regimen), bortezomib combined with dexamethasone (BD regimen), etc. [3]. However, most patients still face the problem of disease recurrence after receiving conventional treatment, and the disability rate is high and the quality of life is poor for advanced patients.
Mechanism of KQ-2003 in treating POEMS syndrome
The KQ-2003 developed by Novatim is an autologous chimeric antigen receptor T-cell injection, which is a cell drug that can simultaneously target B-cell maturation antigen (BCMA) and CD19 antigen molecules. When the KQ-2003 CAR-T cells recognize the BCMA and CD19 antigens on the surface of tumor cells and bind to the tumor cells through synapses, the activated KQ-2003 CAR-T cells will kill the tumor cells.
BCMA is widely expressed in the clonal plasma cells of POEMS syndrome, and its expression level in malignant plasma cells is significantly higher than that in normal plasma cells, indicating that it plays a crucial role in the abnormal proliferation of POEMS clonal plasma cells [4]. CD19 is a functional receptor molecule on the surface of B cells, closely related to the proliferation, differentiation and growth regulation of B cells. A large number of studies have shown that CD19 shows high positive expression in POEMS syndrome [5], making it a potential therapeutic target for POEMS.
Novatim
Novatim Immune Therapeutics (Zhejiang) Co., Ltd. was established in 2018. It is a biopharmaceutical technology enterprise specializing in the research and development of innovative drugs for tumor immunotherapy. Based on clinical needs and differentiation, it is committed to establishing three research and development platforms: dual-function antibody platform, nano-bispecific ADC platform, and enhanced dual-target CAR-T platform. It independently developed over 10 novel and differentiated potential FIC/BIC pipelines.
Based on the dual-functional antibody platform, Novatim independently developed the first βγ-biased PD1/IL2 fusion protein in China. Currently, the PD1/IL2 antibody is in Phase Ⅰb clinical trial in China, and has also obtained IND approval in the United States. Based on the nano-bispecific ADC platform, Novatim independently developed the world's first nano-bispecific ADC, and both China and the United States have obtained IND approval. Based on the enhanced dual-target CAR-T platform, Novatim independently developed the world's first parallel enhanced structure dual-target CAR-T, which is currently in clinical Phase Ⅰ/Ⅱa.
References
[1]Dispenzieri A. POEMS syndrome: 2021 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2021;96(7):872-888. doi:10.1002/ajh.26240
[2]周道斌, 李剑. POEMS 综合征的诊断和治疗 [J]. 中国肿瘤临床, 2014, 41(13): 831-5.
[3]李剑.我如何诊断和治疗POEMS综合征[J].中华血液学杂志,2019, 40 (5): 368-371.
[4]Xu Y, Mao X, Que Y, et al.The exploration of B cell maturation antigen expression in plasma cell dyscrasias beyond multiple myeloma[J].BMC Cancer,2023, 23 (1): 123.
[5]Isshiki Y, Oshima M, Mimura N, et al.Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis[J].JCI Insight,2022, 7 (20).
