B Cell Malignancies

The purpose of this study is to assess the feasibility, safety and efficacy of universal CAR T cell therapy against CD19-positive hematological malignancies using a novel CD19-specific CAR T cell product, 4SCAR19U T cells. The study also aims to learn more about the function of the 4SCAR19U T cells and their persistence in patients. This is a phase I trial enrolling patients from multiple clinical centers.

The purpose of this study is to assess the feasibility, safety and efficacy of CD19/79b bi-specific CAR-T cell therapy in patients with CD19 and/or CD79b positive B cell malignancies. Another goal of the study is to learn more about the safety and function of the anti-CD19/79b bi-specific CAR-T cells and their persistency in patients.

The purpose of this study is to assess the feasibility, safety and efficacy of anti-CD19/22 bi-specific CAR-T cell therapy in patients with CD19 and/or CD22 positive B cell malignancies. Another goal of the study is to learn more about the safety and function of the anti-CD19/22 bi-specific CAR-T cells and their persistency in patients.

The purpose of this study is to assess the feasibility, safety and efficacy of CD19/70 bi-specific CAR-T cell therapy in patients with CD19 and/or CD70 positive B cell malignancies. Another goal of the study is to learn more about the safety and function of the anti-CD19/70 bi-specific CAR-T cells and their persistency in patients.

The study will evaluate safety and efficacy of a combination of 4th generation chimeric antigen receptor gene-modified T cells targeting CD19 (4SCAR19) and CD20 (4SCAR20), CD22 (4SCAR22), CD30 (4SCAR30), CD38 (4SCAR38), CD70 (4SCAR70) or CD123 (4SCAR123) for patients with B cell malignancies. Clinical response and development of a standardized lentiviral vector and cell production protocol will be investigated. This is a phase I/II trial enrolling patients from multiple clinical centers.

The study will evaluate safety and efficacy of a 4th generation chimeric antigen receptor gene-modified T cells targeting CD19 (4SCAR19) for patients with B cell malignancies. Clinical response and development of a standardized lentiviral vector and cell production protocol will be investigated. This is a phase I/II trial enrolling patients from multiple clinical centers.

The primary objective of the study for Cohort 1 and Cohort 2 is to assess the anticancer activity of emavusertib in combination with zanubrutinib in participants with CLL.

This is a Phase I/II study designed to evaluate if experimental T cell engaging antibody targeting CD20 AZD5492 is safe, tolerable and efficacious in participants with Relapsed or Refractory B-Cell Malignancies.

B-cell malignancies include a spectrum of cancers originating from abnormal B lymphocytes at different developmental stages (1) that affect the peripheral blood (PB), bone marrow (BM), and lymphatic system. They can be categorized into leukemias and lymphomas. Each has unique characteristics, depending on the type of cells affected, and different behaviors, ranging from chronic conditions with slow progression to aggressive forms that require immediate treatment (2). Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood and the predominant form of precursor B-cell leukemia globally, accounting for 85% of ALL cases. According to recent global burden estimates, ALL incidence increased to over 100 000 cases worldwide by 2021, corresponding to an age-standardized incidence rate of \~1.4 per 100 000 persons per year (3). Its quick course and possibility of systemic involvement make early and prompt diagnosis and efficient treatment essential for enhancing long-term survival, especially in young patients.(4). B-Chronic lymphoproliferative disorders (B-CLPDs) are a diverse collection of illnesses that are defined by the uncontrolled and clonal expansion of mature B cells. Although they can range from indolent to aggressive, they usually impact elderly persons and have a slow-growing, indolent clinical history. These conditions account for more than 90% of all chronic lymphoid cancers (5). B-cell malignancies arise from disruption of immune system regulation through alterations in crucial signaling pathways, such as the B-cell receptor (BCR) signalling defect, imbalance between stimulatory signals (that drive proliferation and differentiation) and inhibitory signals (that enforce tolerance and prevent overstimulation) leading to anti-tumor immunity with development and metastasis of cancer cells (6). An essential part of the immune regulatory system for malignancies, the B7-H family which is an important immune checkpoint provides new opportunities for modifying the tumor microenvironment (TME). This family is well-known for its several functions in controlling both innate and adaptive immunity. It is also involved in the recruitment and polarization of diverse immune cells and can have co-stimulatory or co-inhibitory effects on T cells, affecting processes like T cell activation, differentiation, and effector functions. Two important members in this family are: B7-H1 (PD-L1) also known CD274 and B7-H3 (CD276) (7). Firstly, PD-L1 (CD274) which bind to PD-1 . This interaction primarily result in suppresses effector T cell activity while promoting the activity of immunosuppressive regulatory T cells (Tregs), hence negatively regulating the adaptive immune response. However, in malignancy, cancer cells promote the PD-1/PD-L1 axis to cause immune escape in cancer development and progression (8). It was reported that PD-L1 is widely expressed in solid tumors like melanoma and non-small cell lung cancer (9). Secondly, CD276, also called B7-H3, is abundantly expressed in cancer cells and activated tumor-infiltrating immune cells aiding in the evasion of cytotoxic T-cell and natural killer cell surveillance (10). According to new research, B7-H3 contributes to tumor growth, metastasis, and resistance to treatment, all of which have a negative impact on patient outcomes (11). Till now, the co-expression and functional relationship of CD274 and CD276 in B-cell malignancies remain poorly recognized. Understanding whether malignant B cells utilize multiple immune checkpoint pathways simultaneously may explain resistance to immunotherapy and identify novel prognostic and therapeutic targets.

This is a phase I/II trial of SHB-02-CD19, T-cell expressing an anti-CD19 Chimeric-Antigen-Receptor (CAR) in patients with CD19 expressing B-cell malignancies. This trial is an open label, single-arm, for pediatric and adult patients with relapsed/refractory B-cell malignancies.

Inhibitory immune receptors, including CD85d and CD305 (LAIR-1), act as immune checkpoint-like molecules. They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit SH2-domain phosphatases (e.g., SHP-1), which suppress cellular activation (7,8). CD85d is predominantly expressed in myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes. It is also differentially expressed on NK, T, B cells, and neutrophils. It is expressed at high levels in tumor cells, facilitating immune escape by promoting immune suppression, allowing for tumor evasion (9). CD85d is widely expressed across AML, so it is a top candidate, due to its traditional association with myeloid phenotypes and limited expression in normal haematopoiesis (10). It was reported to be expressed in B cells of CLL patients in contrast to normal B cells. Its expression in CLL patients denotes a distinctive feature, which may be acquired during malignant transformation (8). Therefore, CD85d may have significant prognostic, mechanistic, and therapeutic roles in hematologic malignancies (11). As a novel biomarker in solid malignant tumors to predict the prognosis of patients, upregulation of CD85d in tumors is associated with worse tumor phenotypes. Targeting CD85d may be an effective tool for targeted cancer therapy (12). Concerning CD305, it has been reported in about 60% of CLL patients and may be used as an effective prognostic marker to predict TTFT in CLL patients (13). Despite their potential clinical significance, the expression patterns of CD85d and CD305 across B-cell lymphoid neoplasms subtypes remain incompletely identified. Illustrating their role may help to determine TTFT, prognosis, therapeutic targeting, and refinement of B-cell neoplasms classification in line with WHO-HAEM5 standards.

Malignant hematological tumors mainly derived from adult B cells are mainly acute lymphoblastic leukemia (ALL) and non Hodgkin lymphoma (NHL). Overall, although existing therapies have significantly improved the survival rates of most patients, the treatment of relapsed/refractory patients still faces significant challenges. CD19 is one of the most clinically valuable targets for B-cell malignant hematological tumors. The advent of COVID-19 vaccine has brought LNP mRNA technology into the public's view. After years of development, it not only shines brilliantly in COVID-19 vaccine, but also is widely used in the treatment and exploration of cancer, rare diseases and other fields. Lipid nanoparticles (LNP) are currently the most mature non viral delivery platform, capable of protecting mRNA from nuclease degradation, promoting intracellular uptake, and achieving efficient translation in vivo. The core of LNP-mRNA technology targeting CD19 is to encapsulate the mRNA encoding specific proteins (such as anti-CD19 related proteins) in lipid nanoparticles and deliver them to the body through intravenous or intramuscular injection.

This is a phase I/II trial of T-cell expressing an anti-CD22 Chimeric-Antigen-Receptor (CAR) in patients with CD22 expressing B-cell malignancies. This trial is an open label, single-arm, for pediatric and adult patients with relapsed/refractory B-cell malignancies.

Malignant hematological tumors mainly derived from adult B cells are mainly acute lymphoblastic leukemia (ALL) and non Hodgkin lymphoma (NHL). Overall, although existing therapies have significantly improved the survival rates of most patients, the treatment of relapsed/refractory patients still faces significant challenges. CD19 is one of the most clinically valuable targets for B-cell malignant hematological tumors. The advent of COVID-19 vaccine has brought LNP mRNA technology into the public's view. After years of development, it not only shines brilliantly in COVID-19 vaccine, but also is widely used in the treatment and exploration of cancer, rare diseases and other fields. The core of LNP mRNA technology targeting CD19 is to encapsulate the mRNA encoding specific proteins in lipid nanoparticles and deliver them to the body through intravenous or intramuscular injection. The experimental drug WGb-0301 injection is a CD19 based messenger RNA (mRNA) therapeutic mRNA drug, formed by loading mRNA onto lipid nanoparticles (LNP). WGb-0301 injection has demonstrated efficient B-cell clearance activity and good safety in non clinical settings, supporting further clinical exploration in B-cell malignancies. It is expected to provide an innovative, safe, and accessible immunotherapy for B-cell malignancies, bringing better clinical benefits to more patients with B-cell malignancies.

This study is to provide locally produced, bispecific CD19 CD20 CAR T cells to patients with B-cell lymphoma/leukemia who have no access to commercial CAR T cells or who have relapsed thereafter. The primary objective is to assess the safety of bispecific anti-CD19, anti- CD20 CAR T cell-therapies after lymphodepleting chemotherapy in patients with B cell malignancies with exhausted standard treatment options.

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with relapsed or refractory B-cell Malignancies. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of JY231 injection in the treatment of relapsed or refractory B-cell Malignancies.

This Phase I, open-label, multicenter study evaluates the safety, tolerability, pharmacokinetics, and preliminary efficacy of SYS6005 in advanced malignancies, comprising dose-escalation and expansion phases. The escalation phase employs a BOIN design with accelerated titration across seven dose levels, featuring a 21-day DLT observation period in Cycle 1, with dose adjustments guided by a Safety Monitoring Committee. In the expansion phase, one or more dosing regimens and tumor types will be selected, and participants will receive SYS6005 R2PD for further exploration and validation. Treatment continues until disease progression, unacceptable toxicity, or other discontinuation criteria. Safety monitoring includes AEs, labs, and ECOG PS, while efficacy is assessed via imaging. PK and immunogenicity samples are collected, and survival is tracked quarterly until death or study end. The study aims to determine the maximum tolerance dose (MTD)/recommended phase 2 dose (RP2D) and characterize SYS6005's clinical profile.

This study is a single-center,open-label,single-dose clinical trial of anti-CD20/CD30-CAR-T cell therapy in relapsed/refractory B-cell tumor patients after lymphocyte depletion pre-treatment. In this study phase,a traditional "3+3"trial design is employed for dose escalation.

This study is a single-center, open-label, single-dose clinical trial of anti-CD19-CAR-T cell therapy in relapsed/refractory B-cell tumor patients after Qinglin pre-treatment. In this study phase, a traditional "3+3" trial design is employed for dose escalation.

This is a multicenter, open-label Phase I dose escalation study to evaluate the safety and preliminary efficacy of the TT-01488 tablet, a non-covalent reversible BTK inhibitor, for the treatment of adult patients with B-cell malignancies.