The 2024 Breakthrough Prize in Life Sciences was awarded to Carl June and Michel Sadelain for genetically engineering T cells with chimeric antigen receptors (CARs) that recognize cancer cells in individual patients, and these CAR-T cells have achieved remarkable success against hematological tumors, including leukemia, lymphoma and myeloma. Since the first anti-CD19 CAR-T cell product was approved for B-cell lymphoma treatment in 2017, researchers have broadened its use in treating malignant hematological tumors such as B-cell leukemia, in addition to the wide use of CD19 CAR-T cell in treating autoimmune diseases such as systemic lupus erythematosus [1].

The B-cell antigen receptor CD19 is a surface protein expressed on B lymphocytes and is a member of the immunoglobulin (Ig) superfamily, which is expressed in B cells throughout their maturation and their eventual differentiation into plasma cells [2]. The cancer cells of patients with B-cell malignancies typically express normal to high levels of CD19. Therefore, CD19 is one of the most important target antigens in B-cell malignancies and is the most promising target for the development of CAR-T cells against diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), non-Hodgkin's lymphoma (NHL) and B-cell leukemia (BCL) [3]. However, according to real-world data, approximately 60 % of patients who relapse after treatment exhibit a reduction or complete loss of CD19 cancer cell expression [4]. Despite the effectiveness of anti-CD19 CAR-T cells in the treatment of B-cell malignancies, tumor recurrence often occurs after treatment, and the main cause of tumor recurrence is related to immune escape, as tumor cells that remain after anti-CD19 CAR-T cell therapy do not express CD19 on their surface [5,6]. Therefore, the development of multi-target CAR-T cells is essential to address this challenge. Currently, CD19-CD22, BCMA-CD38 and other dual-target CAR-T cells are in clinical trials [4,[7], [8], [9], [10]].

The human CD38 antigen is a type II transmembrane glycoprotein that is highly expressed in plasma cell tumors, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and NHL [[11], [12], [13]], and CD38 is an intriguing target in hematological cancer therapy research. Currently, the CD38 monoclonal antibodies daratumumab and isatuximab have been approved by the FDA for the treatment of multiple myeloma (MM). In addition, studies have demonstrated that CD38 antibodies are effective in the treatment of NHL, CLL, AML, chronic myeloid leukemia (CML), and NHL. CD38 antibodies have been demonstrated to have an inhibitory effect on various hematological tumors, such as NHL, CLL, and AML [[14], [15], [16], [17]].

In this study, we constructed two sequentially different tandem (Tan) CAR-T cells by combining a CD38 scFv (No.21) [18], which was prescreened and functionally validated in the laboratory, with a CD19 scFv (FMC63) to inhibit tumor immune escape.