Lymphoma is a common malignant tumor of the hematologic system, with B-cell lymphoma accounting for a large proportion. For patients with relapsed/refractory lymphoma, traditional treatments such as chemotherapy and radiotherapy often have limited efficacy. However, immunotherapy targeting the CD19 antigen has brought new hope to these patients. CD19, highly expressed on the surface of B cells, serves as a target for chimeric antigen receptor T-cell (CAR-T) therapy, CAR-NK therapy, and others. These therapies engineer the patient’s own immune cells to specifically recognize and kill tumor cells expressing CD19, achieving remarkable therapeutic effects. In this issue, we will provide a detailed introduction to CD19-based treatments for relapsed/refractory lymphoma.
CD19 is a 95kD transmembrane glycoprotein belonging to the immunoglobulin superfamily and classified as a type I transmembrane protein. Its structure roughly divides into a C-terminal cytoplasmic domain, an N-terminal extracellular domain, and a single transmembrane domain. The biological function of CD19 depends on three tyrosine residues in the cytoplasmic domain: Y391, Y482, and Y513. On mature B cells, CD19 forms a multimolecular complex with the complement receptor CD21, the tetraspanin CD81, and CD225, playing a key role. On one hand, CD19 associates with the B-cell receptor (BCR) as a signaling subunit of the CD19/CD21 complex to enhance B-cell activation. On the other hand, BCR signaling requires activation of protein tyrosine kinases (PTKs), and CD19 can recruit and amplify the activation of src-family PTKs. Additionally, CD19 recruits and activates PI3K and downstream Akt kinase, which strengthens BCR-induced signaling critical for B-cell proliferation.
CD19 is specifically expressed on normal B cells, tumor B cells, and follicular dendritic cells. It is also expressed in most cases of acute lymphoblastic leukemia, chronic lymphocytic leukemia, and B-cell lymphoma, making CD19 an ideal target for treating B-cell lymphomas.
Anti-CD19 chimeric antigen receptor-modified T cells (CD19 CAR-T) represent an effective immunotherapy. The therapy first collects the patient’s T cells through leukapheresis, then genetically modifies them using lentiviral or retroviral vectors to express a chimeric antigen receptor (CAR). This CAR includes an antibody-derived antigen-binding domain, a transmembrane spacer, a co-stimulatory domain (usually CD28 or 4-1BB), and an intracellular signaling domain (CD3ζ). Expression of CAR on T cells endows them with high affinity for cancer antigens, enabling them to kill cancer cells effectively.
Kymriah (Tisagenlecleucel) was the first CD19 CAR-T drug, approved in the U.S. in August 2017 for treating acute precursor B-cell leukemia, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). In October of the same year, Yescarta (Axicabtagene ciloleucel) was approved in the U.S. for treating large B-cell lymphoma, DLBCL, primary mediastinal large B-cell lymphoma, and FL; it was approved in China in 2021. In February 2021, Breyanzi (Lisocabtagene maraleucel) was approved in the U.S. for treating large B-cell lymphoma, DLBCL, primary mediastinal large B-cell lymphoma, and FL. Notably, Beinuoda (Relmacabtagene autoleucel injection) was officially approved and marketed in China in September 2021, becoming the first domestic CD19 CAR-T drug.
In patients with relapsed/refractory large B-cell lymphoma, CD19 CAR-T therapy achieves an overall response rate (ORR) exceeding 80%, with a complete remission (CR) rate around 50%-60%. For example, in the ZUMA-1 phase II clinical trial, patients treated with Axicabtagene ciloleucel showed an ORR of 83% and a CR rate of 58%. In the TRANSCEDE trial, patients receiving Lisocabtagene maraleucel had an ORR of 73% and a CR rate of 53%.
The most common adverse reactions to CD19 CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS typically manifests as fever, hypotension, and hypoxemia of varying severity; some patients may require treatment with drugs like tocilizumab. ICANS manifests as neurological symptoms such as headache, confusion, and seizures, with severity varying among individuals. Additionally, hematologic toxicities such as neutropenia and thrombocytopenia may occur, along with hypogammaglobulinemia.
CAR-NK cells are engineered using genetic modification to introduce a CAR structure into natural killer (NK) cells, enabling them to specifically recognize and kill tumor cells expressing CD19. Compared to CAR-T cells, CAR-NK cells have advantages such as not requiring HLA matching and not causing graft-versus-host disease (GVHD), making them a type of off-the-shelf cell therapy product.
A research team led by Professor Qian Wenbin from the Second Affiliated Hospital of Zhejiang University School of Medicine and Professor Liang Aibin from Tongji Hospital affiliated with Tongji University published a study in Nature Cancer, where they innovatively developed a new CD19-targeted CAR-NK cell therapy using 4-1BB as the co-stimulatory molecule. This represents a significant breakthrough in CAR-NK cell therapy in China. In a dose-escalation Phase I clinical trial (NCT05472558), eight patients with refractory/relapsed large B-cell lymphoma who had failed multiple prior treatments received CAR-NK cell therapy. The results showed no dose-limiting toxicity, and the maximum tolerated dose was not reached. No patients experienced CRS, neurotoxicity, or GVHD. At 30 days post-infusion, the overall response rate (ORR) was 62.5%, with 4 patients (50%) achieving complete remission (CR). With a median follow-up of 25 months, the median progression-free survival (PFS) was 9.5 months, and the median overall survival (OS) had not yet been reached.
Overall, immunotherapies targeting CD19 have brought new hope for patients with relapsed/refractory lymphoma. Both CAR-T and CAR-NK therapies have demonstrated significant efficacy and favorable safety profiles. However, there are still limitations to these therapies—for example, CAR-T therapy involves high production costs and lengthy preparation times, while the durability of CAR-NK therapy's efficacy needs further improvement. Therefore, continued clinical research into CD19-targeted treatments and ongoing optimization of immunotherapies targeting CD19 are needed to better understand their effectiveness and safety, ultimately providing more therapeutic options for lymphoma patients.
