Application of CAR-T Cell Non Hodgkin Lymphoma Therapy
Application of CAR-T Cell Non Hodgkin Lymphoma Therapy
In the past, cancer was primarily treated through surgery, chemotherapy, and radiotherapy. In recent years, cancer immunotherapy, which stimulates and monitors the patient’s immune response, has emerged as a new cancer treatment modality. Chimeric antigen receptor (CAR) T cells, generated through adoptive T cell transfer and genetic engineering, can recognize tumor cell surface antigens independently of MHC restrictions and are widely studied in clinical trials. The basic principle involves collecting T cells from the patient, activating, transducing, modifying, and expanding them through genetic engineering, and then reinfusing them into the patient’s body to elicit an anti-tumor immune response.
Non-Hodgkin’s lymphoma (NHL) is a group of malignant tumors originating from lymph nodes and other lymphoid tissues, representing a major type of lymphoma (excluding Hodgkin’s lymphoma). NHL encompasses a range from the most indolent to the most aggressive human malignancies and is a relatively common cancer in China, ranking among the top 10 most prevalent malignancies. Current immunotherapies, such as cellular immunotherapy and immune checkpoint inhibitors, have shown promising clinical trial results. This article discusses the clinical research and management of adverse events related to the application of CAR-T cell therapy in NHL.
Clinical Research
The National Cancer Institute (NCI) in the United States first reported successful cases of second-generation CD19 CAR-T cell therapy. One patient with refractory stage IVB follicular lymphoma (FL) achieved a partial response (PR) lasting 32 weeks after receiving CAR-T cell infusion and IL-2 treatment. In the NCI’s follow-up study of 15 patients with advanced diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), or indolent lymphoma, 8 patients achieved complete remission (CR), 4 achieved PR, and 1 had stable disease. In this study, patients received cyclophosphamide-fludarabine preconditioning before CAR-T cell infusion.
At Memorial Sloan-Kettering Cancer Center (MSKCC), the efficacy of CAR-T cells as consolidation therapy after autologous hematopoietic stem cell transplantation (AHSCT) was evaluated. In a phase I clinical trial, six high-risk NHL patients received CAR-T cell infusions on days 2 and 3 after AHSCT. All patients achieved CR at the first follow-up after transplantation and maintained disease remission for a median of 6 months.
In a study conducted at the Fred Hutchinson Cancer Research Center and the University of Pennsylvania (UPenn), the Fred Hutchinson group treated patients using a defined ratio of CD8+ central memory T cells and CD4+ T cells. Of the 9 NHL patients, 1 achieved CR, and 5 achieved PR.
In a phase IIa clinical trial of CD19 CAR-T cells at the UPenn Abramson Cancer Center, enrolled patients had relapsed/refractory FL, DLBCL, and mantle cell lymphoma, with an expected survival of less than 2 years. Among the 18 evaluable patients (12 DLBCL, 6 FL), the overall response rate at 3 months was 67%, and the 6-month progression-free survival (PFS) was 59%.
While reports from multiple centers have demonstrated the promising effects of CAR-T cell therapy, there are significant differences among institutions. Further research is needed to optimize CAR-T cell therapy by refining lymphoma cell preconditioning methods, CAR-T cell design strategies, CAR-T cell manufacturing, and the timing of CAR-T cell infusion.
Research has found that some cases exhibit resistance to CAR-T cell therapy. This may be due to the inability of CAR-T cells to overcome the inhibitory effects of T cell inhibitory ligands expressed by tumor cells. Several clinical trials are currently underway combining CAR-T cells with monoclonal antibody immune checkpoint inhibitors, such as the Baylor College of Medicine trial (NCT00586391; ipilimumab with CAR-T cells) and the ongoing UPenn trial (NCT02650999; pembrolizumab with CAR-T cells).
Another potential cause of engineered T cell therapy failure is their short in vivo persistence. The recipient’s immune system may recognize exogenous peptides derived from the CAR and attack the engineered T cells. Current research aims to improve CAR-T cell expansion and persistence through the control of various cytokines (NCT00968760).
The widespread application of CAR-T cell therapy still faces several challenges. For instance, technological challenges in CAR-T cell manufacturing have prompted pharmaceutical companies to develop larger-scale CAR-T cell production facilities. Additionally, the time required to collect, manufacture, and expand CAR-T cells from patient T cells poses significant limitations for urgent treatments.
Adverse Events
Cytokine release syndrome (CRS) is a common adverse event following CAR-T cell infusion, characterized by elevated inflammatory cytokines (particularly IL-6) due to immune activation, which can lead to symptoms such as fever, hypotension, and hypoxia, and potentially life-threatening conditions in severe cases.
Studies have found that the incidence and severity of CRS in lymphoma patients are lower than in patients with more widely disseminated acute lymphoblastic leukemia (ALL). According to a report from the Fred Hutchinson Cancer Research Center, only a subset of ALL patients experienced CRS among those receiving CAR-T cell therapy for ALL and NHL. In the UPenn study, 15 out of 29 NHL patients experienced severe CRS, but most (87%) experienced only grade 2 CRS.
The treatment of CRS should be based on the severity of symptoms and other complications. For grade 1 CRS, supportive care and close monitoring are recommended, while higher-grade CRS may require immunosuppressive agents.
In addition to CRS, neurotoxicity is another adverse event that requires close attention. Among the 20 patients enrolled in the UPenn clinical trial, 3 patients experienced varying degrees of neurological toxicity. Neurotoxicity may reflect the ability of CAR-T cells to penetrate the blood-brain barrier, and studies have reported the detection of CD19 CAR-T cells in the cerebrospinal fluid of 3 patients with neurological complications.
Most observed neurotoxicities can be reversed with dexamethasone administration, as tocilizumab, a monoclonal antibody, is less likely to penetrate the blood-brain barrier. Therefore, corticosteroids are more widely used to alleviate neurological symptoms.
CAR-T cell therapy has demonstrated significant efficacy in treating NHL, although challenges remain in large-scale manufacturing, transportation, and adverse event management. As the mechanisms underlying CAR-T cell efficacy and toxicity become better understood, the prospects for using CAR-T cells in cancer treatment will become more promising.
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612371/
Content Source:细胞基因研究圈