Non Hodgkin’s Lymphoma CAR-T Treatment
Non Hodgkin’s Lymphoma CAR-T Treatment
In the past, cancer was primarily treated with surgery, chemotherapy, and radiation therapy. 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, derived from a patient’s own T cells through genetic engineering to express tumor-targeting receptors, can independently recognize tumor cell surface antigens in an MHC-unrestricted manner. CAR-T cells are being extensively studied in clinical trials. The basic principle involves collecting the patient’s T cells, activating, transducing, modifying, and expanding them using genetic engineering methods, then reinfusing them into the patient to stimulate the body’s immune system to exert an anti-tumor effect.
Non-Hodgkin’s lymphoma (NHL) is a group of malignant tumors originating from lymph nodes and other lymphoid tissues, representing a major category of lymphomas (excluding Hodgkin’s lymphoma). It ranges from the most indolent to the most aggressive human malignancies and is a relatively common type of cancer in China, ranking among the top 10 most common malignancies. Immunotherapies such as cell-based immunotherapy and immune checkpoint inhibitors have shown promising clinical trial results. This article discusses the clinical research on CAR-T technology for NHL treatment and the management of adverse reactions.
Clinical Research
The National Cancer Institute (NCI) in the USA was the first to report a successful case of second-generation CD19 CAR-T cell therapy. The patient had refractory stage IVB follicular lymphoma (FL) and achieved a partial remission (PR) lasting 32 weeks after receiving CAR-T cell infusion and IL-2 treatment. In a follow-up study conducted by the NCI on 15 patients with advanced diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), or indolent lymphoma, 8 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 post-transplant evaluation and maintained 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 with a defined ratio of CD8+ central memory T cells and CD4+ T cells. Among 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%.
Although multicenter studies have reported promising results with CAR-T cell therapy, significant variability exists among institutions. Further research is needed to optimize the CAR-T therapy, including preconditioning methods for lymphoma cells before CAR-T cell infusion, CAR design strategies, CAR-T cell culturing, and the timing of CAR-T cell infusion.
Some cases have shown resistance to CAR-T cell therapy, possibly due to the inability of CAR-T cells to overcome the inhibitory effects of T-cell inhibitory ligands expressed by tumor cells. Clinical trials combining CAR-T cells with monoclonal antibody immune checkpoint inhibitors are ongoing, such as a trial at Baylor College of Medicine (NCT00586391; ipilimumab plus CAR-T cells) and a trial at UPenn (NCT02650999; pembrolizumab plus CAR-T cells).
Another potential reason for engineered T-cell therapy failure is their short in vivo persistence. The recipient’s immune system may recognize and attack the exogenous engineered T cells by identifying foreign peptides derived from the CAR. Current research aims to improve CAR-T cell expansion and persistence by modulating various cytokines (NCT00968760).
The widespread application of CAR-T cell therapy still faces several challenges. For instance, pharmaceutical companies are developing larger-scale CAR-T cell manufacturing facilities to address technical challenges. Additionally, the time required to collect, prepare, and expand CAR-T cells from a patient’s T cells poses a significant limitation for emergency treatments.
Adverse Reactions
Cytokine release syndrome (CRS) is a common adverse reaction after CAR-T cell infusion, characterized by immune activation leading to elevated inflammatory cytokines (particularly IL-6), which can cause fever, hypotension, and hypoxia, and can be life-threatening in severe cases.
Studies have found that the incidence and severity of CRS are lower in lymphoma patients compared to acute lymphoblastic leukemia (ALL) patients with more widespread disease. According to a report from the Fred Hutchinson Cancer Research Center, only a portion of ALL patients experienced CRS among those receiving CAR-T treatment for ALL and NHL. In a report from UPenn, 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 reaction that requires close attention. Among 20 patients in the UPenn clinical trial, 3 experienced varying degrees of neurotoxicity. Neurotoxicity may reflect the ability of CAR-T cells to penetrate the blood-brain barrier, and CD19 CAR-T cells have been reported in the cerebrospinal fluid of 3 patients with neurological complications.
Most observed neurotoxicities are reversible with dexamethasone treatment. Since tocilizumab is a monoclonal antibody and less likely to penetrate the blood-brain barrier, corticosteroids are more widely used to alleviate neurological symptoms.
CAR-T cell therapy has demonstrated significant efficacy in treating NHL. Although challenges exist in large-scale manufacturing, transportation, and adverse reaction management, the prospects for using CAR-T cells to treat tumors are promising as the mechanisms underlying CAR-T cell efficacy and toxicities become better understood.
Reference
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612371/
Content Source:细胞基因研究圈