Chimeric Antigen Receptor T-cell (CAR-T) therapy is a groundbreaking advancement in cancer immunotherapy. CARs are recombinant receptors designed to redirect the specificity and function of T lymphocytes and other immune cells within a single molecule. The innovative concept of using CARs in cancer treatment hinges on their ability to target tumor-associated antigens with high precision. These engineered receptors can be replicated rapidly and uniformly, allowing for the direct infusion of tumor-targeting T-cells. This approach circumvents the limitations and complexities of traditional active immunization. Unlike passive immunization methods that rely on direct antibodies, CAR-modified T-cells exhibit supraphysiologic activities, functioning as active agents that interact with tumor-associated antigens. This interaction results in both immediate and long-term anti-tumor effects, offering a powerful and sustained therapeutic impact against cancer.
CAR-T therapy, including the use of the drug Tisagenleucel (Kymriah), has shown promise for treating both Acute Lymphoblastic Leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Tisagenleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients up to age 25 with B-cell precursor acute lymphoblastic leukemia and for adult patients with diffuse large B-cell lymphoma. For the dosing of Tisagenleucel in adults and geriatric patients, the target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum dose of 2 × 108 CAR-positive viable T cells. In pediatric patients, the dosing varies based on weight. For children and adolescents weighing 50 kg or less, the intravenous (IV) dose ranges from 0.2 to 5 × 106 CAR-positive viable T cells per kg body weight. For those weighing more than 50 kg, the IV dose ranges from 0.1 to 2.5 × 108 CAR-positive viable T cells.Tisagenlecleucel (Kymriah®) carries several important warnings and precautions. These include the potential for secondary malignancies, cytopenias (such as low blood cell counts), reactivation of hepatitis B virus, hypersensitivity reactions, hypogammaglobulinemia (reduced levels of antibodies), susceptibility to infections, neurological toxicities, and cytokine release syndrome. Close monitoring and appropriate management strategies are essential to mitigate these risks and ensure patient safety during treatment with Tisagenleucel.
The efficacy and safety of Kymriah were evaluated in the global phase 2 pivotal ELIANA trial, focusing on patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The interim analysis, which formed the basis for FDA approval of Kymriah in 2017, included 68 infused patients, with 63 evaluable for response at three months. An updated analysis, incorporating longer-term data, was later published. This analysis was based on 75 infused patients, all of whom were evaluable for response at three months.
Enrolled patients were between the ages of 3 and 23, with a median age of 11 years. Of these participants, 8% had primary refractory disease, and patients had received a median of three prior therapies. Additionally, 53% had undergone one stem cell transplant (SCT), and 8% had received two SCTs. The median time from the most recent relapse to Kymriah infusion was 3.5 months. The primary endpoint of the trial was the overall remission rate (ORR) within three months post-infusion, requiring remission to be maintained for at least 28 days without clinical evidence of relapse.
One of the main adverse reactions to CAR-T cell therapy is cytokine release syndrome (CRS). This is primarily a systemic inflammatory reaction triggered by the release of numerous inflammatory factors from activated immune cells, including T cells, macrophages, B cells, monocytes, natural killer cells, dendritic cells, and endothelial cells. CRS is characterized by symptoms such as high fever, hypoxia, and mild hypotension. Management of CRS typically involves the use of antipyretics to reduce fever, oxygen therapy, intravenous fluids, and low-dose vasopressors as needed to support blood pressure. In 2017, the FDA approved tocilizumab, an IL-6 receptor antagonist, for treating CAR-T cell-induced CRS. The recommended therapeutic dose of tocilizumab is 12 mg/kg for patients under 30 kg and 8 mg/kg for patients 30 kg or more, with a maximum dose of 800 mg.
In conclusion, Chimeric Antigen Receptor T-cell (CAR-T) therapy, exemplified by Tisagenleucel (Kymriah®), represents a transformative approach in cancer treatment, particularly for diseases like Acute Lymphoblastic Leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). By harnessing the power of genetically modified T-cells to target specific antigens on cancer cells, CAR-T therapy has demonstrated remarkable efficacy in inducing durable remissions. However, its clinical application necessitates careful consideration of potential adverse effects, such as cytokine release syndrome and other immune-related complications. Ongoing research and vigilant management strategies are essential to optimize outcomes and ensure the safe integration of this innovative therapy into clinical practice.
Li, Y., Ming, Y., Fu, R., Li, C., Wu, Y., Jiang, T., Li, Z., Ni, R., Li, L., Su, H., & Liu, Y. (2022b, October 14). The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions. Frontiers in pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616161/
Chimeric Antigen Receptor T-cell (CAR-T) therapy is a groundbreaking advancement in cancer immunotherapy. CARs are recombinant receptors designed to redirect the specificity and function of T lymphocytes and other immune cells within a single molecule. The innovative concept of using CARs in cancer treatment hinges on their ability to target tumor-associated antigens with high precision. These engineered receptors can be replicated rapidly and uniformly, allowing for the direct infusion of tumor-targeting T-cells. This approach circumvents the limitations and complexities of traditional active immunization. Unlike passive immunization methods that rely on direct antibodies, CAR-modified T-cells exhibit supraphysiologic activities, functioning as active agents that interact with tumor-associated antigens. This interaction results in both immediate and long-term anti-tumor effects, offering a powerful and sustained therapeutic impact against cancer.
CAR-T therapy, including the use of the drug Tisagenleucel (Kymriah), has shown promise for treating both Acute Lymphoblastic Leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Tisagenleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients up to age 25 with B-cell precursor acute lymphoblastic leukemia and for adult patients with diffuse large B-cell lymphoma. For the dosing of Tisagenleucel in adults and geriatric patients, the target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum dose of 2 × 108 CAR-positive viable T cells. In pediatric patients, the dosing varies based on weight. For children and adolescents weighing 50 kg or less, the intravenous (IV) dose ranges from 0.2 to 5 × 106 CAR-positive viable T cells per kg body weight. For those weighing more than 50 kg, the IV dose ranges from 0.1 to 2.5 × 108 CAR-positive viable T cells.Tisagenlecleucel (Kymriah®) carries several important warnings and precautions. These include the potential for secondary malignancies, cytopenias (such as low blood cell counts), reactivation of hepatitis B virus, hypersensitivity reactions, hypogammaglobulinemia (reduced levels of antibodies), susceptibility to infections, neurological toxicities, and cytokine release syndrome. Close monitoring and appropriate management strategies are essential to mitigate these risks and ensure patient safety during treatment with Tisagenleucel.
The efficacy and safety of Kymriah were evaluated in the global phase 2 pivotal ELIANA trial, focusing on patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The interim analysis, which formed the basis for FDA approval of Kymriah in 2017, included 68 infused patients, with 63 evaluable for response at three months. An updated analysis, incorporating longer-term data, was later published. This analysis was based on 75 infused patients, all of whom were evaluable for response at three months.
Enrolled patients were between the ages of 3 and 23, with a median age of 11 years. Of these participants, 8% had primary refractory disease, and patients had received a median of three prior therapies. Additionally, 53% had undergone one stem cell transplant (SCT), and 8% had received two SCTs. The median time from the most recent relapse to Kymriah infusion was 3.5 months. The primary endpoint of the trial was the overall remission rate (ORR) within three months post-infusion, requiring remission to be maintained for at least 28 days without clinical evidence of relapse.
One of the main adverse reactions to CAR-T cell therapy is cytokine release syndrome (CRS). This is primarily a systemic inflammatory reaction triggered by the release of numerous inflammatory factors from activated immune cells, including T cells, macrophages, B cells, monocytes, natural killer cells, dendritic cells, and endothelial cells. CRS is characterized by symptoms such as high fever, hypoxia, and mild hypotension. Management of CRS typically involves the use of antipyretics to reduce fever, oxygen therapy, intravenous fluids, and low-dose vasopressors as needed to support blood pressure. In 2017, the FDA approved tocilizumab, an IL-6 receptor antagonist, for treating CAR-T cell-induced CRS. The recommended therapeutic dose of tocilizumab is 12 mg/kg for patients under 30 kg and 8 mg/kg for patients 30 kg or more, with a maximum dose of 800 mg.
In conclusion, Chimeric Antigen Receptor T-cell (CAR-T) therapy, exemplified by Tisagenleucel (Kymriah®), represents a transformative approach in cancer treatment, particularly for diseases like Acute Lymphoblastic Leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). By harnessing the power of genetically modified T-cells to target specific antigens on cancer cells, CAR-T therapy has demonstrated remarkable efficacy in inducing durable remissions. However, its clinical application necessitates careful consideration of potential adverse effects, such as cytokine release syndrome and other immune-related complications. Ongoing research and vigilant management strategies are essential to optimize outcomes and ensure the safe integration of this innovative therapy into clinical practice.
Li, Y., Ming, Y., Fu, R., Li, C., Wu, Y., Jiang, T., Li, Z., Ni, R., Li, L., Su, H., & Liu, Y. (2022b, October 14). The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions. Frontiers in pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616161/
Zhang, C. (2022a, October 3). Chimeric antigen receptor T-cell therapy. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK537294/