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/
CAR T-cell therapy, otherwise known as chimeric antigen receptor therapy, is a newly approved immunotherapy that specializes in altering the body’s T cells in a unique manner. FDA-approved medications include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta). Each drug has various differing indications of approved treatments ranging from leukemia, lymphoma, and multiple myeloma.
The extensive treatment process requires critical patient evaluations to determine eligibility.
Patients undergo leukapheresis in which white blood cells and T cells are collected from the patient, flowing into an apheresis machine. The apheresis machine returns blood back to the body through a different tube as it collects the required cells. The performing facility sends the collected cells to a laboratory to genetically modify the cells, placing chimeric antigen receptors on their surfaces. Over 2-3 weeks, the lab continues to grow the T cells as they multiply. Upon adequate multiplication and growth, the now-frozen cells are sent back to the performing facility. In the meantime, the patient may be given chemotherapy before CAR T cell infusion to improve the treatment efficacy of the CAR T cells. It is recommended not to give an intensive round of chemotherapy as some cancer cells are needed for attachment. The CAR T cell therapy is infused back into the patient where they are then monitored for several days for immediate potential side effects. Unfortunately, a severe response to the therapy may still be seen 2-3 months after administration of the therapy.
Many of the drug-approving clinical trials displayed high levels of remission in patients. For example, “ELIANA and ENSIGN studies showed a complete remission of 67% at 3 months in patients with acute lymphoblastic leukemia (ALL), which was maintained in almost 40% of patients after a median follow-up of 9 months. For non-Hodgkin’s lymphoma (NHL) patients, the objective response rate was 82%, with a 54% complete remission rate in 101 patients, after a minimum follow-up of 6 months.” These astonishing results came with high rates of severe side effects, especially cytokine release syndrome (CRS). CRS is seen due to an over-activation of the immune system and is associated with neurotoxicity. As seen in the ELIANA and ENSIGN studies, CRS and severe neurotoxicity were reported in 77.2% of patients. In another study, the ZUMA-1 study, CRS and severe neurotoxicity were reported in 13% and 28% of patients, leading to 2 deaths. The ROCKET trial had 5 deaths and ultimately led to its discontinuation. At the moment, research facilities are looking for methods to quickly and efficiently control potential cases of CRS in studies. Current approved treatment for grade 3 or 4 CRS includes tocilizumab, an IL-6 receptor inhibitor, and dexamethasone. Many facilities cannot differentiate between CRS and a severe infection, resulting in patients receiving preventative antibiotics as opposed to addressing CRS symptoms early on.
Unfortunately, such unique, specialized, newly approved medications come with a price in the world of cancer. Between biopsies, apheresis, CAR T cell engineering, hospital stays, imaging, and the medication itself, the cost ranges from $500,000 to $1,000,000. Other non-included costs are housing, travel, and caregiver support, as patients must stay at most 2 hours away for at least 4 weeks. In many instances, private insurances have covered a portion of costs. Medicare may cover the process of CAR T cell therapy in certain states, including everything except the drug itself. In instances where the medication is covered, it has been found to not cover the required supplies to perform the therapy. High response rates have been witnessed, however, the cost-effectiveness is controversial due to the excessive costs. Follow-up periods in trials were short as obtaining new evidence to support long-term efficacy and safety would be more costly. Over the past decade, immunotherapies have displayed great results in effectively treating cancer. Although the cost of CAR T cell therapy makes it not as accessible, the new category of ‘immunotherapy’ is now a standard first-line treatment in various cancers.
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/
CAR T-cell therapy, otherwise known as chimeric antigen receptor therapy, is a newly approved immunotherapy that specializes in altering the body’s T cells in a unique manner. FDA-approved medications include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta). Each drug has various differing indications of approved treatments ranging from leukemia, lymphoma, and multiple myeloma.
The extensive treatment process requires critical patient evaluations to determine eligibility.
Patients undergo leukapheresis in which white blood cells and T cells are collected from the patient, flowing into an apheresis machine. The apheresis machine returns blood back to the body through a different tube as it collects the required cells. The performing facility sends the collected cells to a laboratory to genetically modify the cells, placing chimeric antigen receptors on their surfaces. Over 2-3 weeks, the lab continues to grow the T cells as they multiply. Upon adequate multiplication and growth, the now-frozen cells are sent back to the performing facility. In the meantime, the patient may be given chemotherapy before CAR T cell infusion to improve the treatment efficacy of the CAR T cells. It is recommended not to give an intensive round of chemotherapy as some cancer cells are needed for attachment. The CAR T cell therapy is infused back into the patient where they are then monitored for several days for immediate potential side effects. Unfortunately, a severe response to the therapy may still be seen 2-3 months after administration of the therapy.
Many of the drug-approving clinical trials displayed high levels of remission in patients. For example, “ELIANA and ENSIGN studies showed a complete remission of 67% at 3 months in patients with acute lymphoblastic leukemia (ALL), which was maintained in almost 40% of patients after a median follow-up of 9 months. For non-Hodgkin’s lymphoma (NHL) patients, the objective response rate was 82%, with a 54% complete remission rate in 101 patients, after a minimum follow-up of 6 months.” These astonishing results came with high rates of severe side effects, especially cytokine release syndrome (CRS). CRS is seen due to an over-activation of the immune system and is associated with neurotoxicity. As seen in the ELIANA and ENSIGN studies, CRS and severe neurotoxicity were reported in 77.2% of patients. In another study, the ZUMA-1 study, CRS and severe neurotoxicity were reported in 13% and 28% of patients, leading to 2 deaths. The ROCKET trial had 5 deaths and ultimately led to its discontinuation. At the moment, research facilities are looking for methods to quickly and efficiently control potential cases of CRS in studies. Current approved treatment for grade 3 or 4 CRS includes tocilizumab, an IL-6 receptor inhibitor, and dexamethasone. Many facilities cannot differentiate between CRS and a severe infection, resulting in patients receiving preventative antibiotics as opposed to addressing CRS symptoms early on.
Unfortunately, such unique, specialized, newly approved medications come with a price in the world of cancer. Between biopsies, apheresis, CAR T cell engineering, hospital stays, imaging, and the medication itself, the cost ranges from $500,000 to $1,000,000. Other non-included costs are housing, travel, and caregiver support, as patients must stay at most 2 hours away for at least 4 weeks. In many instances, private insurances have covered a portion of costs. Medicare may cover the process of CAR T cell therapy in certain states, including everything except the drug itself. In instances where the medication is covered, it has been found to not cover the required supplies to perform the therapy. High response rates have been witnessed, however, the cost-effectiveness is controversial due to the excessive costs. Follow-up periods in trials were short as obtaining new evidence to support long-term efficacy and safety would be more costly. Over the past decade, immunotherapies have displayed great results in effectively treating cancer. Although the cost of CAR T cell therapy makes it not as accessible, the new category of ‘immunotherapy’ is now a standard first-line treatment in various cancers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954171/
https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
https://hillman.upmc.com/mario-lemieux-center/treatment/car-t-cell-therapy/fda-approved-therapies