CAR T Cells and Toxicities/Efficacy
Bianca Santomasso, MD, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Fellow Summary
Authored by Onyee Chan
Dr. Santomasso delivered a well-organized, engaging presentation on chimeric antigen receptor T (CAR-T) cell therapy and its associated toxicities. She began her talk by providing some historical perspectives and major milestones achieved by prominent figures in the evolution of CAR. The basic concept of CAR-T cell therapy involves
- Isolating T-cells from patients,
- Engineering these T-cells so that they express CARs that recognize cancer cells,
- T-cells expansion, and
- Infused modified and expanded T-cells back into the patients.
Several products such as axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) are recently approved by the FDA for relapsed/refractory (R/R) large B-cell lymphoma in adults. In addition, tisagenlecleucel is also approved for patients up to age 25 with R/R B-cell acute lymphoblastic leukemia (ALL). Pivotal trials leading to these approvals include ZUMA-1 and ELIANA, which showed unprecedented response rate in these populations. These impressive disease responses come with a price, namely the potential for unique and severe toxicities including but not limited to cytokine release syndrome (CRS) and neurotoxicity or immune cell associated neurotoxicity syndrome (ICANS). Being a neurologist by training, Dr. Santomasso shared some specific examples she encountered during her inpatient service highlighting the importance of early recognition of CRS and timely administration of tocilizumab and/or corticosteroids. It appears that certain toxicities occur in a distinct pattern. After receiving CAR-T cells infusion, CRS and neurotoxicity have a usual onset of 2-3 days and 4-10 days, respectively. Interleukin 6 (IL-6) levels were found to correlate with CRS, which explained why tocilizumab is an effective treatment. CRS typically consists of any number of the following signs and symptoms: fever, hypotension, capillary leak, respiratory insufficiency, coagulopathy, hyperferritinemia, and multi-organ failure. ICANS may include global encephalopathy, aphasia, tremor, obtundation, seizure (or seizure-like activity), hallucinations, and rapid onset cerebral edema. When symptoms are severe, IL-6 receptor blockade is not effective. Consider obtaining baseline MRI brain, correcting electrolyte abnormalities (e.g. sodium, magnesium, phosphate), and performing lumbar puncture (LP) if concerned for altered mental status when caring for patients receiving CAR-T cell therapy. A team-based, multidisciplinary approach cannot be overemphasized. Factors associated with toxicity after CAR-T infusion can be broadly divided into host/tumor or therapy-related factors. For instance, patients who have a high tumor burden are at a higher risk of developing toxicities. Other factors such as high baseline C-reactive protein (CRP) and thrombocytopenia before lymphodepletion; type of malignancy may also play a role. Those who experienced severe ICANS seem to have a higher peak CAR-T cell expansion in blood, earlier onset of fever, elevated serum chemokines/cytokines in CSF (e.g. MCP-1, IL-8, IP-10), and coagulopathy. The American Society for Transplantation and Cellular Therapy (ASTCT) recently published a consensus document on how to grade CRS and ICANS. Even though there are still gray areas needing to be addressed, the document provided some standardizations in this important part of a rapidly evolving field.
In summary, Dr. Santomasso delivered an excellent and educational lecture in the fascinating area of CAR-T cell therapy efficacy and associated toxicities.
Fellow Summary
Authored by Galina Lagos
Dr. Bianca Santomasso discussed the development and clinical experience with CAR-T cell therapies with a focus on the unique side effects associated with treatment, including cytokine release syndrome and neurotoxicity.
CAR-T cells are T cells isolated from a patient and engineered to express chimeric antigen receptors that target cancer cells. After growth and expansion, these cells are infused back into the patient and have proven efficacy in the treatment of refractory hematologic malignancies including ALL and B cell lymphomas. The currently approved CAR-T therapies are axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah). Despite the impressive clinical outcomes seen with this treatment approach, including >50% of patients with durable complete responses, these treatments are associated with unique and prominent toxicities. Dr. Santomasso used several clinical cases to describe some of these toxicities.
The first case illustrated some of the unique features of neurotoxicity compared to CRS in response to CAR-T. CRS is typically an early side effect seen within 2-3 days of exposure and responds well to the anti-IL-6 antibody, tocilizumab, with or without corticosteroids. On the other hand, the typical time to onset of neurotoxicity is 4-10 and is characterized by a global encephalopathy that does not respond to tocilizumab. Instead, the preferred treatment for severe neurotoxicity is corticosteroids. Dr. Santomasso also highlighted that the risk of developing some of these side effects is specific to the CAR product, with grade 3 neurotoxicity more commonly seen with Yescarta.
The second case demonstrated the development of reversible diffuse cerebral edema after CART infusion. In this case, the patient developed significant neurologic symptoms and MRI changes that eventually resolved to baseline. The case highlighted the importance of having a baseline brain MRI to assess changes with treatment, that lumbar puncture can be helpful for diagnosis and therapeutics, and that experience in treating CAR-T patients is important in being able to manage these side effects.
Dr. Santomasso and others have worked to elucidate factors that may be predictive of the development of severe toxicities and that correlate with the severity of neurotoxicity. These factors include a higher peak CAR-T expansion in the blood, earlier fever onset, elevated serum cytokines, thrombocytopenia and coagulopathy, blood-CSF barrier breakdown, MRI changes, and excitotoxins in the CSF. She also described the importance of using a consensus grading for monitoring the development of neurotoxicity and the approaches to aggressive supportive care. There are ongoing efforts to standardize management strategies and to use the current understanding of the pathophysiology of the toxicities to develop better approaches.
Fellow Summary
Authored by Aiko Nagayama
The emergence of T-bodies/chimeric antigen receptor T cells dates back to the early 1990s, to the invention of chimeric antibody receptor and the appearance of evidence of successful redirection of immune system to mediate antitumor activity. In principle, T cells are isolated from the patient and engineered to express CARs that recognize cancer cells, and the modified T cells are grown and expanded in culture, then infused into the patient. So far, two commercially available CARs, axicabtagene ciloleucel and tisagenlecleucel, are applied in the clinic.
Dr. Santomasso introduced the first FDA approval of CAR T cell treatment in 2017 based on the ELIANA trial, which enrolled 92 patients wth relapsed pediatric and adult ALL. The indication later expanded to triple hit DLBCL, 1º mediastinal LCL, and DLBCL arising from follicular NHL. The treatment showed more than 50% of durable complete responses with clinically significant toxicity, including cytoxine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). She presented a case of a 60 year-old female patient with B-ALL who received CAR T infusion and quickly developed a worsening neural toxicity. She emphasized the clinical case points that 1) there is a distinct time course of CRS and neurotoxicity, and 2) symptoms related to CRS would resolve with IL-6R blockade, whereas severe neurotoxicity would not. Dr. Santomasso also explained that the reversible diffuse cerebral edema developing after CD19 CAR T cells and IL6 elevation are the main pathogenesis of CRS, and the treatment options include IL6 inhibition and corticosteroids.
Dr. Santomasso’s research project is primarily focused on comprehensive assessment of neurologic toxicity of CAR T product at the clinical as well as molecular level. She pointed out that host/tumor factors such as type of malignancy, tumor burden, high baseline CRP, and therapy related factors such as lymphodepleting therapy, CAR T-cell dose, and presence of prior severe CRS are associated with toxicity after CAR T-cell therapy. Also, the clinical parameters listed below correlate with severe ICANS (Cancer Discovery 2018. Santomasso et al).
Correlates of severe ICANS
- Higher peak CAR T cell expansion in blood
- Earlier onset of fever
- Elevated serum cytokines
- Endothelial activation/brain microvascular compromise
- Low platelet count even at the baseline
- Blood-CSF barrier breakdown
- MRI changes
- Excitotoxins in CSF
As toxicity management, she raised the points that baseline exam, including vitals and encephalopathy screening, is important, and grade 3 or more ICANS should be treated with corticosteroids. Cytokine intervention trials such as IL1RA, direct IL6 blockade, and GM-CSF neutralization were also mentioned. She conluded that CAR T therapy is associated with unique acute toxicities that require vigilant monitoring, aggressive supportive care, and specialized management.
As CAR T therapies for hematologic malignancies are exploding with solid tumor strategy soon to follow, the management of toxicity and study of its mechanism study are an important part of development of this new category of cancer treatment.
Fellow Summary
Authored by Yosuke Togashi
Chimeric antigen receptors (CAR) combine the antigen binding portion of a monoclonal antibody with the signal activating machinery of T cells, usually the intracellular domains of the zeta chain of the T-cell receptor (TCR)/CD3 complex. Second generation CAR-T cells include other stimulatory domains such as CD28 or 4-1BB. Second generation CAR-T cell therapies, targeting CD19, have been tested in clinical trials, and two of them have been already approved for relapsed/refractory pediatric and young adult acute lymphoid leukemia (ALL) and relapsed/refractory adult non-Hodgkin lymphoma (NHL), in 2017 and 2018, respectively.
Dr. Santomasso gave a lecture about the induced toxicities of CAR-T cell therapy in addition to their efficacy. Although more than 50% of patients show durable complete response to CD19 CAR-T cell therapies, unique and prominent toxicities including cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) are reported in a significant fraction of patients, requiring intensive monitoring and a multidisciplinary management. CRS, characterized by fever, hypotension, capillary leak, respiratory insufficiency, coagulopathy, hyperferritinemia, and multi-organ failure, typically occurs 2 or 3 days after CAR-T cell infusion. IL-6 inhibition with tocilizumab +/- corticosteroids generally resolves CRS. By contrast, ICANS, characterized by encephalopathy, aphasia, tremor, obtundation, seizure, hallucinations, and rapid onset cerebral edema, occurs 4-10 days after infusion. ICANS can occur even if CRS is completely resolved. Compared with CRS, tocilizumab does not resolve severe ICANS, and corticosteroids may be used for management of ICANS, although some cases resolve without them.
Risk factors for severe ICANS are higher peak CAR-T cell expansion in blood (CD28 > 4-1BB), earlier onset of fever, elevated serum cytokines, endothelial activation, low platelet count, coagulopathy, blood-CSF barrier breakdown, MRI change, and excitotoxins in CSF. There seem to be some safer CAR-T cell therapies. Macrophage infiltration was observed in ICANS histopathology, and IL-1R antagonist (anakinra) could be effective in mouse models. Thus, cytokine intervention trials of IL-1R antagonist (anakinra), IL-6 blockade (siltuximab), and GM-CSF neutralization are under investigation or consideration.
These unique severe toxicities require intensive monitoring, aggressive supportive care, and specialized management. New consensus guidelines for grading will facilitate the safe administration of CAR-T cells by providing a framework for developing best management strategies.
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