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Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy (PDQ®)–Health Professional Version

Chimeric Antigen Receptor (CAR) T-Cell Therapy for Pediatric Cancer

T cells attack cellular targets (viruses or cancer cells) by binding to class I major histocompatibility complex (MHC) molecules on the surface of the target cells. T cells also have to avoid suppressor signals sent by regulatory T cells and other surface molecule interactions. Gene transfer technologies can modify T cells to express MHC-independent, antibody-binding domains (CAR molecules) on the surface of the modified T cells. The CAR molecules aim at specific target proteins on the surface of tumors. Lymphodepleting chemotherapy is generally given before CAR T-cell infusions to minimize the chance of suppressor mechanisms (affecting CAR T-cell function) and to create a cytokine milieu favorable for CAR T-cell expansion.[1] CAR T-cell–mediated responses are further enhanced by adding intracellular costimulatory domains (e.g., CD28, 4-1BB), which cause significant CAR T-cell expansion and may increase the lifespan of these cells in the recipient.[1]

CAR T-Cell Therapy Indications for Pediatric Cancer

Investigators using this technology have targeted a variety of tumors/surface molecules, but the best-studied example in pediatric patients is CAR T cells aimed at CD19, a surface receptor on B cells. Several research groups have reported significant rates of remission (70%–90%) in children and adults with refractory B-cell acute lymphoblastic leukemia (ALL),[2-5] with some groups reporting persistence of CAR T cells and remission beyond 6 months in most patients studied.[5,6] Early loss of the CAR T cells is associated with relapse, and the best use of this therapy (bridge to transplant vs. definitive therapy) is under study.

Indications for hematopoietic stem cell transplant vary over time as risk classifications for a given malignancy change and the efficacy of primary therapy improves. It is best to include specific indications in the context of complete therapy for any given disease. With this in mind, links to sections in specific summaries that cover the most common pediatric CAR T-cell therapy indications are provided below.

  1. B-cell acute lymphoblastic leukemia.
  2. B-cell non-Hodgkin lymphoma.

CAR T-Cell Toxicities

Cytokine release syndrome (CRS)

Responses to CAR T-cell therapies have been associated with a significant increase in inflammatory cytokines, termed cytokine release syndrome (CRS). CRS can be successfully treated with anti–interleukin-6 receptor (IL-6R) therapies (e.g., tocilizumab), often in combination with steroids.[7,8] CRS presents as a sepsis-like situation, with fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. The severity of the CRS determines whether patients require therapy. The progression of CRS can be measured by staging. The American Society for Transplantation and Cellular Therapy Consensus guidelines for CRS have been broadly adopted (see Table 1).[9] While treatment of grade 1 and early grade 2 CRS is generally not offered, patients with some forms of grade 2 and all patients with grades 3 and 4 CRS receive therapy.[10]

Table 1. ASTCT CRS Consensus Gradinga,b
CRS ParameterGrade 1Grade 2Grade 3Grade 4
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.
aReprinted from Biology of Blood and Marrow Transplantation, Volume 25, Issue 4, Daniel W. Lee, Bianca D. Santomasso, Frederick L. Locke et al., ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells, Pages 625–638, Copyright 2019, with permission from Elsevier.[9]
bOrgan toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
cFever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
dCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.
eLow-flow nasal cannula is defined as oxygen delivered at ≤6L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.
FevercTemperature ≥38°CTemperature ≥38°CTemperature ≥38°CTemperature ≥38°C
HypotensionNoneNot requiring vasopressorsRequiring a vasopressor with or without vasopressinRequiring multiple vasopressors (excluding vasopressin)
HypoxiaNoneRequiring low-flow nasal cannulae or blow-byRequiring high-flow nasal cannulae, facemask, nonrebreather mask, or Venturi maskRequiring positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation)
Approaches to mitigating CRS toxicities

Early studies of CD19-targeted CAR T cells using both CD28 and 4-1BB costimulatory domains varied in approach. The use of tocilizumab or steroids was limited to patients who experienced severe toxicities because of concern about the loss of CAR T-cell persistence (with excessive use of immune suppressive agents). These toxicities included hypotension requiring high-dose vasopressors, severe hypoxia, or intubation. After one early study showed similar efficacy in patients treated with and without tocilizumab,[11] investigators designed approaches aimed at early treatment of CRS to limit organ damage secondary to grade 4 CRS. Some approaches have decreased toxicity without obvious effects on efficacy.

Evidence (early interventions for CRS):

  1. Investigators at Seattle Children’s Hospital compared a strategy of early intervention versus standard practice. Early intervention included treatment with tocilizumab for patients with a fever higher than 39°C that was unresponsive to acetaminophen, persistent hypotension after a 10 mL/kg bolus, or initiation of oxygen. Steroids were given after tocilizumab if symptoms persisted or worsened 6 to 12 hours later.[12]
    • The early intervention approach doubled the number of patients requiring tocilizumab or steroids but did not affect the overall minimal residual disease–negative remission rate, infection rate, long-term persistence of CAR T cells, or overall survival (OS).
    • In addition, early intervention for patients with CRS resulted in a decreased need for intubation or inotropic support, from 30% to 15%. However, this finding was not statistically significant (P = .29), possibly because of the small number of patients.
  2. Investigators at Children's Hospital of Philadelphia performed a prospective trial of a different strategy of early intervention. Because of earlier findings that showed that high disease burden at the time of CAR T-cell treatment was associated with severe CRS,[6] they defined a high–tumor burden cohort as patients with 40% or more marrow blasts before infusion. Planned early intervention for this cohort was tocilizumab, given for two fevers of 38.5°C or higher, at least 4 hours apart, in a 24-hour period.[13]
    • Grade 4 CRS decreased from 50% (in a comparator cohort) to 27% in the high–tumor burden cohort (P = .18), with no change in efficacy and long-term CAR T-cell persistence.

Immune effector cell–associated neurotoxicity syndrome (ICANS)

Neurological toxicities, including aphasia, altered mental status, and seizures, have also been observed with CAR T-cell therapy. This clinical syndrome (ICANS) is graded according to the most severe event of the following five measures that are not attributable to any other cause:[9]

  1. Standardized neurological responsiveness score (tests vary by age: Immune Effector Cell-Associated Encephalopathy [ICE] score for children aged ≥12 years and Cornell Assessment of Pediatric Delirium [CAPD] for children aged <12 years).
  2. Level of consciousness.
  3. Seizure activity.
  4. Motor weakness.
  5. Elevated intracranial pressure/cerebral edema.

Most neurological toxicities after CD19-targeted CAR T-cell therapy have been short lived (1–5 days). However, rare, fatal events such as severe cerebral edema have been reported.[14] The pathophysiology of central nervous system (CNS) toxicity is likely related to disruption of the blood-brain barrier secondary to systemic cytokine release,[14] high levels of cytokines in the cerebrospinal fluid,[14] and/or direct attack of CD19-positive brain mural cells in the CNS tissue by the CAR T cells.[15] CNS symptoms have not responded well to IL-6R–targeting agents and have generally been treated with high-dose steroids or other approaches. The exact timing of required treatment for ICANS is controversial, but concerns about its rare, fatal form have led to near-uniform recommendations for the treatment of patients with grade 3 or higher ICANS.[16]

Hemophagocytic lymphohistiocytosis (HLH)–like toxicities

A portion of patients undergoing CAR T-cell therapy will have HLH-like toxicities associated with CRS (hyperferritinemia with organ dysfunction). Severity of symptoms and outcomes vary by CAR construct. It is not known whether early or preventive treatment can improve patient outcomes.

Evidence (effect of HLH-like toxicities on patient outcomes):

  1. Investigators at the National Cancer Institute noted increased HLH-like toxicities in a trial of CD22-targeted CAR T-cell therapy.[17]
    • HLH-like toxicity was seen in 19 of 58 patients (32.8%). The average time to onset of HLH-like toxicity was 14 days after CAR T-cell therapy. CRS had resolved or was resolving before the onset of HLH-like features.
    • CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility. However, after this modification, patients experienced heightened HLH-like toxicities, which led to dose de-escalation.
    • HLH-like toxicity did not alter survival outcomes but often required intense interventions such as anakinra.
  2. Investigators from the Pediatric Real World CAR Consortium analyzed 183 evaluable children and adolescent and young adult patients treated with tisagenlecleucel for B-cell ALL and found that 14% had HLH-like toxicities.[18]
    • HLH-like toxicity was associated with poor OS (hazard ratio [HR], 4.61; 95% confidence interval [CI], 2.41–8.83) and relapse-free survival (RFS) (HR, 3.68; 95% CI, 2.15–6.32). The 1-year RFS and OS rates were 25.7% and 4.7%, respectively, for patients with HLH-like toxicities, compared with 80.1% and 57.6%, respectively, for patients without HLH-like toxicities.
    • Patients who developed HLH-like toxicity had higher pre-infusion disease burden, ferritin levels, and C-reactive protein levels, compared with patients who did not develop HLH-like toxicity. Patients who developed HLH-like toxicity also had lower pre-infusion platelet and absolute neutrophil counts.
    • Patients who developed HLH-like toxicity subsequently had higher rates of infection, relapse, and nonrelapse mortality.

Other side effects of CAR T-cell therapy

Other CAR T-cell therapy side effects include the following:

  • Coagulopathy.
  • Cardiac dysfunction.

Early studies of patients with high levels of disease and delayed CRS therapy resulted in 20% to 40% of patients requiring treatment in the intensive care unit (ICU) (mostly vasopressor support, with 10% to 20% of patients requiring intubation and/or dialysis).[2,5,6] However, current real-world data show that ICU requirements are now approximately 10% to 20%.[19]

Approved CAR T-Cell Therapies

An international trial in children led to U.S. Food and Drug Administration approval of tisagenlecleucel for patients aged 1 to 25 years with CD19-positive B-cell ALL that is refractory or in second or later relapse.[20]

Tisagenlecleucel has also been approved for adults with relapsed or refractory B-cell lymphoma, as has axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel.[21,22]

  1. Kalos M, Levine BL, Porter DL, et al.: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3 (95): 95ra73, 2011. [PUBMED Abstract]
  2. Grupp SA, Kalos M, Barrett D, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368 (16): 1509-18, 2013. [PUBMED Abstract]
  3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al.: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385 (9967): 517-28, 2015. [PUBMED Abstract]
  4. Davila ML, Riviere I, Wang X, et al.: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6 (224): 224ra25, 2014. [PUBMED Abstract]
  5. Gardner RA, Finney O, Annesley C, et al.: Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129 (25): 3322-3331, 2017. [PUBMED Abstract]
  6. Maude SL, Frey N, Shaw PA, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371 (16): 1507-17, 2014. [PUBMED Abstract]
  7. Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124 (2): 188-95, 2014. [PUBMED Abstract]
  8. Maude SL, Barrett D, Teachey DT, et al.: Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20 (2): 119-22, 2014 Mar-Apr. [PUBMED Abstract]
  9. Lee DW, Santomasso BD, Locke FL, et al.: ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 25 (4): 625-638, 2019. [PUBMED Abstract]
  10. McNerney KO, Hsieh EM, Shalabi H, et al.: INSPIRED Symposium Part 3: Prevention and Management of Pediatric Chimeric Antigen Receptor T Cell-Associated Emergent Toxicities. Transplant Cell Ther 30 (1): 38-55, 2024. [PUBMED Abstract]
  11. Mueller KT, Waldron E, Grupp SA, et al.: Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res 24 (24): 6175-6184, 2018. [PUBMED Abstract]
  12. Gardner RA, Ceppi F, Rivers J, et al.: Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 134 (24): 2149-2158, 2019. [PUBMED Abstract]
  13. Kadauke S, Myers RM, Li Y, et al.: Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol 39 (8): 920-930, 2021. [PUBMED Abstract]
  14. Gust J, Ponce R, Liles WC, et al.: Cytokines in CAR T Cell-Associated Neurotoxicity. Front Immunol 11: 577027, 2020. [PUBMED Abstract]
  15. Parker KR, Migliorini D, Perkey E, et al.: Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell 183 (1): 126-142.e17, 2020. [PUBMED Abstract]
  16. Ragoonanan D, Khazal SJ, Abdel-Azim H, et al.: Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer. Nat Rev Clin Oncol 18 (7): 435-453, 2021. [PUBMED Abstract]
  17. Shah NN, Highfill SL, Shalabi H, et al.: CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. J Clin Oncol 38 (17): 1938-1950, 2020. [PUBMED Abstract]
  18. McNerney KO, Si Lim SJ, Ishikawa K, et al.: HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL. Blood Adv 7 (12): 2758-2771, 2023. [PUBMED Abstract]
  19. Pasquini MC, Hu ZH, Curran K, et al.: Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv 4 (21): 5414-5424, 2020. [PUBMED Abstract]
  20. Maude SL, Laetsch TW, Buechner J, et al.: Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 378 (5): 439-448, 2018. [PUBMED Abstract]
  21. Chow VA, Shadman M, Gopal AK: Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood 132 (8): 777-781, 2018. [PUBMED Abstract]
  22. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PUBMED Abstract]

Latest Updates to This Summary (06/13/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of CAR T-cell therapy in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy are:

  • Thomas G. Gross, MD, PhD (National Cancer Institute)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Sarah K. Tasian, MD (Children's Hospital of Philadelphia)

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PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: Accessed <MM/DD/YYYY>. [PMID: 35133769]

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