Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

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Abstract

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19 ⁺ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

Abstract

Chimeric antigen receptor (CAR) T cell therapies have impressive activity in the treatment of cancer but are associated with potentially fatal toxicities. In light of the approval of CAR T cell therapy for paediatric patients, a panel of experts from the Hematopoietic Stem Cell Transplantation (HSCT) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, the CAR T Cell Therapy-Associated Toxicity (CARTOX) Program at The University of Texas MD Anderson Cancer Center, and several other institutions have developed consensus guidelines for the use and management of these treatments in paediatric patients, which are presented herein.

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Most cited references 91

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Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

Catherine Lindgren, Assaf P. Oron, Daniel Li … (2017)

Publisher's Note: There is an [Related article:] Inside Blood Commentary on this article in this issue. Defined-composition manufacturing platform of CD19 CAR T cells contributes to >90% intent-to-treat complete remission rate. Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization. Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD − ) remission rate for this phase 1 study was 89%. The MRD − remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

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Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.

K. S. Schluns, W. Kieper, S. Jameson … (2000)

The naïve and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naïve CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL-7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.

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Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity

R Basar, M H Bdaiwi, R. G. Cai … (2017)

Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

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Author and article information

Contributors

Kris M. Mahadeo: kmmahadeo@mdanderson.org

Journal

Journal ID (nlm-ta): Nat Rev Clin Oncol

Journal ID (iso-abbrev): Nat Rev Clin Oncol

Title: Nature Reviews. Clinical Oncology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1759-4774

ISSN (Electronic): 1759-4782

Publication date (Electronic): 6 August 2018

Publication date (Print): 2019

Volume: 16

Issue: 1

Pages: 45-63

Affiliations

[1 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[2 ]ISNI 0000 0001 2153 6013, GRID grid.239546.f, Department of Pediatrics, Blood and Marrow Transplantation Program, Keck School of Medicine, University of Southern California, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA

[3 ]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Department of Anesthesiology and Critical Care, Division of Critical Care, University of Pennsylvania Perelman School of Medicine, , Children’s Hospital of Philadelphia, ; Philadelphia, PA USA

[4 ]ISNI 0000 0000 9026 4165, GRID grid.240741.4, Department of Pediatrics, Division of Hematology–Oncology, University of Washington, , Seattle Children’s Hospital, ; Seattle, WA USA

[5 ]ISNI 0000 0004 1936 9510, GRID grid.253615.6, Center for Cancer and Immunology Research and Department of Pediatrics, , Children’s National and The George Washington University, ; Washington DC, USA

[6 ]ISNI 0000 0001 2200 2638, GRID grid.416975.8, Department of Pediatrics, Stem Cell Transplantation, Baylor College of Medicine, , Texas Children’s Hospital, ; Houston, TX USA

[7 ]ISNI 000000041936754X, GRID grid.38142.3c, Pediatric Hematology–Oncology, Dana-Farber Cancer Institute, , Harvard University, ; Boston, MA USA

[8 ]ISNI 0000 0000 8499 1112, GRID grid.413734.6, Department of Pediatric Critical Care, Weil Cornell Medical College, , New York Presbyterian Hospital, ; New York, NY USA

[9 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Pediatrics, Division of Critical Care, University of Minnesota, Masonic Children’s Hospital, , University of Minnesota, ; Minneapolis, MN USA

[10 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Department of Pediatrics, Division of Critical Care, Duke Children’s Hospital, , Duke University, ; Durham, NC USA

[11 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Pediatrics, Critical Care, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[12 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Pediatrics, Neurology, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[13 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Pediatrics, Division of Blood and Marrow Transplantation, Nationwide Children’s Hospital, , the Ohio State University, ; Columbus, OH USA

[14 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Stem Cell Transplantation and Cellular Therapy, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[15 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Department of Pediatrics, Division of Blood and Marrow Transplant, Duke Children’s Hospital, , Duke University, ; Durham, NC USA

[16 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Department of Pediatrics, Division of Critical Care, , St. Jude’s Children’s Research Hospital, ; Memphis, TN USA

[17 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Pharmacy, Children’s Hospital at Montefiore, , Albert Einstein College of Medicine, ; Bronx, NY USA

[18 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Pharmacy, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[19 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Lymphoma and Myeloma, CARTOX Program, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

Author information

Sajad J. Khazal http://orcid.org/0000-0002-3731-608X

Chani Traube http://orcid.org/0000-0003-1863-7950

Article

Publisher ID: 75

DOI: 10.1038/s41571-018-0075-2

PMC ID: 7096894

PubMed ID: 30082906

SO-VID: 325b5aec-f416-48be-84cd-3c77feaed81c

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Keywords: haematological cancer,cancer immunotherapy,immunotherapy,paediatric cancer,adverse effects

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Keywords: haematological cancer, cancer immunotherapy, immunotherapy, paediatric cancer, adverse effects

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

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Cancer Immunotherapy

Most cited references 91

Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity

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