Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

Acharya, Utkarsh; Dhawale, Tejaswini; Yun, Seongseok; Jacobson, Caron A.; Chávez, Julio C.; Ramos, Jorge; Appelbaum, Jacob; Maloney, David G.

doi:10.1080/17474086.2019.1585238

Cited by 74 publications

(58 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Clinical experts in China and abroad have a relatively clear understanding of grading and controlling serious ADRs, such as CRS, neurotoxicity, and macrophage activation syndrome. 24 – 26 For example, verifying tocilizumab (two doses) is ordered and available for administration before a dose of CAR T-cell product is administered according to the risk evaluation and mitigation strategy of Food and Drug Administration-approved Yescarta and Kymriah. 27 , 28…”

Section: Resultsmentioning

confidence: 99%

Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

Huo

Ding

et al. 2020

Ther Adv Med Oncol

View full text Add to dashboard Cite

Aims: Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials. Methods: A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers. Results: Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety. Conclusion: The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

Huo

Ding

et al. 2020

Ther Adv Med Oncol

View full text Add to dashboard Cite

show abstract

“…However, several patients are resistant to therapeutic effects of tocilizumab. Moreover, patients with CRS-related neurotoxicity do not benefit from tocilizumab due to its poor penetration through the blood-brain barrier [14]. Hence, the development of novel therapeutic approaches for CRS remains an unmet clinical need.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the effect of tocilizumab against severe CRS-associated neurotoxicity is extremely low, likely due to its limited ability to penetrate the blood-brain barrier [13]. Moreover, prophylactic use of tocilizumab did not prevent the development of neurotoxicity [14]. Therefore, IL-6/IL-6R blockade alone would be insufficient in treating severe CRS in patients undergoing CAR T-cell therapy.…”

Section: Introductionmentioning

confidence: 99%

The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

Futami

Suzuki²,

Kato

et al. 2020

PLoS ONE

View full text Add to dashboard Cite

Cancer immunotherapy using chimeric antigen receptor-armed T (CAR T) cells have been shown to improve outcomes significantly in patients with hematological malignancies. However, cytokine release syndrome (CRS) remains a risk. CRS is characterized by the excessive activation of CAR T cells and macrophages. Signs and symptoms of CRS are usually resolved after steroid administration, but steroids abrogate the expansion and persistence of CAR T cell populations. Tocilizumab is a humanized monoclonal antibody (mAb) that attenuates CRS without significant loss of CAR T cell activity. However, interleukin-6 (IL-6)/ IL-6 receptor (IL-6R) blockade alone cannot relieve CRS symptoms fully, and novel treatments are needed to prevent or cure CRS. TO-207 is an N-benzoyl-L-phenylalanine derivative that significantly inhibits inflammatory cytokine production in human monocyte and macrophage-specific manner. We investigated whether TO-207 could inhibit cytokine production without impairing CAR T cell function in a CRS-simulating co-culture system.

show abstract

“…CRS is a major toxicity [27]. CRES [28,29] is also emerging as a challenge in the CAR-T cell therapies.…”

Section: Car-t Distribution and The Safety In Nhl Patientsmentioning

confidence: 99%

Distribution Measurements of Chimeric Antigen Receptor-Modified T Cells Against CD19

Ying¹,

He²,

Wang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Backgroud: The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumor. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo.Methods: We demonstrated the distribution of CAR-T cells in the absence of target cells or with target cells in the mice and the dynamic changes in the patient blood over time after infusion were deteced by qPCR and FACS. Results: CAR-T cells still proliferated in the mice without target cells and peaked at 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at 6 weeks. In the clinical trial, we found that CAR-T cells peaked at 7-21days after infusion and can last for as long as 510 days in the peripheral blood of patients. Simultaneously, mild side-effects were noted which can be effectively controlled within two months in these patients.Conclusions: CAR-T cells can expand themselves with or without target cells in mice. CAR-T cells can persistence for a long time in patients.

show abstract

Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

Cited by 74 publications

References 52 publications

Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

Distribution Measurements of Chimeric Antigen Receptor-Modified T Cells Against CD19

Contact Info

Product

Resources

About