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Curated Papers > Highly Cited Authoritative Literature on "CAR-T Therapy"

CAR T Cell Therapy for Neuroblastoma. ​

Literature Information ​

DOI10.3389/fimmu.2018.02380
PMID30459759
JournalFrontiers in immunology
Impact Factor5.9
JCR QuartileQ1
Publication Year2018
Times Cited89
KeywordsCAR T cells, adoptive T cell therapy, clinical trials, immunotherapy, neuroblastoma
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1664-3224
Pages2380
Issue9()
AuthorsRebecca M Richards, Elena Sotillo, Robbie G Majzner

TL;DR ​

This review examines the potential of chimeric antigen receptor (CAR) T cell therapy as a promising treatment for high-risk neuroblastoma, where current therapies yield only a 50% five-year survival rate despite the effectiveness of anti-GD2 monoclonal antibodies. It highlights the challenges faced in CAR T cell efficacy, such as T cell persistence and the tumor microenvironment, while discussing ongoing clinical trials and strategies to enhance the therapeutic impact for affected patients.

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CAR T cells · adoptive T cell therapy · clinical trials · immunotherapy · neuroblastoma

Abstract ​

Patients with high risk neuroblastoma have a poor prognosis and survivors are often left with debilitating long term sequelae from treatment. Even after integration of anti-GD2 monoclonal antibody therapy into standard, upftont protocols, 5-year overall survival rates are only about 50%. The success of anti-GD2 therapy has proven that immunotherapy can be effective in neuroblastoma. Adoptive transfer of chimeric antigen receptor (CAR) T cells has the potential to build on this success. In early phase clinical trials, CAR T cell therapy for neuroblastoma has proven safe and feasible, but significant barriers to efficacy remain. These include lack of T cell persistence and potency, difficulty in target identification, and an immunosuppressive tumor microenvironment. With recent advances in CAR T cell engineering, many of these issues are being addressed in the laboratory. In this review, we summarize the clinical trials that have been completed or are underway for CAR T cell therapy in neuroblastoma, discuss the conclusions and open questions derived from these trials, and consider potential strategies to improve CAR T cell therapy for patients with neuroblastoma.

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Primary Questions Addressed ​

  1. What are the specific challenges in improving T cell persistence and potency in CAR T cell therapy for neuroblastoma?
  2. How do recent advances in CAR T cell engineering address the immunosuppressive tumor microenvironment in neuroblastoma?
  3. What are the differences in efficacy between CAR T cell therapy and traditional treatments for high-risk neuroblastoma?
  4. How might the integration of other immunotherapies enhance the effectiveness of CAR T cell therapy in neuroblastoma patients?
  5. What ongoing clinical trials are exploring novel target identification strategies for CAR T cell therapy in neuroblastoma?

Key Findings ​

Background and Purpose ​

Neuroblastoma is a common pediatric cancer originating from neural crest cells, with high-risk patients facing poor prognoses and long-term treatment sequelae. Despite the introduction of anti-GD2 monoclonal antibody therapy, the 5-year overall survival rate remains around 50%. This review explores the potential of Chimeric Antigen Receptor (CAR) T cell therapy to improve outcomes for neuroblastoma patients, summarizing current clinical trials and identifying barriers to efficacy.

Main Methods/Materials/Experimental Design ​

The review details various clinical trials investigating CAR T cell therapy targeting neuroblastoma, focusing on GD2 and L1-CAM as primary targets. The authors discuss the engineering of CAR T cells to enhance persistence and efficacy through various signaling domains and costimulatory signals.

Technical Route ​

Mermaid diagram

Key Results and Findings ​

  1. Target Identification: GD2 and L1-CAM are the most studied targets for CAR T cell therapy in neuroblastoma. GD2 is expressed on nearly all neuroblastoma cells, while L1-CAM shows promise but poses risks for off-tumor toxicity.
  2. Clinical Responses: Initial trials demonstrated safety and some objective responses, but T cell persistence and potency were often limited. For instance, early GD2 CAR trials yielded modest response rates, with significant variability in patient outcomes.
  3. Engineering Advances: Efforts to improve CAR T cell persistence included using costimulatory domains like 4-1BB and optimizing lymphodepletion strategies, which showed some promise in enhancing CAR T cell activity.

Main Conclusions/Significance/Innovation ​

The review emphasizes that while CAR T cell therapy holds potential for neuroblastoma treatment, challenges such as T cell persistence, effective target selection, and the immunosuppressive tumor microenvironment must be addressed. Advances in CAR engineering and combination therapies could lead to improved clinical outcomes. The findings suggest that neuroblastoma may serve as a valuable model for testing novel CAR T cell strategies in solid tumors.

Limitations and Future Directions ​

  1. Study Limitations: The review highlights the limited number of trials targeting neuroblastoma and the challenges in translating findings from hematologic malignancies to solid tumors.
  2. Future Research: There is a need for more extensive trials focusing on alternative targets, enhanced CAR designs, and strategies to overcome the immunosuppressive tumor microenvironment. Research should also explore the integration of CAR T cells with other therapies, such as checkpoint inhibitors and cytokine modulation, to enhance efficacy.

Summary Table of Key Findings ​

TargetCurrent StatusResponse RateChallenges
GD2Multiple trials ongoingModest responses in some patientsLimited persistence, off-tumor toxicity
L1-CAMEarly-phase trialsLow response rates observedLack of effective costimulation, toxicity concerns

This comprehensive review provides insights into the potential of CAR T cell therapy for neuroblastoma, outlining the significant advancements and ongoing challenges in this evolving field.

References ​

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Literatures Citing This Work ​

  1. Prediction of PD-L1 Expression in Neuroblastoma via Computational Modeling. - Salvo Danilo Lombardo;Mario Presti;Katia Mangano;Maria Cristina Petralia;Maria Sofia Basile;Massimo Libra;Saverio Candido;Paolo Fagone;Emanuela Mazzon;Ferdinando Nicoletti;Alessia Bramanti - Brain sciences (2019)
  2. Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma. - Eugenio Cavalli;Emanuela Mazzon;Santa Mammana;Maria Sofia Basile;Salvo Danilo Lombardo;Katia Mangano;Placido Bramanti;Ferdinando Nicoletti;Paolo Fagone;Maria Cristina Petralia - Brain sciences (2019)
  3. EGFR-specific CAR-T cells trigger cell lysis in EGFR-positive TNBC. - Yan Liu;Yehui Zhou;Kuo-Hsiang Huang;Ying Li;Xujie Fang;Li An;Feifei Wang;Qingfei Chen;Yunchao Zhang;Aihua Shi;Shuang Yu;Jingzhong Zhang - Aging (2019)
  4. Recent advances in tumor associated carbohydrate antigen based chimeric antigen receptor T cells and bispecific antibodies for anti-cancer immunotherapy. - Zahra Rashidijahanabad;Xuefei Huang - Seminars in immunology (2020)
  5. "UniCAR"-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells. - Nicola Mitwasi;Anja Feldmann;Claudia Arndt;Stefanie Koristka;Nicole Berndt;Justyna Jureczek;Liliana R Loureiro;Ralf Bergmann;Domokos Máthé;Nikolett Hegedüs;Tibor Kovács;Congcong Zhang;Pranav Oberoi;Elke Jäger;Barbara Seliger;Claudia Rössig;Achim Temme;Jiri Eitler;Torsten Tonn;Marc Schmitz;Jessica C Hassel;Dirk Jäger;Winfried S Wels;Michael Bachmann - Scientific reports (2020)
  6. Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. - Ombretta Melaiu;Valeria Lucarini;Loredana Cifaldi;Doriana Fruci - Frontiers in immunology (2019)
  7. Targets and Antibody Formats for Immunotherapy of Neuroblastoma. - Jeong A Park;Nai-Kong V Cheung - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2020)
  8. Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma. - Lihong Wang-Bishop;Mohamed Wehbe;Daniel Shae;Jamaal James;Benjamin C Hacker;Kyle Garland;Plamen P Chistov;Marjan Rafat;Justin M Balko;John T Wilson - Journal for immunotherapy of cancer (2020)
  9. Chimeric cytokine receptor enhancing PSMA-CAR-T cell-mediated prostate cancer regression. - Shao Weimin;Asimujiang Abula;Ding Qianghong;Wang Wenguang - Cancer biology & therapy (2020)
  10. Patients' NK cell stimulation with activated plasmacytoid dendritic cells increases dinutuximab-induced neuroblastoma killing. - Assila Belounis;Marina Ayoub;Paulo Cordeiro;William Lemieux;Pierre Teira;Elie Haddad;Sabine Herblot;Michel Duval - Cancer immunology, immunotherapy : CII (2020)

... (79 more literatures)

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