What question did this study set out to answer?

To evaluate the antitumor efficacy of ALK-targeted CAR T cells in neuroblastoma and determine how target antigen and CAR expression densities influence therapeutic function.

July 1, 2017Molecular TherapyOpen Access

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase

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Authors

AWAlec J. WalkerBroad Institute RMRobbie G. MajznerBoston Children's Hospital LZLing ZhangHebei Medical University

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Implication

Preclinical study demonstrates that low target and receptor densities limit ALK CAR T cell efficacy in neuroblastoma, highlighting the importance of stoichiometric tuning for immunotherapy.

Key Points

To evaluate the antitumor efficacy of ALK-targeted CAR T cells in neuroblastoma and determine how target antigen and CAR expression densities influence therapeutic function.
Engineered T cells with an ALK-specific CAR (ALK48 single-chain variable fragment linked to 4-1BB-CD3ζ) and assessed cytolytic activity and interferon-gamma release against ALK-expressing cell lines in vitro.
Evaluated in vivo antitumor efficacy in two human neuroblastoma xenograft mouse models.
Modulated antigen density and CAR expression levels simultaneously to investigate the stoichiometric determinants of CAR T cell activation and receptor internalization.
ALK CAR T cells lysed target lines in vitro but showed limited antitumor efficacy in two human neuroblastoma xenograft models.
Cytokine production and maximal CAR activation were hindered by low ALK target density on neuroblastoma cells and rapid antigen-induced CAR internalization from the T cell surface.
Stoichiometric alignment between CAR and target antigen density governed CAR function, indicating that low expression of either parameter restricts therapeutic efficacy.

Cite This Study

Walker et al. (2017) studied this question.

synapsesocial.com/papers/6a776d0d137c7dcc81bdd1fb https://doi.org/10.1016/j.ymthe.2017.06.008

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Implication

Preclinical study demonstrates that low target and receptor densities limit ALK CAR T cell efficacy in neuroblastoma, highlighting the importance of stoichiometric tuning for immunotherapy.

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase

Discussion

Member takes

Implication

Key Points

Cite This Study

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase

Discussion

Member takes

Implication

Key Points

Cite This Study

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