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A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma

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Abstract

Purpose

A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS®) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy.

Methods

We generated ET019003 T cells, which are autologous CD19-directed AbTCR T cells. We then conducted an early phase I study to evaluate the safety and preliminary efficacy of ET019003 T cells for the treatment of CD19-positive relapsed/refractory (r/r) B-cell lymphoma.

Results

Sixteen patients enrolled in this study and 12 patients were treated. Of the 12 patients treated, 6 patients (50%) achieved a complete response (CR), and 4 (33%) achieved a partial response (PR) (best objective response rate [ORR] of 83%). CRs were durable, including 2 patients with ongoing CRs for 22.7 months and 23.2 months. ET019003 was well-tolerated with an attractive safety profile. No patients experienced severe (grade ≥ 3) cytokine release syndrome (CRS) and only 1 patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. Significant elevations of cytokine levels were not seen, even in patients with marked expansion of ET019003 T cells.

Conclusion

This study provides initial clinical validation of the AbTCR platform as a novel cancer treatment with the potential to provide durable clinical benefit with low toxicity.

Trial registration

NCT03642496; Date of registration: August 22, 2018.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information file.

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Acknowledgements

The authors thank Jing Li, Xin Liu, Mengchang Wang, Jieying Xi, and Haitao Zhang for their involvement in the conduct of the study; Hong Liu for assistance with clinical protocol design; Joy Lin for help with data organization and manuscript preparation; and Vivien Chan, Sal Fuerstenberg, Mei Hong, Michael Kavanaugh, Nicole Nuñez, and Pei Wang for critical review of the manuscript.

Funding

This study was sponsored by The First Affiliated Hospital of Xi’an Jiaotong University in collaboration with Eureka Therapeutics, Inc. This study was supported by National Key R \(\&\) D Program of China (No. 2019YFC1316204), Key Research and Development Program of Shaanxi (No. 2018ZDCXL-SF-01–02-01, 2021ZDLSF02-17 and 2021SF-302), and National Scientific and Technological Major Special Project for Significant Creation of New Drugs (No. 2020ZX09201020).

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Author notes

  1. Pengcheng He, Haibo Liu, and Bryan Zimdahl contributed equally to this study.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Pengcheng He, Haibo Liu, Jie Wang, Minna Luo, Huasheng Liu, Limei Chen, Huaiyu Wang & Mei Zhang

  2. Eureka Therapeutics, Inc., Emeryville, CA, USA

    Bryan Zimdahl, Qi Chang, Fangzhou Tian, Fan Ni, Duo Yu & Cheng Liu

  3. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Stephan A. Grupp

  4. Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Stephan A. Grupp

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  1. Pengcheng He
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Contributions

PH, MZ, HL, and CL conceived and designed the study; PH oversaw the conduct of the study; HL, JW, ML, HL, LC, and HW were involved in the conduct of the study; HL, BZ, and FT analyzed and interpreted clinical data; BZ analyzed and interpreted correlative data and performed statistical analysis; QC oversaw drug product manufacturing, Quality Control, and correlative studies; FT collected correlative data; FT and DY collected drug product data; FN oversaw the Good Manufacturing Practice laboratory and drug product manufacturing; DY analyzed drug product data and established Quality Control testing for drug product release; SAG assisted with the interpretation of clinical and correlative data; BZ wrote the manuscript; and all authors critically reviewed the manuscript and approved the content.

Corresponding author

Correspondence to Cheng Liu.

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Competing interests

BZ, QC, FT, FN, DY, and CL are employed at Eureka Therapeutics, Inc., (Eureka) and have equity and/or stock options in Eureka. CL serves on advisory boards for the following companies: Eureka and JW Therapeutics. SAG has received support from Novartis, Servier, and Kite and serves as a consultant, member of the scientific advisory board or study steering committee for Novartis, Cellectis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Vertex, Cure Genetics, Humanigen, and Roche. The remaining authors declare no competing financial interests.

Ethical approval

This study was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University in China. The study was conducted in accordance with the principles of the Declaration of Helsinki.

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All participants in the study provided written informed consent.

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Patient consent for publication is not required. Patients consented to participate in the study.

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He, P., Liu, H., Zimdahl, B. et al. A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma. J Cancer Res Clin Oncol 149, 2757–2769 (2023). https://doi.org/10.1007/s00432-022-04132-9

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