Phase 1 studies of central memory–derived CD19 CAR T–cell therapy following autologous HSCT in patients with B-cell NHL

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95–105. ©2017 AACR.

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“…1D). For the following in vitro and in vivo studies, we utilized HER2-CARs engineered in T CM cells, as described previously (20,21).…”

Section: Her2-car T Cells Containing a 4-1bb Intracellularmentioning

confidence: 99%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

Self Cite

227

185

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“…Provision of antigen specificity to T cells by insertion of chimeric antigen receptor (CAR) molecules offers an effective therapeutic option for patients with B cell lymphoid malignancies (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The selective expression of the CD19 antigen by normal and malignant B cells has fueled the development of CAR-T therapy, since the associated B cell aplasia is a manageable side effect if objective and sustained clinical responses are achieved (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes

Ramos¹,

Ballard²,

Zhang³

et al. 2017

Journal of Clinical Investigation

301

242

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“…16 Recently, several clinical trials in which tumor-redirected T cells were derived from T CM have been reported. 17,18 However, clinical exploitation of T SCM has so far been hampered by their relative paucity in the circulation and the lack of robust, clinical-grade protocols capable of isolating and maintaining this cell type in vitro.…”

Section: Introductionmentioning

confidence: 99%

Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies

Sabatino

Sommariva

et al. 2016

Blood

285

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Phase 1 studies of central memory–derived CD19 CAR T–cell therapy following autologous HSCT in patients with B-cell NHL

Abstract: Key Points TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT. Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.

Cited by 262 publications

References 34 publications

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes

Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies

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