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

Abstract

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.

CAR T cells for brain tumors: Lessons learned and road ahead

“…Studies comparing routes of delivery for both preclinical models of GBM and breast cancer brain metastases have shown that local delivery (ICT or ICV) outperforms systemic delivery (IV) of CAR T cells. HER2‐CAR T cells (0.5 M dose) delivered ICV was more effective than a 10‐fold higher dose (5 M dose) delivered IV in orthotopic models of breast cancer brain metastases . Similarly, ICT administered IL13Rα2‐CAR T cells resulted in long‐term survival in orthotopic GBM models, whereas IV delivery provided no significant benefit over mock transduced T cells .…”

“…In studies of the HER2‐CAR design, our preclinical work demonstrated decreased cytokine production and improved anti‐tumor efficacy of 4‐1BB vs CD28 costimulation . Moreover, ICV‐delivered CAR T cells were shown to eradicate tumors implanted in both hemispheres.…”

“…95 In studies of the HER2-CAR design, our preclinical work demonstrated decreased cytokine production and improved antitumor efficacy of 4-1BB vs CD28 costimulation. 93 Moreover, ICVdelivered CAR T cells were shown to eradicate tumors implanted in both hemispheres. City of Hope has recently initiated two phase I trials using an optimized HER2-CAR for patients with HER2+ malignant glioma and for patients with breast metastases to the brain (NCT03389230 and NCT03696030, respectively).…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…In glioblastoma patients, the University of Pennsylvania group showed that EGFRvIII-directed CAR T cells effectively trafficked to regions of active tumor after systemic infusion (142), and Ahmed and colleagues reported clinically significant activity of HER2-specific CAR T cells in 8 out of 17 cases, including one PR and 7 persistent SD (143). Besides, local delivery showed encouraging results in this setting: in xenograft models, investigators demonstrated robust antitumor efficacy of anti-HER2 CAR T cells against medulloblastoma (144) and brain metastases of breast cancer (145) and anti-GD2 constructs were effective against midline gliomas (146). In addition, Brown and colleagues reported © 1996-2019 that IL-13Rα2-directed CAR T cells delivered via an implanted reservoir/catheter system exert a significant clinical activity in glioblastoma patients (147), including one CR (148).…”

In situ antitumor vaccination: Targeting the tumor microenvironment

“…Recently, Nishio et al (2014) have overcome the obstacle through inoculating intratumorally with an armed oncolytic virus which effectively attracted CAR‐T cells to the tumor site. In addition, it is reported that directly intratumorally administered CAR‐T cells could generate a potent and long‐lasting antitumor immune response (Adusumilli et al, 2014; H. Liu et al, 2017; Pituch et al, 2018; Priceman et al, 2018). Several related clinical trials of intratumoral immunization are in research phase (Table 5).…”