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Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

ABSTRACT: Chimeric antigen receptor T cell therapy (CAR-T) has been rolled out as a new treatment for hematological malignancies. For solid tumor treatment, CAR-T has been disappointing so far. Challenges include the quantification of CAR-T trafficking, expansion and retention in tumors, activity at target sites, toxicities, and long-term CAR-T survival. Non-invasive serial in vivo imaging of CAR-T using reporter genes can address several of these challenges. For clinical use, a non-immunogenic reporter that is detectable with exquisite sensitivity by positron emission tomography (PET) using a clinically available non-toxic radiotracer would be beneficial. Here, we employed the human sodium iodide symporter to non-invasively quantify tumor retention of pan-ErbB family targeted CAR-T by PET. We generated and characterized traceable CAR T cells and examined potential negative effects of radionuclide reporter use. We applied our platform to two different triple-negative breast cancer (TNBC) models and unexpectedly observed pronounced differences in CAR-T tumor retention by PET/CT (computed tomography) and confirmed data ex vivo. CAR-T tumor retention inversely correlated with immune checkpoint expression in the TNBC models. Our platform enables highly sensitive non-invasive PET tracking of CAR-T thereby addressing a fundamental unmet need in CAR-T development and offering to provide missing information needed for future clinical CAR-T imaging.

SUBMITTER: Volpe A

PROVIDER: S-EPMC7544977 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

Volpe Alessia A Lang Cameron C Lim Lindsay L Man Francis F Kurtys Ewelina E Ashmore-Harris Candice C Johnson Preeth P Skourti Elena E de Rosales Rafael T M RTM Fruhwirth Gilbert O GO

Molecular therapy : the journal of the American Society of Gene Therapy 20200627 10

Chimeric antigen receptor T cell therapy (CAR-T) has been rolled out as a new treatment for hematological malignancies. For solid tumor treatment, CAR-T has been disappointing so far. Challenges include the quantification of CAR-T trafficking, expansion and retention in tumors, activity at target sites, toxicities, and long-term CAR-T survival. Non-invasive serial in vivo imaging of CAR-T using reporter genes can address several of these challenges. For clinical use, a non-immunogenic reporter t ...[more]

PMID: 32645298

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Project description:BackgroundPreclinical breast cancer models recapitulating the clinical course of metastatic disease are crucial for drug development. Highly metastatic cell lines forming spontaneous metastasis following orthotopic implantation were previously developed and characterized regarding their biological and histological characteristics. This study aimed to non-invasively and longitudinally characterize the spatiotemporal pattern of metastasis formation and progression in the MDA-MB-231-derived triple negative LM2-4 and HER2+ LM2-4H2N cell lines, using bioluminescence imaging (BLI), contrast enhanced computed tomography (CT), fluorescence imaging, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography ([18F]FDG-PET).Material and methodsLM2-4, LM2-4H2N, and MDA-MB-231 tumors were established in the right inguinal mammary fat pad (MFP) of female SCID mice and resected 14-16 days later. Metastasis formation was monitored using BLI. Metabolic activity of primary and metastatic lesions in mice bearing LM2-4 or LM2-4H2N was assessed by [18F]FDG-PET. Metastatic burden at study endpoint was assessed by CT and fluorescence imaging following intravenous dual-modality liposome agent administration.ResultsComparable temporal metastasis patterns were observed using BLI for the highly metastatic cell lines LM2-4 and LM2-4H2N, while metastasis formed about 10 days later for MDA-MB-231. 21 days post primary tumor resection, metastases were detected in 86% of LM2-4, 69% of LM2-4H2N, and 60% of MDA-MB-231 inoculated mice, predominantly in the axillary region, contralateral MFP, and liver/lung. LM2-4 and LM2-4H2N tumors displayed high metabolism based on [18F]FDG-PET uptake. Lung metastases were detected as the [18F]FDG-PET uptake increased significantly between pre- and post-metastasis scan. Using a liposomal dual-modality agent, CT and fluorescence confirmed BLI detected lesions and identified additional metastatic nodules in the intraperitoneal cavity and lung.ConclusionsThe combination of complementary anatomical and functional imaging techniques can provide high sensitivity characterization of metastatic disease spread, progression and overall disease burden. The described models and imaging toolset can be implemented as an effective means for quantitative treatment response evaluation in metastatic breast cancer.

Project description:(1) Purpose: The glycoprotein non-metastatic melanoma B (gpNMB) is a type 1 transmembrane protein that is overexpressed in numerous cancers, including triple-negative breast cancer (TNBC). Its overexpression is associated with lower overall survival of patients with TNBC. Tyrosine kinase inhibitors such as dasatinib can upregulate gpNMB expression, which has the potential to enhance therapeutic targeting with anti-gpNMB antibody drug conjugates such as glembatumumab vedotin (CDX-011). Our primary aim is to quantify the degree and identify the timeframe of gpNMB upregulation in xenograft models of TNBC after treatment with the Src tyrosine kinase inhibitor, dasatinib, by longitudinal positron emission tomography (PET) imaging with the 89Zr-labeled anti-gpNMB antibody ([89Zr]Zr-DFO-CR011). The goal is to identify the timepoint at which to administer CDX-011 after treatment with dasatinib to enhance therapeutic efficacy using noninvasive imaging. (2) Methods: First, TNBC cell lines that either express gpNMB (MDA-MB-468) or do not express gpNMB (MDA-MB-231) were treated with 2 μM of dasatinib in vitro for 48 h, followed by Western blot analysis of cell lysates to determine differences in gpNMB expression. MDA-MB-468 xenografted mice were also treated with 10 mg/kg of dasatinib every other day for 21 days. Subgroups of mice were euthanized at 0-, 7-, 14-, and 21-days post treatment, and tumors were harvested for Western blot analysis of tumor cell lysates for gpNMB expression. In a different cohort of MDA-MB-468 xenograft models, longitudinal PET imaging with [89Zr]Zr-DFO-CR011 was performed before treatment at 0 (baseline) and at 14 and 28 days after treatment with (1) dasatinib alone (2) CDX-011 (10 mg/kg) alone, or (3) sequential treatment of dasatinib for 14 days then CDX-011 to determine changes in gpNMB expression in vivo relative to baseline. As a gpNMB-negative control, MDA-MB-231 xenograft models were imaged 21 days after treatment with dasatinib, combination of CDX-011 and dasatinib, and vehicle control. (3) Results: Western blot analysis of MDA-MB-468 cell and tumor lysates showed that dasatinib increased expression of gpNMB in vitro and in vivo at 14 days post treatment initiation. In PET imaging studies of different cohorts of MDA-MB-468 xenografted mice, [89Zr]Zr-DFO-CR011 uptake in tumors (SUVmean = 3.2 ± 0.3) was greatest at 14 days after treatment initiation with dasatinib (SUVmean = 4.9 ± 0.6) or combination of dasatinib and CDX-011 (SUVmean= 4.6 ± 0.2) compared with that at baseline (SUVmean = 3.2 ± 0.3). The highest tumor regression after treatment was observed in the combination-treated group with a percent change in tumor volume relative to baseline (%CTV) of -54 ± 13 compared with the vehicle control-treated group (%CTV = +102 ± 27), CDX-011 group (%CTV = -25 ± 9.8), and dasatinib group (%CTV = -23 ± 11). In contrast, the PET imaging of MDA-MB-231 xenografted mice indicated no significant difference in the tumor uptake of [89Zr]Zr-DFO-CR011 between treated (dasatinib alone or in combination with CDX-011) and vehicle-control groups. (4) Conclusions: Dasatinib upregulated gpNMB expression in gpNMB-positive MDA-MB-468 xenografted tumors at 14 days post treatment initiation, which can be quantified by PET imaging with [89Zr]Zr-DFO-CR011. Furthermore, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC and warrants further investigation.

Dataset Information

Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

Publications

Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

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