Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma

Sun, Ming; Cao, Yingying; Okada, Reona; Reyes-González, Jeyshka M.; Stack, Hannah G; Qin, Haiying; Li, Nan; Seibert, Charlie; Kelly, Michael C.; Ruppin, Eytan; Ho, Mitchell; Thiele, Carol J.; Nguyen, Rosa

doi:10.1136/jitc-2022-005881

Cited by 14 publications

(5 citation statements)

References 43 publications

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“…GPC2 expression varies widely from very high to extremely low, which is consistent with the data on the low density of Glypican 2 molecules on the tumor cell membrane in some patients (29). The expression of Survivin was relatively low but still markedly positive in nearly all cases.…”

Section: Discussionsupporting

confidence: 89%

Expression Pattern of Tumor-associated Antigens in Neuroblastoma: Association With Cytogenetic Features and Survival

MELESHKO,

KUSHNIAROVA,

SHINKEVICH

et al. 2023

CDP

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Background/Aim: The prognosis of high-risk and relapsed neuroblastoma (NB) patients remains poor. The identification of tumor-associated markers is important for differential diagnosis, prognosis, and the development of targeted therapies. The aim of the study was to determine the expression profile of nine most common NB antigens and assess their association with clinicopathological characteristics and patient survival. Patients and Methods: Tumor samples from 86 patients with NB were evaluated for the expression of tumor-associated antigen (TAA) using quantitative PCR. Twenty-one patients with benign tumors and 17 healthy donors were assigned as controls. Results: Overexpression of tyrosine hydroxylase (TH), PHOX2B, PRAME, GPC2, B7-H3, and Survivin is the most typical for NB. Positive expression of MAGEA3, MAGEA1, and NY-ESO-1 at low levels was detected in 54%, 48%, and 52%, respectively, and was not NB specific. Higher TH expression was observed in samples without MYCN-amplification, while higher expression of Survivin, PHOX2B, and GPC2 was significantly associated with the presence of 1p.36 deletion. Overexpression of TH, PHOX2B, and MAGEA1 was associated with better event-free (EFS) and overall survival (OS). Survivin overexpression was associated with poor EFS but had no impact on OS. Multivariate analysis confirmed Survivin as independent marker for poor survival, and PHOX2B and MAGEA1 for better survival. Conclusion: High expression of TH, PHOX2B, and MAGEA1 genes are favorable prognostic factors for OS and EFS, whereas high expression of Survivin is associated with an increased risk of relapse or progression.

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Section: Discussionsupporting

confidence: 89%

Expression Pattern of Tumor-associated Antigens in Neuroblastoma: Association With Cytogenetic Features and Survival

MELESHKO,

KUSHNIAROVA,

SHINKEVICH

et al. 2023

CDP

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“…The application of human NB xenografts has been useful for treatment evaluations [37][38][39]. Although recipient mice are profoundly immune-deficient, these models are amenable to assessment of some immune interventions, such as adoptive cell therapy [40,41]. However, secondary immune activities cannot be assessed in such models.…”

Section: Discussionmentioning

confidence: 99%

Adaptation of the Th-MYCN Mouse Model of Neuroblastoma for Evaluation of Disseminated Disease

Rahavi

Aletaha

Farrokhi

et al. 2023

IJMS

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High-risk neuroblastoma remains a profound clinical challenge that requires eradication of neuroblastoma cells from a variety of organ sites, including bone marrow, liver, and CNS, to achieve a cure. While preclinical modeling is a powerful tool for the development of novel cancer therapies, the lack of widely available models of metastatic neuroblastoma represents a significant barrier to the development of effective treatment strategies. To address this need, we report a novel luciferase-expressing derivative of the widely used Th-MYCN mouse. While our model recapitulates the non-metastatic neuroblastoma development seen in the parental transgenic strain, transplantation of primary tumor cells from disease-bearing mice enables longitudinal monitoring of neuroblastoma growth at distinct sites in immune-deficient or immune-competent recipients. The transplanted tumors retain GD2 expression through many rounds of serial transplantation and are sensitive to GD2-targeted immune therapy. With more diverse tissue localization than is seen with human cell line-derived xenografts, this novel model for high-risk neuroblastoma could contribute to the optimization of immune-based treatments for this deadly disease.

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“…We generated the CAR lentiviral vectors targeting GPC2, GPC3, and MSLN respectively following the design principle of CAR construct published in our previous study. 29 32 Briefly, the CAR construct consists of a recognition domain, CD8α or CD28 hinge, and CD8α or CD28 transmembrane, followed by a 4-1BB co-stimulatory domain and the CD3ζ signaling moiety. The recognition domain in this study consists of three single-chain variable fragments derived from monoclonal antibodies including humanized YP7 (hYP7), CT3, and humanized YP218 (hYP218), each used individually (named pMH289, pMH394, and pMH348).…”

Section: Methodsmentioning

confidence: 99%

rhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors

Li,

Liang,

Hutchins

et al. 2024

J Immunother Cancer

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BackgroundChimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice.MethodsCAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting.ResultsCompared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4+CAR-T, improved T-cell expansion, reduced exhaustion markers (programmed cell death protein 1 or PD-1 and lymphocyte-activation gene 3 or LAG-3) expression, and increased generation of stem cell-like memory CAR-T cells. The STAT5 pathway was demonstrated to be downstream of NT-I7 signaling, mediated by increased expression of the IL-7 receptor expression in CAR-T cells. Furthermore, CAR-T cells improved efficacy against tumors with low antigen density when combined with NT-I7 in mice, presenting an avenue for patients with heterogeneous antigenic profiles.ConclusionThis study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.

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Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma

Cited by 14 publications

References 43 publications

Expression Pattern of Tumor-associated Antigens in Neuroblastoma: Association With Cytogenetic Features and Survival

Expression Pattern of Tumor-associated Antigens in Neuroblastoma: Association With Cytogenetic Features and Survival

Adaptation of the Th-MYCN Mouse Model of Neuroblastoma for Evaluation of Disseminated Disease

rhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors

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