Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ

Textor, Ana; Listopad, Joanna J.; Wührmann, Lara Le; Pérez, Cynthia; Kruschinski, Anna; Chmielewski, Markus; Abken, Hinrich; Blankenstein, Thomas; Charo, Jehad

doi:10.1158/0008-5472.can-14-0079

Cited by 73 publications

(70 citation statements)

References 34 publications

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“…Since monocytes or macrophages could not by themselves exploit the tumor specificity of the BsAb (since this BsAb was devoid of all Fc receptor binding), this cross talk was most likely orchestrated by tumor-infiltrating T cells. The role of auxiliary leukocytes in supporting T cell-mediated tumor ablation has been observed recently by other groups, where macrophages and IFNγ were shown to be critical for eradicating large solid tumors by destroying stroma cells that support tumor growth (31). …”

Section: Discussionmentioning

confidence: 78%

Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody

Cheng

Guo

et al. 2015

Cancer Immunology Research

110

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Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g. neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunological synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >105-fold selectivity over normal tissues, releasing Th1 cytokines (TNFα, IFNγ and IL2) when GD2(+) tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells.

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Section: Discussionmentioning

confidence: 78%

Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody

Cheng

Guo

et al. 2015

Cancer Immunology Research

110

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“…In addition to the regional delivery route, our proposed HER2-CAR T-cell immunotherapy also addresses potential toxicity issues by the choice of intracellular costimulatory signaling domain (8)(9)(10)(25)(26)(27). Our data show significant dampening of cytokine production, along with a tendency to require higher HER2 expression for cytokine production by HER2-BBz compared with HER2-28z CAR T cells.…”

Section: Discussionmentioning

confidence: 88%

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

250

185

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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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“…Evidences are increasing that successful treatment of advanced tumors requires breaking the barrier and eliminating the stroma cells; the latter is mediated by IFN-γ accompanied by M1 macrophage infiltration [106]. Costimulation increased IFN-γ release into the targeted tumor lesion which then acted on stroma cells in an antigen-independent fashion by both stroma destruction and activating the non-T cell immune compartment.…”

Section: Car T Cell Therapy Of Solid Cancer Is Still Challengingmentioning

confidence: 99%

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

Holzinger¹,

Abken²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Adoptive therapy of malignant diseases by chimeric antigen receptor (CAR) redirected T cells takes advantage of the patient's own immune system to recognize and destroy cancer cells. This is impressively demonstrated by the induction of complete and lasting remissions of leukemia with CAR-engineered T cells in early phase trials. Recent developments in optimizing the CAR design, in the recognition of target cells and the production of modified cells for clinical use, have paved the path for a broader application than currently explored. The chapter reviews the differences in CAR design, the success in the treatment of hematologic malignancies, the challenges in treating solid cancer, the treatment-related toxicities, and strategies to improve safety of CAR T cell therapy. Challenges for future applications are discussed.

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Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ

Cited by 73 publications

References 34 publications

Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody

Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody

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

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

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