Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4

Wilkie, Scott; Burbridge, S.; Chiapero-Stanke, Laura; Pereira, Ana C. Parente; Cleary, Siobhán; Stegen, Sjoukje J. C. van der; Spicer, James; Davies, Daniel; Maher, John

doi:10.1074/jbc.m110.127951

Cited by 170 publications

(158 citation statements)

References 47 publications

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“…After 24 h, 1 3 10 6 ex vivo expanded gd T cells were added to indicated wells for a further 24 h. Monolayers were then fixed and stained with crystal violet and viewed microscopically as described (12).…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

Adoptive Immunotherapy of Epithelial Ovarian Cancer with Vγ9Vδ2 T Cells, Potentiated by Liposomal Alendronic Acid

Parente-Pereira

Shmeeda

Whilding

et al. 2014

The Journal of Immunology

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Adoptive immunotherapy using γδ T cells harnesses their natural role in tumor immunosurveillance. The efficacy of this approach is enhanced by aminobisphosphonates such as zoledronic acid and alendronic acid, both of which promote the accumulation of stimulatory phosphoantigens in target cells. However, the inefficient and nonselective uptake of these agents by tumor cells compromises the effective clinical exploitation of this principle. To overcome this, we have encapsulated aminobisphosphonates within liposomes. Expanded Vγ9Vδ2 T cells from patients and healthy donors displayed similar phenotype and destroyed autologous and immortalized ovarian tumor cells, following earlier pulsing with either free or liposome-encapsulated aminobisphosphonates. However, liposomal zoledronic acid proved highly toxic to SCID Beige mice. By contrast, the maximum tolerated dose of liposomal alendronic acid was 150-fold higher, rendering it much more suited to in vivo use. When injected into the peritoneal cavity, free and liposomal alendronic acid were both highly effective as sensitizing agents, enabling infused γδ T cells to promote the regression of established ovarian tumors by over one order of magnitude. Importantly however, liposomal alendronic acid proved markedly superior compared with free drug following i.v. delivery, exploiting the “enhanced permeability and retention effect” to render advanced tumors susceptible to γδ T cell–mediated shrinkage. Although folate targeting of liposomes enhanced the sensitization of folate receptor–α+ ovarian tumor cells in vitro, this did not confer further therapeutic advantage in vivo. These findings support the development of an immunotherapeutic approach for ovarian and other tumors in which adoptively infused γδ T cells are targeted using liposomal alendronic acid.

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Section: Cytotoxicity Assaysmentioning

confidence: 99%

Adoptive Immunotherapy of Epithelial Ovarian Cancer with Vγ9Vδ2 T Cells, Potentiated by Liposomal Alendronic Acid

Parente-Pereira

Shmeeda

Whilding

et al. 2014

The Journal of Immunology

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“…The protocol involves a cohortbased CAR T-cell and lymphodepletion dose escalation up to a maximum regime of cyclophosphamide (300 mg/m Investigators at Kings College have developed T4 technology in which a CAR targeted against eight of nine possible ErbB homo-and heterodimers 37 is coexpressed with an IL-4-responsive chimeric cytokine receptor. 38 The latter enables the ex vivo enrichment and amplification of gene-modified T-cells by the addition of IL-4 to the culture media. Clinical testing of T4 cells armed with an ErbB family-targeting domain is due to start in the near future involving local administration of the T4 cells to patients with advanced head and neck tumors.…”

Section: University College London Hospital Great Ormond Street Hospmentioning

confidence: 99%

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

Gilham

Anderson²,

Bridgeman

et al. 2015

Human Gene Therapy

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Adoptive T-cell therapy is delivering objective clinical responses across a number of cancer indications in the early phase clinical setting. Much of this clinical activity is taking place at major clinical academic centers across the United States. This review focuses upon cancer-focused cell therapy activity within the United Kingdom as a contribution to the 2015 British Society of Gene and Cell Therapy annual general meeting. This overview reflects the diversity and expansion of clinical and preclinical studies within the United Kingdom while considering the background context of this work against new infrastructural developments and the requirements of nationalized healthcare delivery within the UK National Health Service.

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“…Alternatively, tumor monolayer destruction was visualized by nonquantitative crystal violet staining of residual monolayers, as described (31). In these assays, 1 3 10 6 engineered T cells were cocultivated overnight with a confluent monolayer of tumor cells in a 24-well plate.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

“…Consequently, IL-4 exerts dual effects upon T cells that express 4ab. Signaling via the endogenous IL-4R is maintained, whereas signals delivered through 4ab convert the weak mitogenic action of IL-4 into a potent growth signal, favoring selective growth of the gene-modified cells (31). Following expansion using IL-4, T cells that coexpress T1E28z and 4ab exhibit polyfunctionality of cytokine production (with a Th1 bias) and mediate effective antitumor activity against head and neck or breast cancer, both in vitro and in vivo (29).…”

mentioning

confidence: 99%

Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin

Parente-Pereira

Whilding

Brewig

et al. 2013

The Journal of Immunology

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Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, underscoring the need for better therapies. Adoptive immunotherapy using genetically targeted T cells represents a promising new treatment for hematologic malignancies. However, solid tumors impose additional obstacles, including the lack of suitable targets for safe systemic therapy and the need to achieve effective T cell homing to sites of disease. Because EOC undergoes transcœlomic metastasis, both of these challenges may be circumvented by T cell administration to the peritoneal cavity. In this study, we describe such an immunotherapeutic approach for EOC, in which human T cells were targeted against the extended ErbB family, using a chimeric Ag receptor named T1E28z. T1E28z was coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective ex vivo expansion of engineered T cells using IL-4. Unlike control T cells, T4+ T cells from healthy donors and patients with EOC were activated by and destroyed ErbB+ EOC tumor cell lines and autologous tumor cultures. In vivo antitumor activity was demonstrated in mice bearing established luciferase-expressing SKOV-3 EOC xenografts. Tumor regression was accompanied by mild toxicity, manifested by weight loss. Although efficacy was transient, therapeutic response could be prolonged by repeated T cell administration. Furthermore, prior treatment with noncytotoxic doses of carboplatin sensitized SKOV-3 tumors to T4 immunotherapy, promoting enhanced disease regression using lower doses of T4+ T cells. By combining these approaches, we demonstrate that repeated administration of carboplatin followed by T4+ T cells achieved optimum therapeutic benefit in the absence of significant toxicity, even in mice with advanced tumor burdens.

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Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4

Cited by 170 publications

References 47 publications

Adoptive Immunotherapy of Epithelial Ovarian Cancer with Vγ9Vδ2 T Cells, Potentiated by Liposomal Alendronic Acid

Adoptive Immunotherapy of Epithelial Ovarian Cancer with Vγ9Vδ2 T Cells, Potentiated by Liposomal Alendronic Acid

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin

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