Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

Idorn, Manja; Skadborg, Signe K.; Kellermann, Lauge; Halldórsdóttir, Hólmfridur R.; Olofsson, Gitte Holmen; Met, Özcan; Straten, Per thor

doi:10.1080/2162402x.2018.1450715

Cited by 54 publications

(52 citation statements)

References 42 publications

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“…The percentage of this NK cell population among all NK cells within the affected lymph node was associated with improved prognosis among patients with stage III melanoma. Likewise, genetically modified CXCR2+ T cells displayed increased in vivo migration in murine melanoma models ( 40 , 41 ). A clinical phase I/II trial in patients with metastatic melanoma infused with genetically modified CXCR2+ T cells has been initiated (Table 2 ).…”

Section: The Role Of Cxcr1 and Cxcr2 In Solid Malignanciesmentioning

confidence: 99%

The Role of CXC Chemokine Receptors 1–4 on Immune Cells in the Tumor Microenvironment

et al. 2018

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Chemokines govern leukocyte migration by attracting cells that express their cognate ligands. Many cancer types show altered chemokine secretion profiles, favoring the recruitment of pro-tumorigenic immune cells and preventing the accumulation of anti-tumorigenic effector cells. This can ultimately result in cancer immune evasion. The manipulation of chemokine and chemokine-receptor signaling can reshape the immunological phenotypes within the tumor microenvironment in order to increase the therapeutic efficacy of cancer immunotherapy. Here we discuss the three chemokine-chemokine receptor axes, CXCR1/2–CXCL1-3/5-8, CXCR3–CXCL9/10/11, and CXCR4-CXCL12 and their role on pro-tumorigenic immune cells and anti-tumorigenic effector cells in solid tumors. In particular, we summarize current strategies to target these axes and discuss their potential use in treatment approaches.

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Section: The Role Of Cxcr1 and Cxcr2 In Solid Malignanciesmentioning

confidence: 99%

The Role of CXC Chemokine Receptors 1–4 on Immune Cells in the Tumor Microenvironment

et al. 2018

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“…TA-specific T cells are readily found in the blood of patients with cancer and these cells infiltrate tumors despite having limited efficacy. Thus, tumors are infiltrated with tumor-reactive T cells but, in most cases, at low frequency [ 3 ]. To this end, a high frequency of tumor infiltrating of lymphocytes (tumor infiltrating lymphocytes, TIL) such as in CD8 + T cells have been associated with improved survival of patients of several cancer diagnoses including melanoma [ 4 ], ovarian [ 5 ], breast [ 6 ], and colorectal cancer [ 7 , 8 ] even though solid prospective phase III clinical data are still missing.…”

Section: Introductionmentioning

confidence: 99%

Chemokine Receptors and Exercise to Tackle the Inadequacy of T Cell Homing to the Tumor Site

Idorn¹,

P²

2018

Cells

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While cancer immune therapy has revolutionized the treatment of metastatic disease across a wide range of cancer diagnoses, a major limiting factor remains with regard to relying on adequate homing of anti-tumor effector cells to the tumor site both prior to and after therapy. Adoptive cell transfer (ACT) of autologous T cells have improved the outlook of patients with metastatic melanoma. Prior to the approval of checkpoint inhibitors, this strategy was the most promising. However, while response rates of up to 50% have been reported, this strategy is still rather crude. Thus, improvements are needed and within reach. A hallmark of the developing tumor is the evasion of immune destruction. Achieved through the recruitment of immune suppressive cell subsets, upregulation of inhibitory receptors and the development of physical and chemical barriers (such as poor vascularization and hypoxia) leaves the microenvironment a hostile destination for anti-tumor T cells. In this paper, we review the emerging strategies of improving the homing of effector T cells (TILs, CARs, TCR engineered T cells, etc.) through genetic engineering with chemokine receptors matching the chemokines of the tumor microenvironment. While this strategy has proven successful in several preclinical models of cancer and the strategy has moved into the first phase I/II clinical trial in humans, most of these studies show a modest (doubling) increase in tumor infiltration of effector cells, which raises the question of whether road blocks must be tackled for efficient homing. We propose a role for physical exercise in modulating the tumor microenvironment and preparing the platform for infiltration of anti-tumor immune cells. In a time of personalized medicine and genetic engineering, this “old tool” may be a way to augment efficacy and the depth of response to immune therapy.

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“…Similar to CCR4, CCR2 is a receptor for CCL2, is poorly expressed on activated T cells (<7%), and its addition in CAR T cells has been shown to increase efficacy in neuroblastoma and melanoma models . Other lymphocyte models have leverage chemokines to increase tumor accumulation with the introduction of receptors such as CXCR4, CXCR1, CXCR2, CCR7, and CX3CR1 . Additional targeting of endothelial adhesion molecules or vascular cytokines upregulated in brain tumors could also be a worthwhile approach to enhance CAR T cell accumulation at the tumor site .…”

Section: Getting Cars To Go: Car T Cell Trafficking To Brain Tumorsmentioning

confidence: 99%

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

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

172

161

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

Cited by 54 publications

References 42 publications

The Role of CXC Chemokine Receptors 1–4 on Immune Cells in the Tumor Microenvironment

The Role of CXC Chemokine Receptors 1–4 on Immune Cells in the Tumor Microenvironment

Chemokine Receptors and Exercise to Tackle the Inadequacy of T Cell Homing to the Tumor Site

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

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