Directing CAR T cells towards the tumor vasculature for the treatment of solid tumors

Akbari, Parvin; Katsarou, Afroditi; Daghighian, Roxanna; Mil, Lotte W.H.G. van; Huijbers, Elisabeth J. M.; Beijnum, Judy R. van

doi:10.1016/j.bbcan.2022.188701

Cited by 13 publications

(12 citation statements)

References 119 publications

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“…The results of these and other studies (see Table 1 ) support the hypothesis that overcoming angiogenesis-induced EC anergy has a potentiating effect on immunity. It should be noted that this is also expected for other immunotherapy strategies, such as adoptive T-cell therapy, CAR T-cell therapy, and multiple vaccination approaches [ 334 , 335 ], and it is expected to be valid for anti-angiogenic strategies that involves signaling apart from the VEGF signaling pathway (e.g. the ANGPT2 pathway).…”

Section: New Concepts In the Field Of Angiogenesismentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

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In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

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Section: New Concepts In the Field Of Angiogenesismentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

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“…Noteworthy, based on the advances and successful practices of engineered chimeric antigen receptor (CAR) T cells therapy, different CAR designs have been exploited to fight against various diseases, in particular malignancies. Therefore, using CAR-T cells to target multiple antigens on tumor vasculature may provide new opportunities for the development of anti-angiogenic therapy [ 415 ].…”

Section: Targeted Therapy Based On Tumor Stromamentioning

confidence: 99%

Targeting the tumor stroma for cancer therapy

Zhang

Xia

et al. 2022

Mol Cancer

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Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.

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“…However, a phase I/ II clinical trial was terminated as no responses were observed using VEGFR2-CAR-T therapy. 24 A recent study by Lanitis et al demonstrated that the upregulation of VEGF-A in cancer cells competed for VEGFR2 binding with VEGFR2-targeting CAR-T cells, thus diminishing the effect of this CAR-T therapy. 25 Combining anti-VEGF/R2 antibodies with VEGFR2-CAR-T therapy may solve this problem.…”

Section: Discussionmentioning

confidence: 99%

Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice

Dong

Ren

Amoozgar

et al. 2023

J Immunother Cancer

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Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells’ delivery and antitumor activity. We previously showed that blocking vascular endothelial growth factor (VEGF) signaling can normalize tumor vessels in murine and human tumors, including GBM, breast, liver, and rectal carcinomas. Moreover, we demonstrated that vascular normalization can improve the delivery of CD8+ T cells and the efficacy of immunotherapy in breast cancer models in mice. In fact, the US FDA (Food and drug administration) has approved seven different combinations of anti-VEGF drugs and immune checkpoint blockers for liver, kidney, lung and endometrial cancers in the past 3 years. Here, we tested the hypothesis that anti-VEGF therapy can improve the delivery and efficacy of CAR-T cells in immunocompetent mice bearing orthotopic GBM tumors. We engineered two syngeneic mouse GBM cell lines (CT2A and GSC005) to express EGFRvIII—one of the most common neoantigens in human GBM—and CAR T cells to recognize EGFRvIII. We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.

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Directing CAR T cells towards the tumor vasculature for the treatment of solid tumors

Cited by 13 publications

References 119 publications

Pathological angiogenesis: mechanisms and therapeutic strategies

Pathological angiogenesis: mechanisms and therapeutic strategies

Targeting the tumor stroma for cancer therapy

Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice

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