Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer

By R. Shrimali, Zhiya Yu, M. Theoret, D. Chinnasamy, N. Restifo, S. Rosenberg. Cancer Research, 2010

628 citations recorded by the source corpus.

Adoptive cell transfer (ACT) – based immunotherapies can mediate objective cancer regression in animal models and in up to 70% of patients with metastatic melanoma but it remains unclear whether the tumor vasculature impedes the egress of tumor specific T cells thus hindering this immunotherapy. Disruption of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2) has been reported to “normalize” tumor vasculature, enhancing the efficacy of chemotherapeutic agents by increasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine cancer model. The administration of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularised, B16 melanoma (p=0.009) and improve survival (p=0.003). Additive effects of an antibody against VEGFR-2 in conjunction with ACT were seen in this model (p=0.013). Anti VEGF, but not anti VEGFR-2, antibody significantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration of combining antiangiogenic agents with ACT for the treatment of patients with cancer.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/33a633f13e64e1fe4bf5c1e2ccd9c5d72749dba5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. M. Postow
2. Peter Carmeliet
3. Rakesh K. Jain
4. N. Ferrara
5. G. Dranoff
6. J. Wolchok

In Molecular Biology

1. Rakesh K. Jain
2. N. Ferrara
3. Peter Carmeliet
4. A. Adamis
5. R. Apte
6. Daniel Chen
7. M. Postow
8. Matthew Vanneman

In Oncology

1. N. Ferrara
2. Daniel Chen
3. R. Apte
4. Peter Carmeliet
5. Rakesh K. Jain
6. M. Postow
7. A. Adamis
8. J. Wolchok

Citations in the corpus

• Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases (2011, background): “VEGF blockade also improves immunotherapy in experimental models by increasing the accessibility of immune cells into the tumour”
• Ten years of anti-vascular endothelial growth factor therapy (2016, background): “This is because VEGFA inhibition was shown in preclinical studies to result in a significant increase in the number of tumour-infiltrating lymphocytes, which could be exploited in immunotherapeutic approaches 245 .”
• ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA (2014, neutral): “…VEGF mAb- anti-gp100 pmel-1 T cells, gp100 vaccine, IL-2 after lymphodepletion melanoma [ immune cell infiltration [ tumor growth delay [ survival (Shrimali et al., 2010) VEGFR-1 CAR-modified T cells lung carcinoma Y endothelial tube formation in vitro [ tumor growth delay and Y metastasis (Wang…”
• Combining Immunotherapy and Targeted Therapies in Cancer Treatment (2012, background): “In the B16 melanoma model, a VEGFA antibody combined with adoptive T cell transfer intensified tumour infiltration, decreased tumour growth and prolonged survival compared with either monotherap”
• Cold Tumors: A Therapeutic Challenge for Immunotherapy (2019, background): “induce the upregulation of the leukocyte adhesion molecules ICAM-1 and VCAM-1 on tumor endothelial cells (83), leading to increased T cell infiltration (84).”
• Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. (2015, background): “In addition to antiangiogenic effects, blockade of VEGF has been reported to possess immunomodulatory effects such as promoting increased effector T-cell trafficking [95, 96], and reducing MDSCs, T-regulatory cells, and suppressive cytokines at the tumor microenvironment [97].”
• Vascular normalization as an emerging strategy to enhance cancer immunotherapy (2013, neutral): “Combination of antiVEGF agentswith immunotherapies has been successful against highly immunogenic tumors (26, 27), but has shown little or no benefit against immunotolerant neoplasms (27).”
• Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “These changes are therapeutically targetable, as in vitro inhibition of VEGF-A and ETBR resulted in a restored amount of TILs and an improved response to immunotherapy.(124,125) Similarly, FasL (CD95L or CD178), a pro-apoptotic cell surface protein, might also be targeted, as it is frequently overex”
• Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. (2016, background): “In addition to antiangiogenic effects, blockade of VEGF has been reported to possess immunomodulatory effects such as promoting increased effector T-cell trafficking [95, 96], and reducing MDSCs, T-regulatory cells, and suppressive cytokines at the tumor microenvironment [97].”