Immunomodulating antibodies in the treatment of metastatic melanoma: The experience with anti-CTLA-4, anti-CD137, and anti-PD1

Simeone, Ester; Ascierto, Paolo A.

doi:10.3109/1547691x.2012.678021

Cited by 82 publications

(65 citation statements)

References 24 publications

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“…It is believed that tumor cell expression of PD-L1 is used as a mechanism to evade recognition/ destruction by the immune system. In fact, expression of PD-L1 in tumors is associated with poor outcome for patients with certain epithelial cancers (50). PD-L2 expression is restricted only to macrophages and dendritic cells and is also upregulated upon activation.…”

Section: Pd-1 Biomarker Developmentmentioning

confidence: 99%

Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

Ascierto

Kalos

Schaer

et al. 2013

Clinical Cancer Research

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130

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Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4-blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success.

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Section: Pd-1 Biomarker Developmentmentioning

confidence: 99%

Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

Ascierto

Kalos

Schaer

et al. 2013

Clinical Cancer Research

Self Cite

130

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“…Impressive antitumor effects in patients with cancer have been obtained with other antibodies that enhance tumor immunity, including anti-PD1, anti-PD-1L, and ipilimumab (anti-CTLA-4; ref. 50). Unlike these antibodies, which inhibit negative feedback pathways in immune cell activation, bavituximab seems to act by reversing the immunosuppressive effects of exposed phosphatidylserine in the tumor microenvironment, resulting in activation of local tumor immunity and damage to tumor vasculature.…”

mentioning

confidence: 99%

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Yin

Huang

Lynn

et al. 2013

Cancer Immunology Research

132

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Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphatidylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2-to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity. Cancer Immunol Res; 1(4); 256-68. Ó2013 AACR.

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“…However, strong CD137 agonists may induce adverse effects, including liver toxicity and cytokine storm, in naive or irradiated mice and in humans (24,39,44). Therefore, the prophylactic use of antagonist anti-CD137-saporin immunotoxin may be needed to suppress GVHD.…”

Section: Discussionmentioning

confidence: 99%

Depletion of Alloreactive T-Cells by Anti-CD137-Saporin Immunotoxin

et al. 2015

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Depletion of alloreactive T-lymphocytes from allogeneic bone marrow transplants may prevent graft-versus-host disease (GVHD) without impairing donor cell engraftment, immunity, and the graft-versus-leukemia (GVL) effect. Alloreactive T-cells may be identified by their expression, upon activation, of CD137, a costimulatory receptor and putative surrogate marker for antigen-specific effector T-cells. In this context, we tested the use of anti-CD137-saporin immunotoxin to selectively deplete mouse and human alloreactive T-cells. Anti-CD137 antibodies were internalized by cells within 4 h of binding to the cell surface CD137, and anti-CD137-saporin immunotoxin effectively killed polyclonally activated T-cells or antigen-stimulated T-cells. Transfer of donor T-cells after allodepletion with anti-CD137-saporin immunotoxin failed to induce any evident expression of GVHD; however, a significant GVL effect was observed. Targeting of CD137 with an immunotoxin was also effective in killing polyclonally activated or alloreactive human T-cells. Our results indicate that anti-CD137-saporin immunotoxin may be used to deplete alloreactive T-cells prior to bone marrow transplantation and thereby prevent GVHD and the relapse of leukemia.

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Immunomodulating antibodies in the treatment of metastatic melanoma: The experience with anti-CTLA-4, anti-CD137, and anti-PD1

Cited by 82 publications

References 24 publications

Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Depletion of Alloreactive T-Cells by Anti-CD137-Saporin Immunotoxin

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