Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17-28. ©2016 AACR.

Wu X ，Giobbie-Hurder A ，Liao X ，Connelly C ，Connolly EM ，Li J ，Manos MP ，Lawrence D ，McDermott D ，Severgnini M ，Zhou J ，Gjini E ，Lako A ，Lipschitz M ，Pak CJ ，Abdelrahman S ，Rodig S ，Hodi FS ... -  《-》

Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities.

The emergence of immune checkpoint inhibitors for solid tumor treatments represents a major oncologic advance. Since the approval of ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, for the treatment of metastatic melanoma, many drugs, especially those targeting PD-1/PD-L1, have demonstrated promising antitumor effects in many types of cancer. By reactivating the immune system, these immunotherapies have led to the development of new toxicity profiles, also called immune-related adverse events (irAE). IrAEs can involve many organ systems, and their management is radically different from that of cytotoxic drugs; irAEs require immunosuppressive treatments, such as corticoids or TNFα antibody. In addition, the occurrence of irAEs has raised significant questions. Here, we summarize progress that has been made toward answering these questions, focusing on (i) the impact of immunotherapy dose on irAE occurrence, (ii) the correlation between irAE and patient outcome, (iii) the safety of immune checkpoint inhibitors in patients already treated for autoimmune disease, and (iv) the suspected effect on tumor growth of steroids used for the management of irAEs. Clin Cancer Res; 22(18); 4550-5. ©2016 AACR.

Cousin S ，Italiano A 《-》

Masterful Antibodies: Checkpoint Blockade.

Cancer therapeutics that target the immune system rather than the cancer cell itself are becoming standard of care in a growing number of different malignancies. Although cancer immunotherapy is not a new concept, the potential importance of this class of drugs was probably not fully appreciated as recently as a decade ago when much of the focus of cancer drug discovery was on cancer cell-targeted medicines. The authors were lucky enough to be able to witness and participate in the discovery and development of ipilimumab and nivolumab, two relatively early examples of immune system-targeted drugs. The challenges associated with discovering and developing these molecules may be of historical interest and instructive for moving cancer immunotherapy forward for greater numbers of patients. Cancer Immunol Res; 5(4); 275-81. ©2017 AACR.

Lonberg N ，Korman AJ 《-》

Immune-checkpoint inhibitors for the treatment of metastatic melanoma: a model of cancer immunotherapy.

Melanoma has always been described as an immunogenic tumor. Despite that, until 2011 the standard of care in metastatic melanoma was chemotherapy, with low response rates and no clear impact on overall survival. Melanoma was the first cancer type to drive the use of immune-checkpoint inhibitors into clinical practice, which revolutionized the therapeutic paradigm not only in melanoma, but also in an increasing number of tumors. In this review, the preclinical bases and the main clinical studies that led to the approval of immune-checkpoint inhibitors in advanced melanoma will be described with insights on novel combinations of treatments and on prognostic and predictive biomarkers.

Queirolo P ，Boutros A ，Tanda E ，Spagnolo F ，Quaglino P ... -  《-》

Immune checkpoint blockade: Releasing the brake towards hematological malignancies.

Tumor cells utilize co-inhibitory molecules to avoid host immune destruction. Checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector function and breaking a tumor permissive microenvironment. Patients with hematological malignancies often have immune dysregulation, thus the role of checkpoint blockade in treatment of these neoplasms is particularly intriguing. In early trials, antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) or the programmed death 1 (PD-1) signaling pathway have displayed significant efficacy with minimal toxicity in patients with relapsed and refractory hematological neoplasms. In this review, we provide evidence of dysregulation of CTLA-4 and PD-1/PD-Ls in the context of several major types of hematological neoplasms and summarize relevant clinical practice points for checkpoint blockade. The preclinical rationale and preliminary clinical data of potential combination approaches designed to optimize checkpoint antagonists are well presented.

Xia Y ，Medeiros LJ ，Young KH 《-》