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Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond.

ABSTRACT: Is breast cancer (BC) immunogenic? Many data suggest that it is. Many observations demonstrated the prognostic role of tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2 (HER-2)-positive BC. TNBCs are poorly differentiated tumors with high genetic instability and very high heterogeneity. This heterogeneity enhances the 'danger signals' and select clone variants that could be more antigenic or, in other words, that could more strongly stimulate a host immune antitumor response. The response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). ICD elicits an adaptive immune response. Which are the clinical implications of all 'immunome' data produced in the last years? First, validate prognostic or predictive role of TILs. Second, validate immune genomic signatures that may be predictive and prognostic in patients with TN disease. Third, incorporate an 'immunoscore' into traditional classification of BC, thus providing an essential prognostic and potentially predictive tool in the pathology report. Fourth, implement clinical trials for BC in the metastatic setting with drugs that target immune-cell-intrinsic checkpoints. Blockade of one of these checkpoints, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or the programmed cell death 1 (PD-1) receptor may provide proof of concepts for the activity of an immune-modulation approach in the treatment of a BC.

SUBMITTER: Migali C

PROVIDER: S-EPMC4981297 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond.

Migali Cristina C Milano Monica M Trapani Dario D Criscitiello Carmen C Esposito Angela A Locatelli Marzia M Minchella Ida I Curigliano Giuseppe G

Therapeutic advances in medical oncology 20160710 5

Is breast cancer (BC) immunogenic? Many data suggest that it is. Many observations demonstrated the prognostic role of tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2 (HER-2)-positive BC. TNBCs are poorly differentiated tumors with high genetic instability and very high heterogeneity. This heterogeneity enhances the 'danger signals' and select clone variants that could be more antigenic or, in other words, that could more strongly stimul ...[more]

PMID: 27583028

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Project description:Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

Project description:Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.

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Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond.

Publications

Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond.

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