Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors (original) (raw)
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Journal of Cancer Metastasis and Treatment, 2021
Triple-negative breast cancer (TNBC) represents the subtype of breast cancer with the most aggressive biological behavior and the worst prognosis compared to other breast cancers. Metastatic TNBC is characterized by a high proliferative index, rapid progression with metastases to the viscera and central nervous system, and generally an unfavorable prognosis with a survival of about one year. It is, therefore, necessary to identify specific targets and more effective treatments for patients with TNBC. Evidence of the effect of the tumor immune microenvironment on clinical outcomes is considered a significant issue in breast cancer therapeutics. Compared to other subtypes of breast cancer, TNBC is characterized by a higher mutational burden and is recognized as the most immunogenic among them. Based on these findings, immune checkpoint inhibition was evaluated in TNBC with encouraging results. Indeed, enhancing antitumor immunity in TNBC by blocking the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) axis or the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway is a promising treatment option. In this review, we examine the role of monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 in this breast cancer subtype and discuss combination approaches for early and advanced disease.
Targeted immunotherapy with a checkpoint inhibitor in combination with chemotherapy: A new clinical paradigm in the treatment of triple-negative breast cancer, 2019
Recent advances in the development of cancer immunotherapy using immune checkpoint inhibitors against either programmed death receptor-1 (PD-1) or its ligand PD-L1 have revolutionized treatment of several solid tumors [1-4]. The interaction between PD-1 on T-cells and its ligands PD-L1 and PD-L2 on cancer cells promotes T-cell exhaustion and conversion of T effector cells to immunosuppressive T regulatory (Treg) cells (Figure 1) [5]. Immune checkpoint inhibitors (against either PD-1 or PD-L1) block the suppressor PD-1/PD-L1 axis contributing to the reactivation of cytotoxic T effector cells and consequently enhancing the anticancer activity of the immune system (Figure 1) [5]. Stunning successes of monoclonal antibody-based immune checkpoint inhibitors against PD-1/PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab) have been achieved in various cancers [6]. These include non-small cell lung carcinoma (NSCLC), renal, bladder, head and neck, gastric/gastroesophageal junction (GEJ), microsatellite instable (MSI-H) colorectal, cervical, hepatocellular and Merkel cell carcinoma, as well as in malignant melanoma (both pediatric and adult) and classical Hodgkin' s lymphoma [6,7]. In addition, an anti-PD-1 agent pembrolizumab has been approved for all solid MSI-H cancers regardless the histotype ("tumor agnostic approach") [7-10]. Triple-negative breast cancer (TNBC) is a complex and highly aggressive subtype of breast cancer lacking estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2) receptors, thereby making it difficult to treat [11]. It carries the highest metastatic potential and has the poorest clinical outcome among all the subtypes of breast cancer [11]. Due to the advances in molecular characterization of TNBC, various novel therapeutic targets including poly ADP-ribose polymerase-1 (PARP-1) inhibitors, tyrosine kinase inhibitors, immune checkpoints, anti-androgens, and epigenetic targets have come into focus [11]. Although breast cancer has been initially considered a "non-immunogenic" cancer, numerous studies have now shown PD-L1 expression in both cancer and inflammatory cells (tumor infiltrating lymphocytes [TILs]). PD-L1 positivity in cancer or inflammatory cells has been reported across the breast cancer histotypes [12-26]. In particular, ER-negative breast cancers (TNBC and HER2 positive) have been shown to be "immunogenic" and potentially amenable for the trials
A narrative review of immune checkpoint inhibitors in early stage triple negative breast cancer
2021
Triple negative breast cancer (TNBC) is an aggressive disease characterized by heterogeneous molecular and immunological characteristics that portends worse overall survival compared to other breast cancer subtypes. Until now, chemotherapy has remained the cornerstone of TNBC treatment despite recent efforts to explore new molecularly targeted therapeutic targets and personalized treatments. Given TNBC has a more immunogenic tumor microenvironment than other breast cancer subtypes, there is hope that immunotherapy will emerge as a new pillar of treatment in TNBC. Based on the IMPASSION130 and KEYNOTE-355 studies, the combination of nab-paclitaxel plus atezolizumab, and chemotherapy plus pembrolizumab, respectively, have been approved by the Food and Drug Administration for locally recurrent, unresectable, or metastatic TNBC in the first line setting. Several studies have now been published demonstrating PD-1/PD-L1 inhibitors given alongside neoadjuvant taxane and anthracyclinebased ...
Cancers, 2020
Chemotherapy based on the sequential use of anthracyclines and taxanes has long represented the most efficacious approach in the management of early-stage, triple-negative breast cancer, whose aggressive behavior is widely renowned. This standard chemotherapy backbone was subsequently enriched by the use of carboplatin, based on its association with increased pathologic complete response and efficacy in the metastatic setting. Following the results from the IMpassion130 trial, the recent approval of the immunotherapic agent atezolizumab in combination with chemotherapy as first-line treatment for programmed-death ligand 1-positive, unresectable locally advanced, or metastatic triple-negative breast cancer increasingly fueled the flourishing of trials of immune-checkpoint inhibitors in the early setting. In this work, we review the most recent inherent literature in light of key methodological issues and provide a quantitative summary of the results from phase II–III randomized trial...
Clinical advances in hematology & oncology : H&O, 2016
Immunotherapy encompasses both vaccines that direct immune responses to tumor-associated antigens, and checkpoint blocking antibodies that inhibit immune system suppression by targeting key pathways mediated by cytotoxic T-lymphocyte-associated antigen 4, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1). Both of these approaches currently are being explored as potential strategies for the treatment of breast cancer. Recent studies suggest that immunotherapy is poised to change the therapeutic landscape for some breast cancers. Specifically, overall response rates of 19% with PD-1/PD-L1-directed antibodies have been reported in 2 small studies of women with PD-L1-positive, heavily pretreated advanced triple-negative breast cancer. In combination with nab-paclitaxel, confirmed response rates were 46% in a PD-L1-unselected population in the first-line metastatic triple-negative breast cancer setting. Checkpoint-blocking antibodies also have been evaluated in small studi...
Acta Facultatis Medicae Naissensis, 2016
SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. ...
Neoplasma, 2021
Immune checkpoint receptors (ICRs) were recently found to modulate the anti-tumoral immune response. This study aimed to determine the clinical and pathological associations of ICRs expression on tumor-infiltrating lymphocytes (TILs) in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy (NAC). Expressions of ICRs including PD-1, LAG-3, TIM-3, TIGIT, and CTLA-4 on CD8 + T lymphocytes and Natural Killer (NK) cells on TILs were analyzed by flow cytometry. Patients <50 years were more likely to express CTLA-4 on CD8 + T lymphocytes compared to those ≥50 years (p=0.004). In addition, patients with ypT3-4 tumors were more likely to have increased LAG-3 expression on CD16-CD56 bright NK cells (p=0.042) and PD-1 (p=0.014) and CTLA-4 (p=0.018) expressions on CD8 + T cells in regard to those with ypT1-T2, respectively. Contrarily, PD-1 expression on CD16-CD56 bright NK cells was found to be decreased in patients with ypN+ compared to those with ypN-(p=0.022). Furthermore, patients with HER2+ tumors were more likely to have increased TIM-3 expression on CD8+ T cells (p=0.043), whereas patients with a better response to NAC were more likely to express TIGIT on CD8 + T (p=0.014) and CD16-CD56 bright NK cells (p=0.003), respectively. The new generation ICRs, TIM-3, LAG-3, and TIGIT are highly expressed in LABC following NAC in patients with poor prognostic factors. Therefore, new evolving therapies using inhibitory mAbs directed to TIM-3, LAG-3, and TIGIT could be also be considered in locally advanced breast cancers expressing these ICRs.
Immune-Based Therapy in Triple-Negative Breast Cancer: From Molecular Biology to Clinical Practice
Cancers
Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a “cold tumor”, exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs). In particular, compared to standard CT, the immune-based approach has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in metastatic PD-L1-positive TNBC and the pathological complete response rate in the early setting, regardless of PD-L1 expression. To date, PD-L1 has been widely used as a predictor of the response to ICIs; however, man...