Semir Vranić - Academia.edu (original) (raw)

Papers by Semir Vranić

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 aga... more 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

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 aga... more 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