ABSTRACT
Novel therapies to treat patients with solid cancers that have developed resistance to chemotherapy represent unmet needs of considerable dimensions. In the present review, we will address the attempts to develop chimeric antigen receptor (CAR) targeted immunotherapy against osteosarcoma (OS). This aggressive cancer displays its peak incidence in children and young adults. The main cause of patient death is lung metastases with a 5-year survival as low as 5%-10% in the primary metastatic setting and 30% in the relapse situation, respectively. Effective adjuvant combination chemotherapy introduced more than 40 years ago improved the survival rates from below 20% to around 60% in patients; however, since then, no major breakthroughs have been made. The use of immune checkpoint inhibitors has been disappointing in OS, while other types of immunotherapies such as CAR T cells remain largely unexplored. Indeed, for CAR T-cell therapy to be efficacious, two main criteria need to be fulfilled: (a) CAR T cells should target an epitope selectively expressed on the cell surface of OS in order to prevent toxicities in normal tissues and (b) the target should also be widely expressed on OS metastases. These challenges have already been undertaken in OS and illustrate the difficulties in developing tomorrow's CAR-T treatment in a solid tumour. We will discuss the experiences with CAR-T therapy development and efficacy to combat the clinical challenges in OS.
Subject(s)
Bone Neoplasms/therapy , Immunotherapy, Adoptive/methods , Osteosarcoma/therapy , Bone Neoplasms/immunology , Bone Neoplasms/mortality , Cancer-Associated Fibroblasts/physiology , Endopeptidases , Gangliosides/antagonists & inhibitors , Gelatinases/physiology , Humans , Membrane Proteins/physiology , Osteosarcoma/immunology , Osteosarcoma/mortality , Receptor, ErbB-2/analysis , Receptor, IGF Type 1/physiology , Receptors, Interleukin-11/antagonists & inhibitors , Serine Endopeptidases/physiology , Tumor MicroenvironmentABSTRACT
Cancer-associated fibroblasts (CAF) are recognized as one of the key determinants in the malignant progression of lung adenocarcinoma. And its contributions to chemoresistance acquisition of lung cancer has raised more and more attention. In our study, cancer associated fibroblasts treated with cisplatin conferred chemoresistance to lung cancer cells. Meanwhile, Interleukin-11(IL-11) was significantly up-regulated in the CAF stimulated by cisplatin. As confirmed in lung adenocarcinoma cells in vivo and in vitro, IL-11 could protect cancer cells from cisplatin-induced apoptosis and thus promote their chemoresistance. Furthermore, it was also observed that IL-11 induced STAT3 phosphorylation and increased anti-apoptotic protein Bcl-2 and Survivin expression in cancer cells. The effect could be abrogated by suppressing STAT3 phosphorylation or silencing IL-11Rα expression in cancer cells. In conclusion, chemotherapy-induced IL-11 upregulation in CAF promotes lung adenocarcinoma cell chemoresistance by activating IL-11R/STAT3 anti-apoptotic signaling pathway.
Subject(s)
Adenocarcinoma/genetics , Antineoplastic Agents/pharmacology , Cancer-Associated Fibroblasts/drug effects , Cisplatin/pharmacology , Gene Expression Regulation, Neoplastic , Interleukin-11/metabolism , Lung Neoplasms/genetics , Receptors, Interleukin-11/metabolism , STAT3 Transcription Factor/metabolism , A549 Cells , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Animals , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Cell Communication/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Humans , Interleukin-11/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Phenanthrenes/pharmacology , Phosphorylation/drug effects , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Interleukin-11/antagonists & inhibitors , Receptors, Interleukin-11/genetics , STAT3 Transcription Factor/genetics , Signal Transduction , Survival Analysis , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma. EXPERIMENTAL DESIGN AND RESULTS: First, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile. CONCLUSIONS: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.
Subject(s)
Antineoplastic Agents/pharmacology , Leukemia/drug therapy , Lymphoma/drug therapy , Peptides/pharmacology , Receptors, Interleukin-11/antagonists & inhibitors , Amino Acid Sequence , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Ligands , Molecular Sequence DataABSTRACT
Recent advances have shown that cell surface receptors are expressed differentially in normal and pathological conditions. Novel organ specific and disease specific proteins expressed on tumor vasculature have been identified by in vivo phage display technology and the diversity of the tumor-associated vasculature has provided the basis for the development of targeted therapeutics. Investigators recently screened a phage display library in a human cancer patient. An IL-11 mimic phage displaying the cyclic peptide CGRRAGGSC (single letter amino acid code) specifically bound to immobilized IL-11Rα. It has been demonstrated that the expression of the IL-11Rα is increased in several other types of tumors including osteosarcoma. The ability to selectively target the IL-11Rα may provide an alternative treatment of for a disease where new treatment options are truly needed.
