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Principal Investigator: Christina Annunziata
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2020
Award: $560,328
Funding agency: National Cancer Institute
Goal 1: Monocytes It has been shown in mouse models of chemically induced cancer that Interferons (IFNs) are important in the immune-surveillance and immune-editing of tumors. While IFNs alpha (IFNa) and gamma (IFNg) have been shown to have potent anti-neoplastic and anti-proliferative properties in vitro, they have shown little efficacy in the clinic. Our observations that IFNs play an important role in killing tumor cells in the presence of monocytes suggests that combination therapy of monocytes and IFNs may have a more potent effect than IFNs alone. We and others have shown that IFNs are more potent anti-cancer agents when used in combination with monocytes isolated from the peripheral blood. Based on these studies we have completed a Phase 1 clinical trial of immune cell therapy using autologous transfer of ex vivo monocytes stimulated with IFNs into the peritoneal cavity of patients who have resistant disease. We are now in the process of defining the mechanism of IFN-induced monocyte killing of ovarian cancer cells. we found that IFNs induce a unique set of genes regulated in monocytes that occurs only with the combination of IFNa and IFNg, and this signature may be driven by the transcription factor MZF1. In order to better mimic the peritoneal microenvironment of ovarian cancer, we developed a new model of growing complex ovarian cancer neoplasms from cell culture lines and primary samples. We are able to image and quantify complex interactions of IFNs-stimulated monocytes and cancer growths, providing a superior model for studying functional proteomic interactions. In addition, I have the ability to examine tissue and peritoneal fluid samples from women on our phase 1 trial receiving intraperitoneal autologous monocytes stimulated with IFNs, providing another platform for defining dual-IFN induced mechanisms of monocyte activity in the context of the complete immune response. Goal 2: ADCC A monoclonal antibody was developed against a semi-purified human membrane protein preparation derived from cancer tissues. The protein preparation was used in previous clinical trials for use as a cancer vaccine, where it was demonstrated to be safe and efficacious. The antibody, NEO201, was shown to react with the immunizing antigen preparation, as well as several human tumor cell lines and tissues from colorectal, pancreas, lung, and ovarian cancer patients. NEO201did not cross-react significantly with normal human tissues, thus representing a potential therapeutic product. The target of NEO201was studied and shown to be related to CEACAM-5/6, a member of the carcinoembryonic antigen family of proteins, which has been shown to be associated with several cancer types. Endometrial, breast and ovarian cancer have specifically been found to have increased expression in human tumor samples. In endometrial cancer, 45/88 (51%) of tissue samples show reactivity through immunohistochemistry, 38/72 (53%) of breast, and although 16/129 (12%) of ovarian cancer specimens stain positive in this series, two subtypes, mucinous 15/22 (68%)and signet cell 2/2 (100%) ovarian cancers, shows significant reactivity (50%) in an IHC of ovarian cancer tissue arrays representing over 600 samples. Our phase 1 clinical trial is ongoing to demostrate safety and preliminary activity of the NEO201 in patients with solid tumors likely to express the target. Goal 3: T cells Mesothelin (MESO) is a 41-kD cell surface glycoprotein that is highly expressed in many human cancers, including high grade serous adenocarcinoma of the ovary (75%), pancreatic adenocarcinoma (85%), triple negative breast cancer (66%), epitheliod mesothelioma (95%) of patients with MESO-expressing malignancies. While the function of MESO on normal cells is non-essential, the expression of MESO on cancer cells may contribute to the pathology of cancer, with higher expression associated with poorer prognosis, increased metastatic spread, and activation of cell growth pathways. A tremendously innovative immunotherapeutic approach is the use of chimeric antigen receptor-modified T cells (CAR). CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When expressed in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. The most widely used method for T-cell modification is viral transduction, integration and expression of a genetic construct that expresses the chimeric receptor. Another approach to the generation of CAR T-cell therapies that may provide potent anti-tumor activity and improve safety and product preparation involves the use of mRNA to modify T-cells. Using mRNA to re-engineer a patient's T-cells to express a tumor-antigen targeted CAR T-cell can be accomplished in a few hours, allowing on-site preparation and deployment to multiple treatment locations. mRNA CAR T-cells have the safety factor of a limited lifespan, with half-life times similar to antibody therapeutics, and lack of rapid immune activation and proliferation, limiting the risk for severe cytokine release side effects. Meso-targeted CAR T-cells using mRNA have demonstrated significant promise in preclinical studies and clinical studies by intratumoral, intraperitoneal and intravenous of routes of administration. We are running a phase 1 clinical trial testing the safety of intraperitoneal administration of the CARMA MCY-M11 in women with ovarian cancer and peritoneal carcinomatosis.
Terms: <Alferon><Anti-Cancer Agents><Antibodies><Antigen Targeting><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastic Vaccine><Antineoplastics><Ascitic Fluid><Autologous><Basal Transcription Factor><Basal transcription factor genes><Blood monocyte><Body Tissues><Breast><Breast Cancer><CAR T cell therapy><CAR T cells><CAR T therapy><CEA Family Protein><Cancer Drug><Cancer Patient><Cancer Vaccines><Cancers><Carcinoembryonic Antigen Family Protein><Carcinomatosis><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell Surface Glycoproteins><Cells><Cellular Expansion><Cellular Growth><Cellular immunotherapy><Chemical Models><Clinic><Clinical><Clinical Research><Clinical Study><Clinical Treatment Moab><Clinical Trials><Colo-rectal Cancer><Colorectal Cancer><Combined Modality Therapy><Complex><Cytotoxic cell><Disease Resistance><Early-Stage Clinical Trials><Endometrial Cancer><Endometrial Carcinoma><Endometrium Cancer><Endometrium Carcinoma><Engineering><Gamma interferon><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genes><Genetic><Goals><Greater sac of peritoneum><Growth><HL-A Antigens><HLA Antigens><Half-Life><Hour><Human><Human Leukocyte Antigens><IFN><IFN Alpha><IFN-Gamma><IFN-g><IFN-α><IFN-γ><IFNG><IFNa><IFNα><IFNγ><Image><Immune><Immune Cell Activation><Immune Interferon><Immune Surveillance><Immune response><Immune system><Immunes><Immunize><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunosurveillance><Immunotherapeutic agent><In Vitro><Innate Immunity><Interferon Alfa-n3><Interferon Gamma><Interferon Type II><Interferon-alpha><Interferon-gamma><Interferon-α><Interferons><Intracellular Communication and Signaling><Intravenous><K lymphocyte><Length of Life><Leukocyte Antigens><Leukocyte Interferon><Location><Longevity><Lymphoblast Interferon><Lymphoblastoid Interferon><Malignant Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of pancreas><Marrow monocyte><Membrane Glycoproteins><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mesothelioma><Messenger RNA><Methods><Modeling><Modern Man><Modification><Monoclonal Antibodies><Mucinous><Multimodal Therapy><Multimodal Treatment><NK Cells><Native Immunity><Natural Immunity><Natural Killer Cells><Neoplasm Vaccines><Neoplastic Disease Chemotherapeutic Agents><Non-Specific Immunity><Nonspecific Immunity><Normal Cell><Ovarian Serous Adenocarcinoma><Ovarian Serous Carcinoma><Ovary Cancer><Pancreas Adenocarcinoma><Pancreas Cancer><Pancreatic Adenocarcinoma><Pancreatic Cancer><Pathology><Pathway interactions><Patients><Peritoneal><Peritoneal Cavity><Peritoneal Effusion><Peritoneal Fluid><Phase 1 Clinical Trials><Phase I Clinical Trials><Play><Preparation><Process><Prognosis><Property><Proteins><Proteomics><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Protein><Recombinants><Relapse><Research Specimen><Risk><Role><Route><Running><Safety><Sampling><Series><Serous><Serous Adenocarcinoma of the Ovary><Serous Carcinoma of the Ovary><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid Neoplasm><Solid Tumor><Soluble Mpf/Mesothelin-Related Protein><Specimen><Staining method><Stains><Study models><Surface Glycoproteins><Surface Proteins><T cells for CAR><T-Cells><T-Lymphocyte><TNBC><Therapeutic><Therapeutic antibodies><Time><Tissue Arrays><Tissue Chip><Tissue Growth><Tissue Microarray><Tissue Sample><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Antigens><Tumor Cell><Tumor Cell Line><Tumor Vaccines><Tumor-Associated Antigen><Tumor-Specific Treatment Agents><Viral><Woman><adaptive immunity><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer drug><anticancer agent><anticancer drug><antigen binding><antigen bound><base><biological signal transduction><cancer antigens><cancer cell><cancer initiation><cancer type><cell culture><cell growth><cell-based immunotherapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><combination therapy><combined modality treatment><combined treatment><cytokine><design><designing><extracellular><fighting><host response><human tissue><imaging><immune activation><immune cell therapy><immune drugs><immune-based therapeutics><immunogen><immunologic preparation><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><innovate><innovation><innovative><intraperitoneal><lFN-Gamma><life span><lifespan><lung cancer><mAbs><mRNA><malignancy><malignant breast neoplasm><malignant breast tumor><member><mesothelin><monocyte><mouse model><multi-modal therapy><multi-modal treatment><murine model><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><neoplastic cell><novel><ontogeny><outcome forecast><ovarian cancer><pancreatic malignancy><pathway><peripheral blood><phase 1 trial><phase I protocol><phase I trial><pre-clinical study><preclinical study><receptor><resistance to disease><resistant disease><resistant to disease><safety testing><side effect><social role><synergism><thymus derived lymphocyte><transcription factor><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor-specific antigen><vaccine for cancer>