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Principal Investigator: Katja Michael
Organization: UNIVERSITY OF TEXAS EL PASO
Fiscal Year: 2024
Award: $174,151
Funding agency: National Cancer Institute
A novel gene-based immunotherapy inducing melanoma destruction
In the U.S., nearly 100,000 new melanoma diagnoses and 8,000 deaths are expected in 2023. Despite the
advent of immunotherapy, especially checkpoint inhibitor antibodies (Abs), advanced melanoma remains a
progressive and incurable disease for most patients. There is an urgent need for new melanoma therapies.
Autologous melanoma vaccines that use endogenous anti-a-Gal antibodies (Abs) (present in all human serum)
as adjuvants to enhance the immunogenicity of poorly immunogenic tumor-specific antigens (TSAs) of
melanoma have been explored but were only partially successful. In a different context, anti-a-Gal Abs play a
critical role in the rapid rejection of xenografts, e.g., a pig kidney transplanted into a human recipient. The so
called hyperacute rejection of the xenograft occurs within minutes to hours due to the fact that pig cells express
large amounts of a-Gal, which are foreign to humans, and are recognized by human anti-a-Gal Abs.
Opsonization of the pig cells with the Abs leads to their destruction primarily by complement-dependent
cytotoxicity (CDC), but also Ab-dependent cell-mediated cytotoxicity (ADCC), and Ab-dependent cell-mediated
phagocytosis (ADCP). Similarly, the anti-a-Gal Abs present in Chagas disease patients kill the parasite
Trypanosoma cruzi that causes this disease. T. cruzi expresses large amounts of a-Gal epitopes, one prominent
being Gala1,3Galb1,4GlcNAc (Gala3LN), on its cell surface, and the patient's anti-a-Gal Abs lyse the parasite
within minutes by complement-dependent and independent mechanisms. If cancer cells could be made to
express a-Gal on their cell surface, the patient's own already existing anti-a-Gal Abs could target and destroy
them by CDC, ADCC, and ADCP. The destruction of glycoengineered a-Gal expressing melanoma cells by CDC
in the presence of anti-a-Gal Abs and complement has already been demonstrated in vitro but has never been
explored in vivo. Here we propose a novel melanoma gene therapy in the a1,3-galactosyltransferase knockout
mouse model, in which melanoma cells are selectively transfected in vivo with a gene coding for a1,3-galactosyl
transferase (a1,3GalT). This enzyme is involved in the synthesis of terminal Gala3LN residues on glycoproteins.
Based on recent advances in nanotechnology, we propose to use functionalized lipid nanoparticles (LNPs) as
delivery vehicle for the transfection. The LNPs have a DT7 peptide and folate on their surface that target the
receptors TfR1 and FRa overexpressed in melanoma (and other cancers). These receptors can internalize the
LNP by an active transport, thus delivering the gene. The transcription is under the control of a melanocyte-
specific promoter, which adds another level of selectivity for targeting melanoma. Not all melanoma cells need
to be transfected, as the adaptive immune system would also be activated resulting in specific anti-tumor
immunity. This novel a-Gal based gene therapy could result in the rapid destruction of melanoma cells and anti-
tumor immunity in vivo.
Terms: <7S Gamma Globulin><Ab-dependent cellular cytotoxicity><Active Biologic Transport><Active Biological Transport><Active Transport><Adaptive Immune System><Adjuvant><American Trypanosomiasis><American trypanosome><Antibodies><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Assay><Autologous><Binding Determinants><Bioassay><Biological Assay><Biomedical Engineering><Blood Serum><Body Tissues><Breast Cancer><CD71><Cancer Biology><Cancers><Cell Body><Cell membrane><Cell surface><Cell-Mediated Cytolysis><Cell-Mediated Lympholysis><Cells><Cellular Cytotoxicity><Cessation of life><Chagas Disease><Charge><Checkpoint inhibitor><Chemistry><Code><Coding System><Colorectal Cancer><Complement><Complement Proteins><Complement-Dependent Cytotoxicity><Complementary DNA><Cytolysis><Cytoplasmic Membrane><DNA><DNA Therapy><Death><Deoxyribonucleic Acid><Development><Diagnosis><Diameter><Disease><Disorder><ELISA><Early-Stage Clinical Trials><Effectiveness><Encapsulated><Enzyme Gene><Enzyme-Linked Immunosorbent Assay><Enzymes><Epitopes><Evaluation><FRAs><Family suidae><Folate><Folic Acid><Fos-Related Antigens><Galactosyltransferases><Gene Transcription><Gene Transfer Clinical><Genes><Genetic Intervention><Genetic Transcription><Glycoengineering><Glycolipids><Glycoproteins><Heterograft><Heterologous Transplantation><Histopathology><Hour><Human><IgG><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immune system><Immunization><Immunochemical Immunologic><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><In Vitro><In vivo analysis><Incidence><Injections><Innate Immune System><KO mice><Kidney><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knock-out Mice><Knockout Mice><Lesion><Ligands><Lipids><Lung><Lung Respiratory System><Lymphocyte Cytotoxicity><Lymphocytotoxicity><Lysis><Malignant Breast Neoplasm><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Measurement><Mediating><Melanoma><Melanoma Cell><Melanoma Metastasis><Melanoma Vaccine><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Microscopy><Modern Man><Monitor><Murine><Mus><Nanotechnology><Neoplasm Metastasis><Null Mouse><Organ><Outcome><Parasites><Patients><Peptides><Phagocytosis><Phase 1 Clinical Trials><Phase I Clinical Trials><Pigs><Plasma Membrane><Play><Predisposition><Pteroylglutamic Acid><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA Expression><Receptor Protein><Renal Grafting><Renal Transplantation><Renal Transplants><Role><Secondary Neoplasm><Secondary Tumor><Serum><Slice><South American Trypanosomiasis><Suidae><Surface><Susceptibility><Swine><T cruzi><T. cruzi><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Th-1 Cell><Th-2 Cell><Th1 Cells><Th2 Cells><Tissues><Toxic effect><Toxicities><Transcription><Transfection><Transferase><Transferase Gene><Transferrin Receptor><Transferrin Receptor 1><Trypanosoma cruzi><Tumor Antigens><Tumor Immunity><Tumor-Associated Antigen><Type 1 Helper Cell><Type 2 Helper Cell><Uphill Transport><Vaccines><Visual><Vitamin M><Work><Xenograft><Xenograft procedure><Xenotransplantation><accessory cell><acquired immune system><adaptive immune response><anti-cancer><anti-tumor immunity><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody inhibitor><antibody mediated cellular cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><antitumor immunity><aqueous><arm><bio-engineered><bio-engineers><bioengineering><biological engineering><bioluminescence imaging><bioluminescent imaging><cDNA><cancer antigens><cancer cell><cancer immunity><cancer metastasis><cancer type><cell mediated cytotoxicity><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><complement-mediated cytotoxicity><complementation><delivery vector><delivery vehicle><developmental><enzyme linked immunoassay><experience><folate carrier><folate receptor><folate-binding protein><folate-methotrexate transporter><folic acid binding protein><folic acid receptor><gene repair therapy><gene therapy><gene-based therapy><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><genetic therapy><genomic therapy><host response><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunogenicity><immunoresponse><implantation><in vivo><in vivo evaluation><in vivo testing><indexing><innate immune mechanisms><kidney tx><lipid based nanoparticle><lipid nanoparticle><lung cancer><malignancy><malignant breast tumor><melanocyte><methotrexate-binding protein><mouse model><murine model><nano particle delivery><nano tech><nano technology><nano-technological><nanoparticle delivered><nanoparticle delivery><nanotech><nanotechnological><neoplasm/cancer><novel><overexpress><overexpression><phase I protocol><plasmalemma><porcine><promoter><promotor><pulmonary><receptor><renal><side effect><social role><suid><therapeutic vaccine><treatment vaccines><tumor><tumor cell metastasis><tumor growth><tumor-specific antigen><uptake><vaccine for the treatment><vaccine for treatment><vitamin Bc><xeno-transplant><xeno-transplantation>