Wednesday, February 5, 2025
2/5/2025
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.
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