Chapter 10 - Cancer Immunotherapy by Anti-Gal-Mediated In Situ Conversion of Tumors Into Autologous Vaccines

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Invisible micrometastases may develop into lethal metastases after the resection or ablation of detectable lesions. Destruction of micrometastases may be feasible by activating the immune system to react against tumor associated antgens (TAA) of the patient’s tumor cells. Most TAA are generated because of genomic instability in tumor cells, which causes the formation of multiple mutations that are unique to the tumor of each patient. It is not feasible at present to identify the wide range of immunogenic TAA peptides in tumor lesions in order to prepare customized vaccine for each individual patient. Therefore, the autologous tumor cells may be considered as the source for vaccinating TAA. The immunogenicity of TAA in patients developing metastases is very low. Increasing the immunogenicity of TAA of autologous tumor cells requires effective targeting of these cells for uptake by antigen presenting cells (APC). Such targeting may be achieved by in situ manipulation of the tumor lesions to present α-gal epitopes on their cells. Binding of the natural anti-Gal antibody to these epitopes activates the complement system that induces complement-mediated lysis of the tumor cells and generates chemotactic complement cleavage peptides that recruit APC such as dendritic cells and macrophages into the tumor. Binding of the Fc portion of anti-Gal opsonizing the tumor cells to FcγR on APC induces effective uptake of tumor cells and cell membranes by the APC and transport of the internalized TAA by the APC to the regional lymph nodes. These APC further process the immunogenic TAA peptides and present them on class I and II MHC molecules for the activation of TAA-specific CD8+ and CD4+ T cells, respectively. The activated T cells mediate a protective anti-tumor immune response against metastatic cells. Analysis of various methods for inducing α-gal epitope expression indicated that intratumoral injection of α-gal glycolipid micelles is the most effective method tested. The method was found to be safe in cancer patients with advanced disease. It is suggested that in addition to the use of this immunotherapy method in patients who are likely to have micrometastases, this method may elicit a protective immune response as a neoadjuvant immunotherapy prior to the resection of the primary tumor. This method may also synergize with checkpoint inhibitors therapy by amplifying the anti-tumor specific immune response and reducing the risk of autoimmune adverse events.