Role of α-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer

Pancreatic cancer is one of the most common causes of death from cancer. Despite the availability of various treatment modalities, such as surgery, chemotherapy and radiotherapy, the 5-year survival remains poor. Although gemcitabine-based chemotherapy is typically offered as the standard care, most patients do not survive longer than 6 months. Therefore, new therapeutic approaches are needed. The α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) is abundantly synthesized from glycoproteins and glycolipids in non-primate mammals and New World monkeys, but is absent in humans, apes and Old World monkeys. Instead, they produce anti-Gal antibody (Ab) (forming approximately 1% of circulating immunoglobulins), which specifically interacts with α-gal epitopes. Anti-Gal Ab can be exploited in cancer immunotherapy as vaccines that target antigen-presenting cells (APC) to increase their immunogenicity. Tumor cells or tumor cell membranes from pancreatic cancer are processed to express α-gal epitopes. Subsequent vaccination with such processed cell membranes results in in vivo opsonization by anti-Gal IgG in cancer patients. The interaction of the Fc portion of the vaccine-bound anti-Gal with Fcγ receptors of APC induces effective uptake of the vaccinating tumor cell membranes by the APC, followed by effective transport of the vaccinating tumor membranes to the regional lymph nodes, and processing and presentation of the tumor-associated antigens. Activation of tumor-specific B and T cells could elicit an immune response that in some patients is potent enough to eradicate the residual cancer cells that remain after completion of standard therapy. This review addresses these topics and new avenues of clinical importance related to this unique antigen/antibody system (α-gal epitope/anti-Gal Ab) and advances in immunotherapy in pancreatic cancer.