Inovio Pharmaceuticals has announced that its SynCon WT1 cancer immunotherapy was capable of breaking immune tolerance and inducing neo-antigen-like T cell responses to cause tumor regression in pre-clinical studies. Breaking tolerance has been a major challenge for developing a potent cancer therapy; researchers have tried many other methods and been unsuccessful for decades. Notably, the WT1 antigen is over-expressed in multiple cancer types but not found in most normal tissue, giving it potential to be used as part of a universal cancer vaccine against multiple tumor types.

Results of these pre-clinical studies appear in the online edition of Molecular Therapy in a paper entitled, “A novel DNA vaccine platform enhances neo-antigen-like T-cell responses against WT1 to break tolerance and induce anti-tumor immunity,” authored by Inovio and its collaborators at The Wistar Institute.

Study results revealed that while mice did not mount an immune response to native mouse WT1 antigens, mice immunized with Inovio’s SynCon WT1 antigen broke tolerance and generated robust neo-antigen-like T cells. Furthermore, the immunized mice exhibited smaller tumors and prolonged survival in a tumor challenge study. SynCon WT1 DNA vaccination also broke tolerance and generated neo-antigen-like T cell immune responses in Rhesus monkeys, a species whose immune system closely resembles that of humans. Inovio’s ability to overcome the immune system’s usual tolerance of WT1 antigen suggests the potential of its SynCon WT1 antigen to tackle any WT1-expressing cancer in humans, which include pancreatic, brain, lung, thyroid, breast, testicular, ovarian, and melanoma.

Dr J. Joseph Kim, Inovio's president and chief executive officer, said, "Our SynCon antigens’ ability to overcome the immune system’s inability to recognize tumor self-antigens is unique and powerful. While we systematically and synthetically mimic the body’s natural process of creating tumor neo-antigens, which possess differentiated but individualized genetic sequences that may then induce an immune response, our ability to break tolerance with broadly prevalent antigens makes our approach more universal across populations. We are pleased to again show such results with an important cancer antigen – in this case, WT1 – and continue to add to our array of promising universal cancer antigens in Inovio’s product development strategy.

“To expand on our capabilities and strategy, the power of our differentiated antigens dovetails with our ability to turn cancer tumors from cold to hot by creating a significant presence of antigen-specific CD8+ killer T cells in a target lesion or tumor microenvironment, which we have shown via biopsies in two human studies. These are critical outcomes: although checkpoint inhibitors have raised the bar for treating cancers by neutralizing cancer cells’ inherent ability to switch off T cells that are hunting them, they do not actually generate the antigen-specific killer T cells required to destroy cancer cells. We believe our DNA-based SynCon immunotherapies are the missing link to take immuno-oncology to the next level.”

“With these accomplishments we could not be more enthusiastic about two immuno-oncology combination human studies to start in the first half of 2017. MedImmune will combine INO-3112 (also named MEDI0457) with their checkpoint inhibitor molecule in an upcoming clinical study. Inovio is also planning to conduct a combination study for INO-5401 with a checkpoint inhibitor in cancer patients. We previously noted that INO-5401 will include our hTERT SynCon antigen. I am pleased to say that INO-5401 will also include our SynCon antigens for WT1 and PSMA. We believe this product has the potential to be a very powerful universal cancer immunotherapy in combination with different checkpoint inhibitors.”