Inovio Pharmaceuticals, Inc. has developed a new DNA-based cytokine immune activator, interleukin -33 (IL-33), that in combination with optimized DNA vaccines delivered by electroporation increased the potency and efficacy of the therapeutic response to the DNA vaccines in a preclinical study. The findings of this study reveal that IL-33 could be an effective immune booster when used with Inovio's products to generate therapeutic immune responses against cancers and chronic viral infections in humans. Inovio has developed a portfolio of patent-protected IL-33 and other immune activators to form combination therapies with its DNA vaccines and immunotherapies with the goal of achieving the greatest possible efficacy against targeted diseases.
A therapeutic vaccine study treating HPV-16 based cancer-bearing mice demonstrated rapid and complete tumour regression after treatment with Inovio's HPV16 (human papillomavirus type 16) vaccine in combination with DNA-based IL-33. Both were delivered using Inovio's Cellectra electroporation device. Previous studies have shown that the HPV 16 DNA vaccine alone was able to prevent tumour growth in mice and delay progression or cure mice of tumours. Addition of the IL-33 immune activator resulted in a more rapid and complete regression of established tumors in the mouse model.
The adjuvant/vaccine combination induced potent CD4 and CD8 T cells. Notably, inclusion of the DNA-based IL-33 immune activator significantly increased the magnitude of vaccine-specific CD8 T cell responses. Prior research has demonstrated that CD4 and CD8 T cells are both important in cellular immune responses; however, CD8 T-cells, or killer T cells, are considered especially integral to fighting cancers and chronic infectious diseases.
The peak vaccine-induced expansion of CD8 T cells at 14 days after vaccination correlated with complete tumour regression. This desirable outcome points to the important role IL-33 and other immune activators may play in combination with Inovio's cancer treatments in development.
The results of this study, conducted by Inovio scientists and collaborators, are detailed in a paper entitled: "Alarmin IL-33 acts as potent immunoadjuvant enhancing antigen-specific cell-mediated immunity and inducing potent anti-tumour immunity," published in Cancer Research.
Dr. J. Joseph Kim, Inovio's President and CEO, said: "To create the most effective arsenal of therapeutic products against cancer and infectious diseases, we are researching combination therapies using our DNA immunotherapies with checkpoint inhibitors and immune activators to optimize their therapeutic effects. While we have already reported best-in-class T cell responses from two DNA vaccines in human trials, this published study shows for the first time how DNA-based IL-33 can boost antigen-specific immune responses generated by our DNA immunotherapies and vaccines.
"We are developing multiple DNA plasmid based cytokine and chemokine genes as immune activators and I am proud to say that Inovio has more of these immune activators in its pipeline than anyone else in the world. We have initiated human studies using other DNA-based cytokines and look forward to moving IL-33 into clinical trials in combination with our DNA vaccines," Dr. Kim added.
Immune activators can play a vital role in augmenting antigen-specific immune responses such as those generated by Inovio's DNA vaccines. Inovio's portfolio of patent-protected immune boosters vary in their ability to enhance (activate) therapeutic T cells or preventive antibodies, modulate the type of immune responses produced by the vaccine, impact durability of immune responses, and drive immune responses to sites of infection, e.g. mucosal surfaces. Different immune activators can therefore play unique roles in achieving desired immune responses generated by DNA immunotherapies and vaccines. Moreover, while some protein based cytokines and chemokines have been shown to have severe toxicity, likely due to their dosing and systemic delivery, Inovio's DNA-based cytokines and chemokines are delivered together with the vaccines as DNA plasmids and are produced locally at the injection site to drive the production of immune responses without systemic effects.
Inovio has deployed two different DNA immune activators in human studies with electroporation delivery. Inovio previously reported that in a published clinical study its DNA-based IL-12 immune activator enhanced antigen-specific T cell immune responses from its HIV DNA vaccine, Pennvax. In that study, 89% of the subjects who received IL-12 DNA together with the Pennvax DNA vaccine delivered with electroporation produced a vaccine specific CD4+ or CD8+ T cell response compared to 67% who received the DNA vaccine alone without the IL-12 DNA. To exploit these boosting properties, Inovio plans to test its cancer immunotherapy products in combination with DNA IL-12 in upcoming cancer trials. Additionally, a second cytokine based DNA immune activator, Inovio's DNA-based IL-28, in combination with its multi-antigen hepatitis C DNA vaccine, INO-8000, is being tested in a phase I study in HCV patients. Inovio has in its portfolio over ten (10) important cytokine and chemokine genes which have shown in preclinical studies to boost either T cell or antibody-based immune responses to the vaccines and therapies.
Inovio is revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases. Its SynCon vaccines, in combination with its proprietary electroporation delivery, are generating best-in-class immune responses, with therapeutic T-cell responses exceeding other technologies in terms of magnitude, breadth, and response rate.