Generating high avidity T-cell responses for more effective immunotherapy.
Cancer vaccines represent a highly attractive approach to cancer therapy. In contrast to current treatments such as chemotherapy and radiotherapy, small non-toxic doses of a vaccine may be administered to a patient to stimulate an immune response. It is generally accepted that to be effective against cancer, a vaccine needs to target dendritic cells to stimulate both parts of the cellular immune system; the helper cell system (known as the CD4-mediated response) which stimulates inflammation at the tumour site; and the cytotoxic T-lymphocyte or CTL response (known as the CD8-mediated response) in which cells of the immune system are primed to recognise and kill specific cells.
A limitation of many cancer vaccines currently in development is that they cannot specifically target dendritic cells in vivo. Several groups have demonstrated successful vaccination by growing dendritic cells ex vivo, pulsing them with tumour antigens and re-infusing them. However, this procedure is patient specific, time consuming and expensive.
Scancell has developed its breakthrough patent protected DNA ImmunoBody® technology to overcome the present limitations of cancer vaccines.
An ImmunoBody® is a DNA plasmid that encodes a human antibody or fusion protein engineered to express helper cell and CTL epitopes from tumour antigens over-expressed by cancer cells. Antibodies are ideal vectors for carrying T cell epitopes from tumour antigens as they have long half-lives and can effectively target dendritic cells via their Fc receptors, allowing efficient stimulation of both helper and CTL responses.
Unlike current vaccine approaches that rely on a single activation mechanism, ImmunoBody® vaccines activate dendritic cells through two distinctly different and complementary mechanisms that maximize T cell activation and avidity: direct- and indirect/cross-presentation.
Dual Mechanism of Action of ImmunoBody® vaccines
(a) Direct presentation: ImmunoBody® DNA targets antigen-presenting cells (APCs) directly via transfection. The DNA is transcribed, translated and the antibody processed. Tumour-specific T cell epitopes are presented via MHC Class I and II molecules to T cells.
(b) Cross presentation: ImmunoBody®DNA transfects other (non-APC) cells, which then secrete the antibody protein which targets APCs via the high affinity Fc receptor.
(c) Dual Mechanism of Action: The combination of direct- and cross-presentation by ImmunoBody®results in amplification of the immune response, inducing high frequency, high avidity T cells that have a potent anti-tumour effect.
As seen above, the ImmunoBody® targets APCs directly via DNA transfection (direct presentation) and by transfecting other cells which then secrete the antibody protein and targets APCs via their high affinity receptor (cross-presentation). The ImmunoBody® antibody is processed and the tumour-specific T cell peptide epitopes are presented via MHC Class I and II molecules to T cells.
The key to the effectiveness of the ImmunoBody® vaccine is the generation of high avidity CD4+ and CD8+ T cell responses. T cell avidity is a critical vaccine parameter that is the combination of multiple signals and results in T cells with increased sensitivity and greater cytolytic activity.
By changing the expressed epitopes, the technology can be adapted to provide the basis for treating any tumour type and may also be of potential utility in the development of vaccines against hepatitis, HIV and other chronic infectious diseases.
The “checkpoint pathway” plays a key role in modulating the immune system. Studies involving the inhibitors of CTLA-4 and PD‐1 have demonstrated promising results in pre-clinical and clinical studies where they alter the tumour microenvironment, making the local environment more permissible for T cells to proliferate and to infiltrate into tumours.
Combining anti‐PD1 therapy with the SCIB-1 ImmunoBody® vaccine significantly enhances survival in a mouse tumour models resulting in 85% survival of immunized mice.
Anti-PD1 antibody and SCIB-1 synergise to eradicate tumours in mice with established tumours.
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