Neoantigens On

Heat Shock Proteins

There are many different mutations that might occur which cause a normal cell to transform into a tumor cell. These mutations are not the same within each tumor type, in fact, mutation type and load may differ between cells of the same tumor in the same person. These mutated proteins are processed and chaperoned by molecules known as heat shock proteins (HSP). The HSP within a tumor cell collectively chaperone the complete repertoire of tumor antigens within a tumor cell, known as “neoantigens”.   When a tumor cell is killed in a manner that causes the internal contents to be released into the microenvironment, specialized cells called dendritic cells (DC) sense the pathological cell death emergency due to the release of ‘danger signals’ and rush to the site. Once at the site, the DC engulf the HSP and process their chaperoned neoantigens. The DC mature into either DC2 (produce IL-10) or DC1 (to produce IL-12) and traffic to the lymph node. DC1 activate a cellular immune response, while DC2 will suppress a cellular immune response and promote a humoral (antibody) response.

DC1 in the lymph node will educate and activate CTL.  The activated and expanded CTL traffic to the tumor and encounter the neoantigens displayed on the tumor MHC I that they were educated to attack.  Upon recognition of the cognate antigen on the MHC I and after simultaneously receiving a co-stimulatory second signal, the CTL will initiate the kill program.

Our Mirror Effect® cancer vaccine protocols stimulate a cellular immune response that begins with an innate killing of tumor cells that causes release of internal heat shock protein-chaperoned tumor neoantigens that are processed by dendritic cells, which in the context of ‘danger’ mature and traffic to lymph nodes to educate and expand a tumor-specific killer T-cells response.

In theory, a therapeutic cancer vaccine containing neoantigen and an adjuvant to support the correct processing by dendritic cells can program specific immunity against tumors or viral infected cells while sparing normal cells. Upon elimination of the diseased cells, the immune system will retain ‘memory’ of the tumor or virus to protect against recurrent disease and metastasis.

However, current cancer vaccines (including peptide/protein vaccines with or without genetically encoded vectors; whole cell or cell lysate vaccines; and ex-vivo dendritic cell vaccines pulsed with disease antigens), have not translated into successful therapies in the clinic. 

The current cancer vaccine approach to therapy is based on the notion that the immune system could possibly mount a rejection strength response against TAA expressed on tumor cells. However, due to the low immunogenicity of TAAs, downregulation of MHC I molecules, the lack of adequate costimulatory molecule expression, secretion of immunoinhibitory cytokines, and other immunosuppressive and immunoavoidance mechanisms of tumors., such expectations are rarely fulfilled

The Mirror Effect® platform technology reverse engineers known immune mechanisms that are proven capable of eliciting an in-situ vaccination effect. The StimVax® protocol is reverse engineered from the GVT effect of Mini-Transplant, where a natural in-situ vaccination occurs as part of the mechanism. In order to enhance this effect, we developed AlloVax® and CryoVax® which are reverse engineered from the immune mechanism called the “abscopal effect”.