Introduction of ComPACTCombination Pan-Antigen Cytotoxic Therapy  June 15, 2015 

 ImPACT Immunotherapy PlatformSpecifically Activates Pan-Antigen CD8+ T-Cells to Kill Tumor Cells  *  Intradermal InjectedImPACT Cells   ①  ImPACT cells secrete Gp96-Ig chaperone + tumor antigens (TAA)  ②  Dual antigen carrier & adjuvant activates Dendritic Cells  ③  Selectively activate CD8+ T-Cells  ④  CD8+ T-cellscirculate & eliminate tumor cells  ⑤ 

 Combination Immunotherapy Design Objectives  We all know that combination immunotherapy will provide superior clinical benefit than any single checkpoint, co-stimulator or vaccine can as monotherapy. How can we implement combination therapy:1. In the simplest and most efficacious way2. With the lowest possible toxicity3. With a simpler cost structure than 1+1+n mAbs/biologics  * 

 ComPACT DesignCombination Pan-Antigen Cytotoxic Therapy  * 

 gp96-Ig  Fc-OX40L  * 

 Construct Prioritization Scheme  There are multiple co-stimulatory receptors that may synergize with gp96-Ig based vaccines. Feasibility was performed by examining the immune response in animals treated with vaccine in combination with agonist antibodies  * 

 ComPACT Characterization  * 

 Feasibility Question  Antibodies rapidly distribute systemically, and produce systemic effectsWith ComPACT, Fc-OX40L is local just in the injection siteCan high enough concentrations be achieved to have an effect?  * 

 ComPACT Enhances CD8 Proliferation   Following primary immunization, locally secreted Fc-OX40L (in ComPACT) produces superior antigen-specific CD8+ T cell expansion than vaccines combined with OX40 antibodies  * 

 Kinetics of CD8+ T Cell Response  * 

 ComPACT Increases Specificity  ComPACT leads to increased antigen-specific CD8 cellsOX40 antibodies also lead to non-specific increases in CD4 cells and T regulatory cells  * 

 ComPACT Increases CD8+ Memory  The increase in antigen-specific CD8 cells seen with ComPACT is associated with an increase in memory precursor cells (CD127+KLRG1-), not seen with OX40 antibodies  * 

 ComPACT Increases Ag-Specific CD8+ Activation  OX40 antibodies lead to increased activation of both Ag-specific and non-specific CD8, while ComPACT activates only Ag-specific CD8 cells  * 

 Therapeutic Tumor Immunity  ComPACT leads to improved survival in a mouse colon cancer model, similar to OX40 antibody combined with vaccine  * 

 Summary  Incorporation of OX40L-Fc into a gp96-Ig vaccine vector is feasibleThis construct leads to enhanced antigen-specific immunity at both priming and boostingThe immune-stimulatory effect of ComPACT is superior to separate administration of vaccine and OX40 agonist antibodyThis is due to enhanced specificity, with OX40 antibodies causing systemic cytokine release and off-target proliferationHeat plans to file its first IND for the ComPACT platform in 2H 2016  * 

 *  ComPACT Video