Our Platform: A novel neoantigen-based therapeutic cancer vaccine

mTEV is a first-in-class immunotherapy platform, which is designed to block the principal  immunosuppressant microRNA (i.e. the key inhibitor) that prevents the natural expression of both CD28 / CD80 costimulatory proteins on the surfaces of T cells and antigen presenting cells (APC), respectively.

By delivering a broad pool of immunogenic tumor-cell derived neoantigens via nano-particle-sized extracellular vesicles, mTEVs effectively resuscitates healthy immune cell function allowing these cells to release cytokines (i.e. interleukin-2), permitting T cell differentiation, expansion, and migration into the tumor micorenvironment and transform into competent effector T cells (i.e. cytotoxic T cells) that kill cancer cells. 

Once the T cell are reactivated by the mTEVs, they will naturally attempt to control the strong stimulation by putting on the "breaks" via the expression of immunosuppressant Programmed Cell Death Protein-1 (PD-1) on the cell's surface (i.e. the checkpoint protein).  Upon the activation of the T cells checkpoint,  sequential administering of an anti-PD1 antibody (i.e. checkpoint inhibitor), blocks the engagement with its corresponding ligand, PDL-1, on the antigen presenting cells (APC) allowing for sustained activation and long term therapeutic benefit.

Below are some of the ways mTEVs can be deployed as a therapeutic: 

1. In late stage cancers, mTEVs in combination with checkpoint inhibitors functions as a therapeutic cancer vaccine by helping restore the T cell anti-tumor immune response through the delivery of a broad spectrum of immunogenic neoantigens (RNA, DNA and peptides).
2. In early stages of cancers, mTEV can function as a prophylactic cancer vaccine by stimulating long-term memory cells by activating acquired immunity. Thus, mTEVs act as effective immune prevention in minimal residual disease (MRD) patients.

The Problem: TEV carry immune suppressive factors that down-regulate CD28/ CD80 expression rendering checkpoint inhibitor ineffective 

Summary:

1. As tumor transforms from early- to late-stage cancer, hypoxia (i.e. a low oxygen condition) within the tumor microenvironment (TME) drives up the production and release of TEV (tumor-derived extracellular vesicles) into the extracellular space. These TEVs contain few immune stimulating neo-antigens.  In the most prevalent cancer patient population (MSS sub-type, 85%) a low number of surface antigens are expressed.

2. TEVs carry many immune suppressive miRNAs (a non-coding RNA), which are taken up by both dendritic cells (a major antigen presenting cell) and T cells.

3. A low number of expressed surface antigens suppresses T-cell priming, which is the initial trigger of internal cell signaling.

4. The immunosuppressive miRNAs in TEVs decrease the expression of key immune costimulatory proteins CD28 and CD80 in both T-cell and dendritic cells, respectively. This causes a weak/no costimulation, which is the essential secondary signaling trigger.

5. The combined poor T cell priming and weak T cell costimulation (i.e. T cell activation) blocks PD1 and PDL-1 expression on T cell and dendritic cells, respectively.  Checkpoint inhibitor antibodies administered to cancer patient cannot bind to PD1 or PDL-1 receptors, thus prevent a sustained T cell response and prevent their therapeutic benefit.

Summary:

1. mTEV are derived from cGMP cancer cell line(s). 

2. mTEVs are prepared by harvesting TEV and depleting them of immunosuppressant (miRNA-) while immune stimulating neoantigens (Ag+) are kept.

3. Upon internalization of the mTEV into the dendritic cells the neo-antigens are prepared for presentation via the MHC I complex onto the surface, which then binds to the corresponding T-cell Receptor (TCR). This triggers the initial T cell signaling also known as priming. 

4. Systemic administration of mTEV restores the expression of CD28 and CD80 on T-cells and dendritic cell surfaces, respectively.

5. High affinity binding of CD28 with CD80 (or CD86 with lower affinity) is required for a strong T-cell costimulation.  This triggers the secondary T cell signaling within the cell.

6. A primed and costimulated T-cell allows for high expression of key checkpoint inhibitor proteins (i.e. PD1 and PDL-1) on their corresponding cell surfaces.

7. The sequential administration of checkpoint inhibitor antibody allows a sustained anti-tumor immune response and inhibition of PD-1 and PDL-1 pathways.