Feasibility study of a novel NK and CD8 T cells stimulating agent

Abstract Cell-based therapies, whether NK or T cell-based therapies, have demonstrated great efficacy in treating hematological malignancies in the clinic. To date, there are at least seven CAR-T based therapies, including four CD19CAR-T and two BCMA CAR-T, have been approved for treating hematological malignancies. These successes brough excitement and promises to use cell-based therapy treating solid tumors. Currently, there are over 300 CD8T-cell based therapy and over 150 NK cell-based for solid tumors in clinical trials, but the outcomes from completed studies are disappointing. The foremost common challenges of T and NK cell-based therapy for solid tumors is persistence and sustained function of infused cells in solid tumors. Two factors could contribute to this problem: 1) solid immune suppressive tumor microenvironment; 2) over-stimulation of NK or CD8 T cells during ex vivo expansion to drive cells to a terminal differentiation status. To circumvent these challenges, we have discovered a new complex molecule composed of a soluble peptide and its conformational binding agent that can be used as an additive during NK and antigen-specific CD8 T cell expansion to enable their superior efficacy in treating solid tumors. We understood that complex programming can induce polyfunctional heterogenic subpopulations with enriched cell pool of TCF1+ stemlike NK and CD8 T cells, in addition to upregulating the expression of key effector molecules in respective effector cell subsets. However, the complex could bring two potential challenges for IND-enabling studies and clinical use: i) the batch-to-batch consistency in the complex formation; ii) a significantly higher cost in CMC (chemistry, manufacturing, and controls) of producing two GMP-grade materials than a single CMC-grade reagent. These challenges will subsequently bring difficulty in technology commercialization or Pharma partnership. To circumvent these challenges, CanCure has designed and generated a panel of fusion proteins composed of the peptide and the binding agent. The goal/milestone of this SBIR Phase I application is to screen this panel of fusion proteins for the best candidate to move forward or make a GO vs. NO-GO decision with the fusion product and inform future plans. The screening will be based on biological activity and pilot de-risking biochemical/biophysical characterizations for the developability.