Engager T cell: A Simple Solution for Off-the-shelf T Cell Therapy for Cancer

Project Summary Autologous chimeric antigen receptor T (CAR T) cell therapy poses logistical and economical challenges despite curative potential. Donor-derived allogeneic off-the-shelf (OTS) cell therapies have become the holy grail of cell therapy as they can be mass-produced and are immediately available to cancer patients at affordable prices. However, current OTS strategies involve

complex manufacturing process and gene-editing with safety concerns such as carcinogenesis risk. Non-αβ T cell-based OTS strategies such as NK cells have potency concerns as they lack persistence and durability. Immunebro Therapeutics is developing a simple and novel platform technology to produce donor-derived αβ T cell-based OTS products named

engager T cells. Engager T cells are engineered donor T cells expressing and secreting an artificial modular protein that can 1) target donor T cells to a desired cancer target and 2) curb donor T cells' alloreactivity of inducing graft versus host disease (GvHD). Donor derived engager T cell is a simple solution for OTS T cell therapy with no need of gene editing. It involves

a well-established and much less complex manufacturing process in comparison to gene edited OTS CAR T cells currently in development. Preliminary data have demonstrated that donor derived CD19-targeting engager T cells have low xenogeneic GvHD risk and are efficacious in treating xenograft CD19+ leukemia mouse model. However, in a side-by-side comparison,

CD19 engager T cells are inferior to 2nd gen CD19 CAR T cells on efficacy due to the lack of co- stimulation. As efficacy is crucial for regulatory and commercial success of any drug candidates, this proposal is aiming at developing enhanced CD19 engager T cells with low GvHD risk. Specific Aim 1 is to develop enhanced CD19 engager T cells and assess transgene expression

and secretion. Three strategies will be used to produce enhance CD19 engager T cells by 1) co- expressing a CD19 CAR; 2) co-expressing T cell promoting cytokine IL15; 3) co-expressing costimulatory factor 4-1BBL and CD80. Specific Aim 2 is to demonstrate one or more of the enhanced CD19 engager T cells have low xenogeneic GvHD risk in immune deficient mice.

Specific Aim 3 is to demonstrate one or more of enhanced CD19 engager T cells have comparable efficacy to 2nd gen CD19 CAR T cells. By the end of Phase 1 work, Immunebro will have enhanced CD19 engager T cells as the first product prototype built from the simple and novel OTS platform. This platform can be used to build a rich pipeline of OTS T cells

targeting a variety of cancers with less complex manufacturing, safer profile, and comparable or better efficacy than gene edited OTS CAR T cells currently in development.