Development of a novel CAR T cell immunotherapy for cancer

Patient-derived T cells are now being genetically engineered to attack cancer cells more aggressively and specifically. While remarkable improvements have been achieved in leukemia patient survival, current chimeric antigen receptor (CAR) T cell therapies remain encumbered by limitations that prevent their broader use in oncology, including:

1. poor efficacy in solid tumors,

2. a tendency to induce a cytokine storm with potentially lethal consequences,

3. an inability to terminate cytotoxic activity after all cancer has been eradicated,

4. a failure to kill cancer cells that downregulate the targeted tumor antigen, and

5. a tendency to become exhausted and quit killing tumor cells before all diseased tissue has been destroyed.

We have developed a new universal CAR T cell strategy that solves each of these problems by exploiting a low molecular weight bispecific adapter that must bridge between the CAR T cell and cancer cell to initiate cancer killing. Using the fluorescein end of this adapter to bind an scFv on the CAR T cell and the "tumor-specific ligand" end of the adapter to bind a receptor on the cancer cell, we have shown that the rate and specificity of cancer cell killing can be sensitively controlled by adjusting the dosing frequency, dosing concentration and tumor specificity of the bispecific adapter. A cocktail of bispecific adapters that will enable our universal anti-fluorescein CAR T cell to engage any cancer cell regardless of tumor antigen expression has also been developed. Moreover, methods to rejuvenate exhausted CAR T cells have been identified and implemented in-vivo (see representative publications).