This clinical translational proposal aimed to assess the therapeutic potential of genetically targeted T cells in the treatment of leukemia and lymphoma. The introduction of genes that code for tumor-specific receptors into T lymphocytes, which are cells of the immune system that mediate tumor elimination, was a novel approach to cancer therapy.
Dr. Sadelain demonstrated that human peripheral blood T cells could be effectively redirected to recognize the CO19 antigen and eradicate established, systemic human B cell tumors borne by immunodeficient mice, This was the first publication showing that genetically modified human T cells can induce durable remissions in an in vivo setting.
Importantly, he found that T cell stimulation with the cytokine lnterleukln-15, but not the widely used lnterteukin-2, is critical for sustaining the therapeutic activity of infused CO19-spedflc T cells. Having examined the nature of the signals required by the T cells for their own survival and sustained functionality, Dr. Sadelain designed improved antigen receptors that provide both activating and co-stimulatory signals to the tumor-targeted T cell.
The specific alms of the 2004 application included:
- Demonstrating the therapeutic efficacy of leukemia and lymphoma patients’ cos+ T lymphocytes transduced with the 19/28z receptor In tumor-bearing mice
- Establishing clinical conditions for patient T cell purification, transduction and expansion, for review by the FDA
- Investigating, in a phase I clinical trial In patients with relapsed B cell leukemias, the safety, persistence and therapeutic efficacy of autologous IL15-actlvated CDS+ T cells that express 19/2Sz