Immunotherapy enlists more than just T cells to treat leukemia
April 10, 2013 | by Shawn Le
Most cancer immunotherapies are designed to take a patient’s own T cells, a type of white blood cell, and genetically engineer them to target, and destroy, cancer cells. But T cells are only one part of the immune response, and eliciting an effective response from an immune system already weakened by cancer can be difficult – especially in leukemia, in which defective white blood cells are the problem.
City of Hope researchers may have found a way around this hurdle.
They’ve developed a gene therapy that both stimulates an immune response against cancer cells and uses short-interfering RNA to shut off the STAT3 gene, which is crucial in helping many cancers grow. Shutting down this gene enhances the immune system’s response against the cancer cells and discourages growth of the tumor.
Marcin Kortylewski, Ph.D., assistant professor in City of Hope’s Department of Cancer Immunotherapeutics and Tumor Immunology, recently led an investigation of the new gene therapy, known as CpG-STAT3 siRNA, in treating acute myeloid leukemia. Results from his study in mice were presented today at the annual meeting of the American Association for Cancer Research in Washington, D.C. The new therapy combines three distinct anti-cancer agents and targets into one. The researchers began with engineered strands of DNA, known as CpG oligonucleotides, that stimulate an immune response. These strands were attached to molecules that honed in on a gene active in acute myeloid leukemias and other cancers. Then the researchers used short-interfering RNA to shut off the STAT3 gene. In the study, shutting down the STAT3 gene weakened the leukemia’s defenses and discouraged growth of the tumor, allowing the newly stimulated immune system to wipe out the cancer cells.
All together, the CpG-STAT3 siRNA drug kick-starts an immune response specifically against leukemia cells and thwarts a critical gene that keeps the cancer cells alive. Researchers say the treatment could be given alone – or alongside a T cell-based immunotherapy. Together, the new therapy and a T cell-based therapy could attack multiple weaknesses in the blood cancers. Already, combination therapies – such as drug cocktails for HIV – are an emerging area of interest for cancer researchers.
The researchers wrote in the study abstract: “Our results demonstrated that intravenous injections of CpG-STAT3 siRNA (5 mg/kg) … into mice with established leukemia (1-2 weeks after challenge) resulted in elimination of leukemic cells from bone marrow, spleen, lymph nodes and blood.”
They also found that when mice were treated with CpG-STAT3 siRNA prior to leukemia being introduced into their system, it prevented the mice from developing leukemia. The authors note that this protection was dependent on having a functioning immune system at the outset, “as CpG-STAT3 siRNA failed to eliminate leukemia in immunodeficient mice.”
The researchers are continuing the development of the gene therapy and investigating its use in other cancers.
The members of the City of Hope research team included: Stephen Forman, M.D., the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation; Ravi Bhatia, M.D., director, Ya-Huei Kuo, Ph.D., assistant professor, Hongjun Liu, Ph.D., research associate, and Cedric Dos Santos, Ph.D., research fellow, in the Division of Hematopoietic Stem Cell and Leukemia Research; research fellows Sakib Hossain, Ph.D., and Qifang Zhang, Ph.D., in the Department of Cancer Immunotherapeutics and Tumor Immunology; and Piotr Swiderski, Ph.D., research professor, and Claudia Kowolik, Ph.D., assistant research professor, in the Department of Molecular Medicine.
The study was supported by the National Cancer Institute under the grant number R01CA155367.