Researchers have developed a novel approach to genetically instruct human immune cells to recognize and kill cancer cells in a mouse model. The investigators plan to ultimately apply this strategy in a clinical trial setting for patients with a wide variety of cancers, although their initial work will be with certain forms of leukemias and lymphomas.
Scientists at Memorial Sloan-Kettering Cancer Center (MSKCC) genetically engineered an antigen receptor, introduced it into cultured human T cells, and infused the T cells in mice that bear widespread tumor cells. The modified T cells, now able to recognize the targeted antigen present on the tumor cells, eradicated the cancer.
The research, published in the journal Nature Medicine, represents the first time that adoptive immunotherapy with engineered human T cells has demonstrated in vivo efficacy in mice.
"Our findings represent a step forward in the field of adoptive T cell therapy," said senior author Michel Sadelain, MD, PhD, Head of the Gene Transfer and Gene Expression Laboratory and Co-Director of the Gene Transfer and Somatic Cell Engineering Laboratory at MSKCC. "Our studies aim to better understand the biological needs of T cells that are targeted to tumors."
Earlier experiments have shown that genetically modified human T cells could kill tumor cells in vitro, but the cells could not successfully carry out other immunological responses such as maintaining cell division, and would die prematurely when they were infused into the body of a mouse. In this study, researchers may have overcome some of these limitations by designing a method whereby human T cells, genetically altered to recognize certain blood cancers, multiply in such a manner that they retain the ability to eliminate human tumors in vivo in mice.
Investigators genetically instructed the T cells to target cells that express CD19, a protein found on the surface of normal and cancerous B cells, a type of white blood cell. B cell cancers include acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), and most non-Hodgkin's lymphomas.
"This unique methodology enables us to expand the number of specific T cells to clinically relevant numbers and extend their viability, thereby enhancing their therapeutic effectiveness and enabling them to eradicate disease, in this case a B cell tumor," said Dr. Sadelain.
The researchers also tested the genetically modified human T cells (or lymphocytes) in vivo. They established a mouse model in which human tumors are disseminated throughout the body and administered the T cells intravenously. In collaboration with nuclear medicine experts at MSKCC, the scientists used molecular imaging (Positron Emission Tomography or PET scanning) to map out exactly where the tumor cells were in the mice and to track the effectiveness of the therapy.
In addition, researchers were able to show that T cells obtained from patients with advanced CLL could be targeted in this manner to efficiently kill their own tumor cells in vitro.
"Collectively, these findings show that we have met many of the criteria necessary to conduct a clinical trial and test this approach in humans," said lead author Renier Brentjens, MD, PhD, an attending medical oncologist on the Leukemia Service at MSKCC and a member of Dr. Sadelain's laboratory.
"This field holds a lot of promise and we are currently investigating other genes to try to make T cells more robust in mounting immune responses against tumor cells," said Isabelle Rivière, PhD, Co-Director of the Gene Transfer and Somatic Cell Engineering Laboratory at MSKCC and a co-author of the study.
SOURCES:
Nature Medicine, March 2003
Memorial Sloan-Kettering Cancer Center (http://www.mskcc.org)
