UCLA and California Institute of Technology scientists from the UCLA Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research and the Jonsson Comprehensive Cancer Center (JCCC) led by James Heath, member of both centers, professor of molecular and medical pharmacology at UCLA and professor of chemistry at Caltech, have made an important discovery to improve a promising treatment for melanoma, an often deadly form of skin cancer. The breakthrough was published in April in Cancer Discovery.
The treatment uses human immune cells (T cells) taken from a patient with melanoma that are genetically modified in the laboratory to specifically attack that patient’s tumors when given back to the patient. In early clinical trials this treatment has shrunk tumors dramatically in many patients, but the positive effects were often short-lived.
Heath and his colleagues demonstrated that the function of T cells engineered to kill melanoma change over time after the modified T cells are returned to patients. The researchers used newly developed nanotechnology chips (multidimensional and multiplexed immune monitoring assays) that allowed them to examine the function of single engineered T cells with high resolution.
The T cells studied were from blood samples taken at different time points from patients who were given this therapy, each of whom had a different level of response to the treatment. The scientists found that the genetically engineered T cells initially had a high tumor-killing effect but the effect faded within two to three weeks.
“The engineered T cells did not recover their tumor-killing effect, but after one month another group of T cells appeared that did have tumor-killing effects for another two months," said Heath. "Those were not the genetically engineered T cells and appeared to be a byproduct of a process called antigen spreading by the original engineered cells. After 90 days those cells lost their tumor-killing ability as well.”
Antigen spreading is a process by which a T cell that has been engineered to attack a particular tumor expands the immune response to other T cells able to attack the same tumor focused on different antigens (what the immune system uses to recognize and attack tumors).
“Our results have led us to possible ways to improve the T cell therapy to extend its positive effect,” Heath confirmed. “We need to incorporate strategies that maintain the functional properties of the engineered T cells used for therapy. This might include modifying how we grow the T cells in the laboratory to make their tumor-killing effect last longer, or make them resistant to the effects of the patient’s T cells during recovery from conditioning, and possibly increase the antigen spreading of antitumor T cells.”
One of Heath’s key collaborators, Dr. Antoni Ribas, UCLA professor of medicine and also a member of the BSCRC and JCCC, added, “One of the possible approaches to resolve the problem identified by this study is to use engineered blood stem cells instead of the peripheral blood used in the original trials with this therapy with the hope that the engineered blood stem cells will provide a renewable source of engineered T cells.” This approach is being moved forward into the clinic with clinical trials expected to open in two years.
“This study points to the value of these single cell functional analyses for probing the successes and failures of a sophisticated immunotherapy,” said the study’s first author Dr. Chao Ma. “I am excited to see its use as a monitoring tool to understand a spectrum of other cellular immunotherapies in the near future.”
This research was funded by the National Cancer Institute, the Jean Perkins Foundation, The California Institute for Regenerative Medicine, the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, The Seaver Institute, the PhaseOne Foundation, the Garcia-Corsini Family Fund, the Caltech/UCLA Joint Center for Translational Medicine, the Melanoma Research Alliance, Rosen Fellowship, and the Jonsson Comprehensive Cancer Center.
