Melanoma is a life-threatening form of skin cancer that is more common in Sunbelt areas such as Los Angeles. UCLA and California Institute of Technology have discovered a promising new treatment for the cancer for the cancer that has drastically shrunk the tumors in clinical trials. The breakthrough was published online ahead of print on March 21 in the journal Cancer Discovery.
UCLA and California Institute of Technology scientists from the UCLA Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research (Broad Stem Cell Research Center (BSCRC)) and the Jonsson Comprehensive Cancer Center (JCCC) were led by James Heath, PhD. Dr. Heath is a member of both centers; he is a professor of molecular & medical pharmacology at UCLA and professor of chemistry at Caltech. Dr. Heat’s team used human immune cells (T cells) taken from a patient with melanoma; the cells were then 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; however, the positive effects were often short-lived. The investigators demonstrated that the function of T cells engineered to kill melanoma change over time after the modified T cells are returned to patients. To combat this problem, 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 investigators found that the genetically engineered T cells initially had a high tumor-killing effect; however, the effect faded within two to three weeks. Dr. Heath noted, “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. 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 whereby 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). Dr. Heath noted, “Our results have led us to possible ways to improve the T cell therapy to extend its positive effect. 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 Dr. Heath’s key collaborators, Dr. Antoni Ribas, UCLA professor of medicine and also a member of the BSCRC and JCCC explained, “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.” first author Dr. Chao Ma noted, “This study points to the value of these single cell functional analyses for probing the successes and failures of a sophisticated immunotherapy. I am excited to see its use as a monitoring tool to understand a spectrum of other cellular immunotherapies in the near future.”