Chimeric antigen receptor (CAR) T-cell therapy has had excellent results in late-stage leukemia and varying degrees of success in some other hematologic cancers, but thus far, solid tumors have not responded to this therapy.
CAR T-cell therapy entails extracting a patient’s own T-cells and genetically re-engineering them ex vivo to express an antigen on cancer cells (ie, the manufacturing process). Then, the CAR T-cell product is reinfused back into the patient, where it hopefully undergoes expansion.
The CAR T-cell drug is not always successfully manufactured in all patients with leukemia or in patients with solid tumors. The problem with unsuccessful CAR T-cell drug manufacturing appears to be the poor quality of T-cells harvested from some patients, according to an abstract presented at the 2018 American Association for Cancer Research (AACR) annual meeting.
“There are a number of challenges to making the CAR T-cell product. Manufacturing techniques vary at different centers. We found that sometimes T-cells didn’t work at all in some cases of leukemia, and there were a number of patients we could not treat because the T-cells died. When we went back and looked, we found a difference in the starting material [ie, the T-cells],” explained lead investigator David M. Barrett, MD, PhD, Assistant Professor of Pediatrics, Children’s Hospital of Philadelphia, PA, who presented the results.
Studies by Dr Barrett’s group showed that metabolic pathways were implicated in T-cell quality. T-cells that used glutamine and fatty acid pathways as fuel sources had excellent CAR T-cell potential, whereas those that depended on glycolysis, another fuel source, were poorly equipped to undergo the CAR T-cell manufacturing process.
Preliminary studies by Dr Barrett’s group suggest that it is possible to manipulate T-cells so that they use fatty acids for fuel rather than glycolysis, and studies are ongoing to see if this will improve the CAR T-cell manufacturing process.
As Dr Barrett explained, “We find that T-cells with highly activated glycolysis pathways ended up performing worse when we tried to make them into CAR T-cells. Substituting and supplementing heavily with fatty acids did seem to improve this a little, but it’s not a home run. I think we will need to attack this from multiple pathways. We are working on those experiments now.”
The data he presented at the AACR meeting were based on analysis of peripheral blood samples from 157 pediatric patients with hematologic cancers, such as acute lymphocytic leukemia (ALL) and solid tumors, which was performed at diagnosis and after each cycle of chemotherapy.
“More than 90% of patients with ALL had high-quality T-cells, and more than 50% of those with Wilms’ tumor had good CAR T-cell potential at diagnosis. Lymphomas and solid tumors had poor CAR-T potential. We have not yet developed a CAR-T product for Wilms’ tumor,” Dr Barrett noted.
The researchers looked at CAR T-cell potential after chemotherapy and found that cumulative chemotherapy led to a decline in CAR T-cell potential for all tumor types, suggesting that adjusting chemotherapy regimens could improve T-cell quality. Certain types of chemotherapy (ie, cyclophosphamide- and doxorubicin-containing regimens) were especially harmful to CAR T-cell potential.
“We have gotten CAR T-cells to work for leukemia, but we have not yet been very successful in solid tumors.…Our data suggest that poor T-cell starting material may be a key first problem. The T-cells from solid-tumor patients may need different manufacturing protocols to be successful,” Dr Barrett said.
Other metabolic pathways may be implicated in poor-quality T-cells. Dr Barrett considers this research a first step in elucidating which pathways may be implicated and how to reverse them.
“This study is a great example of the intersection between immunotherapy and precision medicine,” said AACR President Michael Caligiuri, MD, MA, President, City of Hope National Medical Center, Duarte, CA, who moderated a premeeting webinar where these data were presented.
“Gene expression identifies the energy pathways that T-cells use. Some of these T-cells seem to be exhausted,” Dr Caligiuri said. “The energy pathways seem to predict who will do well and who won’t. We can try to develop alternate chemotherapies that don’t exhaust T-cells and also try to reverse the metabolic pathways that seem to be detrimental.”