PHILADELPHIA — Adding a genetically engineered “switch receptor” to second-generation CAR T cells blocked PD-1-mediated immune suppression and made the immunotherapy effective against solid tumors in preclinical models, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.
"Many cancers are still without optimal treatment options and are associated with great disease burden. This is especially true for what are called ‘solid tumors,’” said Edmund Moon, MD, assistant professor of medicine in the Division of Pulmonary, Allergy, and Critical Care at the Perelman School of Medicine at the University of Pennsylvania.
“Immunotherapy, which is really any strategy that stimulates the body’s own immune system to fight disease [e.g., cancer], has shown great promise,” he said, adding that CAR T-cell therapy, a type of investigational immunotherapy in which the T cells taken out of patients’ bodies are made to express an artificially made receptor, called a chimeric antigen receptor (CAR), and reintroduced into the patients’ bodies, has demonstrated success in blood cancers.
“There is a large effort to expand the use of CAR T cells to solid tumors,” Moon said. Many of the drawbacks with using CAR T cells to treat solid tumors are related to the much harsher tumor microenvironment (TME) that these T cells have to deal with in solid tumors as opposed to blood cancers, he explained.
“Our goal was to investigate ways in which CAR T cells can overcome one of the main defense mechanisms put up by the TME of solid tumors to shut down T cells—checkpoint inhibitory receptors (IRs). The specific IR we dealt with in this study was programmed death-1, or PD-1,” Moon said.
The FDA-approved therapeutics pembrolizumab and nivolumab target PD-1 present on T cells, and they prevent PD-1 from engaging PD-L1, present mainly on tumor cells, and suppress the immune-inhibiting signals. Though inhibitors of IRs yield promising responses against melanoma, lung cancer, and some other malignancies, they may not be effective against some solid cancers that do not have sufficient numbers of tumor-reactive immune cells, which require newer approaches, Moon explained.
In this study, using human T cells, Moon and colleagues engineered second-generation CAR T cells that target specific proteins present on cancer cells (CD19, mesothelin, or PSCA), and using special viruses, inserted a genetically engineered switch receptor, PD1CD28, into the CAR T cells.
The researchers engineered the PD1CD28 switch receptor by combining parts of two proteins: the surface (extracellular) portion of PD1 protein that recognizes the PDL1 protein on tumors; and the cell-signaling (transmembrane and intracellular) portion of CD28, a molecule naturally present in T cells that leads to heightened immune activity and immune cell proliferation.
Through laboratory experiments, they confirmed that the PD1CD28 switch receptor of the engineered CAR T cells was able to convert the immune-inhibitory signals induced by PD-L1 into immune-stimulatory signals, which caused tumor cell-killing.
Next, they compared the tumor cell-killing ability of the PD1CD28 CAR T cells with that of pembrolizumab plus CAR T cells (that lacked the switch receptor) in mice bearing human prostate tumor or mesothelioma, and found that the antitumor effect seen in mice treated with PD1CD28 CAR T cells was much stronger than in those treated with pembrolizumab with CAR T cells.
The researchers further demonstrated that the PD1CD28 CAR T cells had enhanced proliferative capacity and enhanced cell-killing ability compared with CAR T cells that lacked the switch receptor, and concluded that these factors may be responsible for superior regression of large solid tumors in mice.
“Some of the tumors we tested are very aggressive and resistant to other forms of therapy. We were surprised to see that the PD1CD28 CAR T cells led to a strong response and increased survival in many mice bearing such tumors as compared with CAR T cells without the switch receptor. We were also surprised to see that other forms of genetically engineered PD-1-based receptors did not have any enhancing effects on the CAR T cells. In fact, in some experiments, they did worse than the regular CAR T cells,” Moon said.
“We are hopeful that the great success seen with investigational CAR T-cell therapy in blood tumors will occur in solid tumors as well, as we continue to study ways to combine other immunotherapies with T-cell therapy, and better understand ways to augment T-cell function in solid tumors,” Moon said.
The study was supported by the National Cancer Institute and the Penn-Novartis Alliance. Moon declares no conflicts of interest. Yangbing Zhao, MD, PhD, is a co-senior author of this study. Zhao has financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight.