Reprogramming patients’ immune cells to treat their cancer has become the front line of cancer therapy, with chimeric antigen receptor (CAR) T-cell therapy now approved by the FDA for several blood cancers. But translating this success to solid tumors remains a challenge. At ASCO 2019, Gianpietro Dotti, MD, Cancer Cellular Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, discussed efforts to extend the application of CAR T-cell therapy to solid tumors.
“The challenge for the next 5 to 10 years is to improve existing CAR T-cell therapy and to transfer it to solid tumors,” said Dr Dotti.
“There are multiple problems that need to be overcome, however, including selection of the right antigen and T-cell migration or infiltration to the solid tumor, which is completely different than in hematologic diseases. The tumor environment in solid tumors is also highly immunosuppressive,” Dr Dotti added.
The good news, he said, is that the identification of antigens in solid tumors is proving promising, with several phase 1 and phase 2 clinical trials exploring a significant number of targets that can help the use of CAR T cells in solid tumors. Investigators are searching for an antigen that is not expressed (or has limited expression) in normal tissues to avoid any organ toxicity.
“We are looking for targets that are both highly expressed in tumors and homogeneously expressed in all tumor cells in the tumor,” Dr Dotti explained. “Ideally, the antigen should be critical for the tumor growth and metastasis to prevent antigen escape.”
B7-H3: The Next Antigen
Over the past 2 to 3 years, Dr Dotti and colleagues have focused on the role of B7-H3 antigen in solid tumors. Like other antigens, including CD-80, CD-86, ICOS-ligand, and PD-L1, the B7-H3 antigen is a member of the murine B-cell B7 antigen family, but its ligand is unknown; however, B7-H3 is assumed to be an inhibitory receptor.
“B7-H3 has limited expression in normal tissues and is very highly expressed in many solid tumors, including pancreatic cancer, ovarian cancer, colon, prostate, and many, many others,” said Dr Dotti, adding that the density of the antigen’s expression on target cells is critical to dictate the antitumor activity of the CAR T-cells.
“Based on the expression of this target on the tumor cells, it seems that we have a therapeutic window to distinguish between tumor cells and normal tissues,” he added.
So far, his team has observed antitumor activity in a pancreatic model using CAR T-cells to target B7-H3, without associated toxicity in immunocompetent mice, but the true test will be in human patients. The investigators are hoping to open a clinical study in ovarian cancer by the end of the year.
Natural Killer T-Cells
The infiltration of CAR T-cells in solid tumors is another issue concerning antitumor activity. As Dr Dotti reported at ASCO, natural killer T- (NKT) cells represent an alternative platform for CAR T-cells for CAR engraftment and may result in better trafficking to the tumor site. In fact, the infiltration of NKT cells has already been shown to correlate with better survival in pediatric patients with stage 4 neuroblastoma.
Dr Dotti and colleagues have engineered NKT-cells with CAR T-cells to be tumor-specific by retaining the native capacity of these cells to recognize CD1-deposit targets, which are usually macrophages associated with the tumor.
“Although we are still at dose level 1, this approach has demonstrated remarkable antitumor activity in one of the first patients treated, completely eliminating a lesion in the sternum,” said Dr Dotti.
Overcoming Tumor Immunosuppression
Finally, for CAR T-cell therapy to be successful in solid tumors, immunosuppression in the tumor microenvironment must be overcome. Although researchers are exploring combination therapy with checkpoint inhibitors or agents that are targeting tumor-associated macrophages and myeloid-derived suppressive cells, they are also designing CAR T-cells to directly overcome immunosuppression.
As Dr Dotti reported, interleukin (IL)-15 expressed by CAR T-cells may improve persistence and antitumor activity of CAR T-cells in several subsets of solid tumors.
“We focused for many years on IL-15 as a way to improve the activity of CAR T-cells in a suppressive environment,” he said. “In a mouse model of very aggressive neuroblastoma, CAR T-cells engineered with IL-15 demonstrated a dramatic antitumor response.”
Furthermore, “expression of PD-1 of these CAR T-cells was also reduced within the tumor microenvironment, which suggests that these cells can be less susceptible to PD-L1 inhibition in the context of an immunosuppressive environment,” Dr Dotti added.
Based on these data, Dr Dotti and colleagues are currently enrolling pediatric patients with neuroblastoma for a clinical study at the University of North Carolina.