CAR T cells have rewritten the playbook for certain blood cancers. Solid tumors are another matter. Breast, lung, prostate and brain cancers remain stubbornly out of reach, and two fresh lines of research show how researchers are trying to change that.
Why solid tumors resist
The obstacles come in three layers. First, blood cancers carry a shared marker on nearly every cell, so the engineered T cells have an obvious target. Solid tumors are patchworks. Cells within a single tumor can display different markers, or none, and the ones that escape fuel a relapse. Second, many of the markers that do exist also sit on healthy tissue, so attacking them can harm the patient. Third, there is the tumor microenvironment, a hostile, sticky fortress that recruits immune cells to fight the incoming CAR T cells.
Christopher Mount and Marcela Maus of the Massachusetts General Brigham Cancer Institute put the first problem bluntly: “Target discovery remains a considerable challenge.” Engineers have tried workarounds, including bacteria to help the cells burrow into tumors and ultra-sensitive cells that spot tiny amounts of a shared marker. Those add complexity and cost, and they leave the tumor’s immune defenses in place.
Idea one: attack the shield too
Two independent teams landed on the same protein, GPNMB. At McMaster University, Sheila Singh’s group searched donated glioblastoma tumors for proteins that marked the most aggressive cells. CAR T cells aimed at GPNMB wiped out most of the tumors built from patients’ samples and kept mice alive longer. The protein also turned up on immune cells that suppress anti-cancer drugs, so the therapy hit both the cancer and its protectors. “Our approach attacks both the tumor and the environment that allows it to thrive,” Singh said.
The second team studied alveolar soft-part sarcoma, a rare cancer that often spreads before it is diagnosed. One patient with relapsed, metastasized disease received a single infusion. The cells stayed detectable for roughly a month with no skin rash or cytokine release syndrome, and imaging showed fewer lung spots for about three months. One patient is not a trial, and the disease stabilized rather than vanished.
Idea two: make a target on demand
At USC’s engineering school, Peter Yingxiao Wang and colleagues took the opposite route. If no good marker exists, create one. Their system, called SHIFTERS, responds to low oxygen inside tumors, but it also needs focused ultrasound from a physician. Only with both keys in place do tumor cells briefly show CD19, a marker CAR T cells already know, for about a week. “Instead of trying to search for a perfect antigen, we basically force them to produce one,” Wang said.
In mice with human brain and liver tumors, treated tumors shrank dramatically while untreated ones kept growing. Doctoral student Tianze Guo noted that even 10% to 25% of cells carrying the marker was enough to set off heavy cell kill throughout the tumor. The work has not been tried in people. Delivering the genetic program into tumors is the biggest hurdle, and the team is comparing lipid nanoparticles with modified viruses.
Sources
- CAR T Revolutionized How We Treat Blood Cancers. Now It's Closing In on Solid Tumors. (SingularityHub)
- Ultrasound Helps CAR T Cells Target Solid Tumors (Technology Networks, from USC Viterbi)
