CAR T-cell Therapy for Solid Tumors?

Because chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of some hematologic malignancies, scientists are eager for a similar revolution in solid tumors. “Ninety percent of everyone who died of cancer last year died of solid tumors,” notes Steven Rosenberg, MD, PhD, of the NIH. “Finding an effective treatment for solid tumors is our major challenge.” In hopes of developing such a treatment, researchers are exploring a slew of approaches for adapting CAR T-cell therapy to solid tumors. However, this undertaking has proven more complicated than many anticipated.

“There are a lot of barriers,” says Crystal Mackall, MD, of Stanford University in California. “But we still have a whole lot of tricks up our sleeve left to try.”

One barrier is that solid tumors are more heterogeneous than hematologic malignancies, making them harder to target with CARs. “Only a subpopulation of tumor cells express a given target antigen—often less than 50%,” explains Steven Albelda, MD, of the University of Pennsylvania in Philadelphia. Thus, a pool of malignant cells that is not susceptible to any one CAR always exists and can grow during treatment.

“Immune escape occurs in CD19-targeted CAR T-cell therapy of hematological malignancies, too,” says Renier Brentjens, MD, PhD, director of Cellular Therapeutics at Memorial Sloan Kettering Cancer Center in New York, NY, and cofounder of Juno Therapeutics, which specializes in developing novel cancer therapies that feature CAR T cells and T-cell receptors. “But it is much more likely to occur in solid tumors.”

To combat this problem, Mackall and colleagues are developing CAR T cells that recognize multiple antigens. “We've already launched a clinical trial of a bispecific CAR in B-cell acute lymphoblastic leukemia,” says Mackall. “And preclinical studies suggest you can make trio and quad CARs.” In the future, CARs with multiple antigens are likely to be developed for solid tumors as well.

Keeping CAR T cells active despite the suppressive effects of the tumor microenvironment is also a challenge, notes Mackall. To do this, researchers have been genetically engineering “armored” T cells to express molecules that mitigate suppression by T regulatory cells. For example, Brentjens and colleagues recently created CAR T cells that secrete checkpoint-blocking antibodies. A recent study showed that in mouse tumor models, the secreted antibodies not only protected the CAR T cells, but also activated nearby T cells to help attack tumor cells (Nat Biotechnol 2018;36:847–56). The next step is to test these armored cells in humans.

Of course, even armored CAR T cells must infiltrate the tumor before they can kill it. Malignant hematologic cells circulate in the blood and bone marrow, where they are relatively easy for CAR T cells to find and destroy. Solid tumor cells, by contrast, are organized into multiple compartments and are often surrounded by other tissues, where they are less accessible to CAR T cells. “CAR T cells don't get there with the same efficiency that they get into bone marrow,” says Mackall. Research aimed at improving CAR T cells' ability to breech tumor defenses will be key to boosting response rates.

Scientists must contend with toxicity, too. Many molecules expressed by solid tumors are also expressed at low levels by normal cells. For this reason, “the targets we choose for solid tumors might not be as clear-cut and safe” as the targets available for hematologic malignancies, says Brentjens.

Potential strategies for minimizing treatment toxicity include identifying the antigens most specific to tumors, tuning CARs to react only to cells that express target antigens at high levels, and incorporating “safety valve” measures such as suicide genes, says Albelda. For example, some CAR T cells are engineered to express caspase-9. If a chemical inducer is administered intravenously—in the case of a serious adverse event, for example—it causes the caspase-9 molecules to dimerize and initiate apoptosis, leading to the death of the CAR T cells.

The challenges are considerable, and not everyone is optimistic about the chances of success. “I don't see any solid path to using CAR T cells to treat solid tumors,” says Rosenberg, whose own lab is focusing on the adoptive transfer of conventional T cells instead. In the past few years, he and colleagues have demonstrated that they can search a patient's immune system for T cells that target the unique constellation of mutations present in the tumor. These cells can then be harvested, expanded, and infused back into the patient. Although no large-scale trial of this personalized therapy has yet been conducted, some patients with metastatic colorectal cancer, breast cancer, and cholangiocarcinoma have experienced tumor regression (N Engl J Med 2016;375:2255–62; Nat Med 2018;24:724–30; Science 2014;344:641–5).

Even so, many researchers are not ready to give up on CAR T-cell therapy for solid tumors, although Brentjens worries that the sudden and dramatic success of CAR T-cell therapy in hematologic malignancies has led to unrealistically high expectations. “The worst thing that can happen is that people will write off CAR T-cell therapy for solid tumors after a few failed trials,” he says. “A sober mind would say the platform is very promising, but there are still lots of questions we need to answer.” –Kristin Harper

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