CAR-Ts targeting a ‘special’ solid tumor antigen work well in some mouse models, but challenges remain

CAR-Ts targeting a ‘special’ solid tumor antigen work well in some mouse models, but challenges remain

Chimeric antigen receptor T cell (CAR-T) therapy has dramatically improved the odds for patients with blood cancer, boosting survival rates from 15% to 40% for some types. But despite ongoing efforts from scientists, biotechs and Big Phama, the same success has yet to be replicated in solid tumors.

Now, researchers at St. Jude Children’s Research Hospital have shown that targeting a ubiquitous antigen called GRP78 could give CAR-Ts a fighting chance against barin tumors, bone cancer and more—though, thanks to cancer’s wily defenses, the path will be a little more challenging for some tumor types. The findings were published Nov. 21 in Cell Reports Medicine.

“We always need to find new targets to improve cancer treatment,” senior co-corresponding author Giedre Krenciute, Ph.D., said in a press release. “We saw high GRP78 expression in a multitude of brain and solid tumor types […] but our therapeutic efficacy was variable.”

GRP78 is normally housed in a part of the cell called the endoplasmic reticulum, where it’s involved in what’s known as the unfolded protein response. However, in some types of cancer cells, the antigen is moved from the endoplasmic reticulum to the surface, where it acts as a “decoy” to keep the immune system from killing the cell.

Prior to their new study, the St. Jude team had already developed CAR-Ts that target GRP78 on acute myeloid leukemia cells. In their new research, they set out to see whether they could replicate that same success in hard-to-treat solid tumors, including aggressive forms of brain cancer, triple negative breast cancer and bone cancers.

After establishing that GRP78 is expressed on a range of solid cancers, the researchers ran cell and mouse studies to see whether CAR-Ts targeting the protein would have anti-tumor activity. The treatment worked well against some tumors but not others, and its efficacy took on an unexpected pattern: Unlike other CAR-T therapies, it wasn’t uniformly successful against tumors that expressed high levels of the target antigen. Instead, high expression of GRP78 seemed to be a disadvantage in some cases, especially for a lethal brain cancer called diffuse midline glioma (DIPG).

The researchers knew from their own research that activated T cells also express GRP78, but they hadn’t previously tested how its expression changes in the context of their interactions with tumors. Cell studies revealed that some types of solid cancers exploited this for their own gain: The tumor cells would provoke the anti-GRP78 CAR-Ts into expressing GRP78 themselves, which ultimately led them to kill each other instead of the cancer.

“GRP78 seems to be a special candidate that did not react as we expected, making it a promising but complicated candidate,” Paulina Velasquez, M.D., another co-corresponding author, said in the release.

The researchers tested a couple of different strategies to overcome this problem, analyzing their effectiveness on a DIPG mouse model. They started by increasing the dose of CAR-Ts; while this kept the tumors from growing and helped the mice live longer, it ultimately ended in relapse.

Next, they tried knocking out the gene for a protein called RASA2 in the anti-GRP78 CAR-Ts, a strategy that their own previous research had shown could improve CAR-T response against tumors that expressed low levels of the antigen. These CAR-Ts performed better than the original version at controlling DIPG tumors, the researchers found, though they noted that a technique used to create them—electroporation—also increased the amount of GRP78 the CAR-Ts expressed, making them more vulnerable to destroying each other. While the scientists were able to improve the treatment’s potency by pairing the CAR-Ts with Bristol Myers Squibb’s chemotherapy Sprycel, they noted that more in-depth studies will be required to understand the mechanism and how to control it.

The researchers have other ideas for improving GRP78 CAR-Ts too, such as dual approaches that involve using a second antigen to boost CAR-T activation. One option might be CAR-Ts that secrete bispecific T cell engagers, or BiTES; another could be the use of switch receptor approaches, where activation of CAR-T cells leads to the expression of additional receptors that help the CAR-Ts infiltrate tumor cells.

Current limitations aside, “GRP78 CAR-T cells have potent anti-tumor activity in both brain and solid tumors,” the researchers wrote in the paper. “We … conclude that GRP78 expression may play a crucial role in T cell biology and anti-tumor function, and investigating this further will be the focus of future work.”

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