HIT cells, a new and promising avenue against pancreatic and ovarian cancers?

BarcelonaFinding therapies to control the progression of cancer is a race against time. Stimulating the immune system to distinguish tumor cells from healthy cells and selectively attack them has been a game-changer. In leukemias, the disease disappears and there are no signs of recurrence after a few years. This revolution would not be understood without the CAR-T (from the English Chimeric Antigen Receptor T-cells), a type of personalized drug. However, in 85% of diseases, cell therapy is not adept at recognizing and attacking tumor cells. So, is it possible to design a similar, but more sensitive, treatment that targets less visible cancers?

Michel Sadelain is considered one of the pioneering scientists of immunotherapy, as he laid the foundations for current CAR-T therapies, treatments in which the patient is their own donor. To put it simply, T lymphocytes (which are natural defenses) are extracted, genetically reprogrammed in the laboratory to neutralize cancer cells, and then reinjected to attack the tumor. However, there are several obstacles that hinder the activity of CAR-T in solid cancers, those that form a compact mass of tissue in an organ, which represent four out of every five tumors. It is noteworthy that not all cancer cells are easily detectable.

Now, Sadelain, director of the Columbia Initiative in Cell Engineering and Therapy (CICET), and research associate Sophie Hanina have proposed a promising alternative to the journal ScienceHIT cells. It's not a new term among the scientific community, but it has now been shown to have potential against human pancreatic, ovarian, and kidney cancers in mouse trials. The first two are tumors extremely resistant to CAR-T cell immunotherapies, which seek out antigens—molecules on the surface of tumor cells that can be recognized by the immune system, like an identity card—to access and eliminate the cancer.

"Reaching every last cell"

A close relative of CAR-T therapy, HIT trains the patient's immune cells to become "killers" of tumor cells, but it does so from a different starting point: the search for a single, shared surface target. Let's break it down. Blood cancer cells are usually easy for CAR-T to detect, since each one is covered with numerous CD19 molecules, a protein found almost exclusively on the surface of B cells of the immune system, which act as a signal to guide the therapeutic tool.

In contrast, in solid tumors, cancer cells are more diverse, and one of the major challenges—key, but not the only one—is identifying specific targets capable of clearly differentiating between the cells that cause the tumor and those of healthy tissue. "With hematological cancers, we kill all the B cells, because we can survive without them. But with solid tumors, we must be selective and not kill healthy tissue," summarizes the leader of the cell immunotherapies group for cancer at the Institute of Biomedical Research (August Piedia) in the ARA.

The study published in Science The focus is on mitigating this problem. In the search for therapeutic targets, Sadelain asserts that there is great heterogeneity in the presence of molecules that can be used to attack the tumor: "Some have been identified that are found in 25%, 50%, or 75% of tumor cells," so they can eliminate them. It's possible to cure someone by eradicating a small fraction or even 90% of the tumor. "We have to reach every last cell," he argues. And Guedan states: "This work aims to find a good target in solid tumors."

But there are several problems. It's not enough to simply detect and quantify these target molecules; it's also necessary to differentiate between tumor precursors and those expressed in healthy tissues to prevent their destruction. To address this, the team led by Sadelain proposes using the CD70 antigen as a guiding light for cell therapy. Since previous studies had suggested that the levels of this protein vary from cell to cell within a tumor, Hanina has developed new methods to detect the molecule and found that all solid tumors have at least a few on their surface.

More trials pending

In the experiment, they found that, with CAR-T cells, this target only worked when CD70 was expressed at high levels. However, with HIT reprogramming, the researchers were able to completely eliminate tumors in mice with pancreatic, kidney, and ovarian cancers, without affecting healthy tissue, regardless of the amount of this protein present. "They are the new generation of CAR-T cells. They can be programmed in the same way, but they have the sensitivity of a natural T cell and can detect cancer cells that have only a tiny number of target molecules," Hanina explained in a press release. "Curing solid tumors is not easy, but this work solves a piece of the puzzle," Sadelain concluded. The team is now considering testing the CD70-targeted HIT cells in patients with other cancers. In fact, they are convinced that this strategy may have potential in almost twenty tumors, including glioblastoma and pancreatic adenocarcinoma, which are known to express CD70 to some degree. Guedan admits that further trials are needed to demonstrate that these positive results are realistic: "Curing tumors in mice is different from curing them in humans, and the cancers mentioned—like pancreatic cancer—are very complex, beyond the lack of known targets." For example, it's a highly fibrous tumor that generates a kind of "tumor scar" around it, preventing drugs from reaching the target tissue. "But we do see a very promising advance," the researcher acknowledges, emphasizing that it's significant progress. "It's important both for this specific treatment and for future therapies for other solid tumors, since they may be expressing other targets at low levels that aren't being detected," Guedan explains.