Toronto researchers say 'double negative,' off-the-shelf CAR-T treatment could bolster cell therapy

 A new study from a team of researchers in Toronto found that a specific kind of “off-the-shelf” CAR-T treatment may be able to fight cancer tumors without attacking the host’s body, with the lead researcher pursuing a possible spinoff company using the therapy. 

The findings, published Friday in Science Immunology, are the latest to come out of the lab of Li Zhang, M.D., Ph.D., who for years has delved into developing more effective allogeneic, or “off-the-shelf”, CAR-T treatments. Current autologous cell therapies are time-consuming and complicated to manufacture, heightening the value of finding a quicker alternative. 

Zhang and team’s latest research, led by Daniel Vasic, found that a particular kind of CAR-T cells, known as “double-negative” CAR-T cells (DNTs), were effective in a mouse model at eradicating blood and lung cancer tumors without spurring graft-versus-host disease. These particular CAR-T’s are called “double-negative” because they don’t express either the CD4 or CD8 proteins. 

To assess this, the researchers converted the DNTs to express an anti-CD19-CAR (CAR19) and studied its efficacy in a mouse model against B-cell acute lymphoblastic leukemia and non–small cell lung cancer. Compared to DNTs without the CD19 transduction, the CAR19-DNTs had similar efficacy to conventional CAR19 T cells, without causing graft versus host disease. The researchers conclude that “collectively, these data support the use of allogeneic CAR-DNTs as a safe and effective therapy against cancer.” 

For Zhang, this study is just the latest in more than 20 years worth of investigating DNTs. What’s notable about the latest research is that many autologous CAR-T treatments have difficulty defeating solid tumors. Zhang's hypothesis is that CAR19-DNTs may be able to hold up a fight,  but actual data is needed.

“We were believing that but of course most studies need to be done,” she said. “Given [that] if we identify a good solid tumor target, then we can put that CAR onto DNT cells. And so we thought that’s something exciting.” 

This research follows inconclusive results from a first-in-human phase 1 trial out of China—which Zhang contributed to—testing DNTs in patients with acute myeloid leukemia who relapsed after allogenous stem cell treatment. Among 10 patients, half experienced varying degrees of complete remission after 28 days. After further follow-up, which was a median of roughly 20 months, half of the 10 treated patients remained alive, four of which remained in complete remission for at least 16 months. However, four out of five living patients were in minimal residual disease complete remission prior to starting DNT treatment. After patients relapsed following the stem cell treatment, they discontinued immunosuppressants; Zhang hopes that a future trial will try the treatments without them altogether. 

Zhang’s work comes as CAR-Ts continue to be a source of new innovation for cancer treatments. J&J and Legend Biotech’s Carvykti was the latest BCMA CAR-T approved by the FDA for multiple myeloma. But using the technique to target solid tumors has been a point of consternation among pharmas and biotechs.

In a previous interview with Fierce Biotech, 2seventy bio’s Phillip Gregory said the “dirty secret” in the industry is that CARs (chimeric antigen receptors) lack the sensitivity of engineers TCRs (t-cell receptors) to work inside of cancer cells. 2seventy also has an approved BCMA CAR-T treatment on the market. 

But companies are looking to pave new ground. A recent presentation from Exuma at the American Association for Cancer Research’s annual meeting highlighted the potential for a new type of rapid cell therapy that combines T-cells and natural killer cells. Early data in mice found that the therapy persisted in blood compared to normal CAR-T cells and was able to clear target cells even at a low starting number. 

As evidence of the therapeutic potential of these DNTs, Zhang herself is pursuing a potential spinoff of her lab's work. She said right now, her team is talking with potential investors. 

“We really hope some company finds it interesting because there’s great potential,” she said. “But I’m kind of more enjoying science discovery.” 

https://www.fiercebiotech.com/biotech/toronto-researchers-say-double-negative-shelf-car-t-treatment-could-bolster-cell-therapy