Using Receptor Architecture to Improve CAR-T Cell Sensitivity in Oncology (ASGCT 2024)

Editor's note: this interview was originally published on BioPharmInternational.com.

Sitting down with Pharmaceutical Technology®, Phillip Gregory, PhD, senior vice-president and head of Regeneron Cell Medicines, Regeneron, discussed current challenges with chimeric antigen receptor T cell (CAR-T) therapies at the American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting, occurring on May 7–11, 2024 in Baltimore, Md.

“The most arduous challenges in CAR-T cell therapies come from the complexity of fusing three different fields,” Gregory said. “There's the field of generating binders that can redirect a cell to a tumor antigen. There's the field of making that T cell do the right thing when it connects with that antigen, and then there's the problem of making those CAR-T cells at the scale and in a GMP [good manufacturing practice] fashion that produces a drug product. Thus, creating a successful CAR-T cell requires advancements across all three of those disciplines,” he explained.

Juggling these three fields is what takes time when creating the CAR-T therapies seen today, he noted. Meanwhile, the most successful aspects of CAR-T cell therapy to date have been in the hematologic malignancies, such as B-cell lymphomas and myeloma, where, Gregory points out, a number of approved therapeutics already exist that are having transformative impacts on patients.

“But this platform has the potential to do much more than just hematologic malignancies,” Gregory enthuses. “[There are] now explorations into autoimmune diseases as well solid tumors, and for solid tumors, that's where we need additional technologies to unlock the potential of cell therapy,” he stated.

In a talk Gregory gave at ASGCT, he highlighted CAR-T cell receptors and “receptor architecture”. He explained that these are engineered proteins that allow a cell to recognize a tumor antigen. “The current CAR-T cells do a great job of that, but there are also limitations to how those function. For example, they're not regulated, so they work whenever they see an antigen. That means that we can't control when those cells act to kill the tumor cell or not,” Gregory explained.

One area that Regeneron is working on is creating regulatable CAR-T cells that only function when the investigator provides an exogenous small molecule. The company is also working on the sensitivity of CAR-T cells. “Unlike the natural way in which T cells recognize an antigen, which is through the T-cell receptor (TCR), CAR-T cells use a chimeric approach, which turns out to be a little bit less sensitive or requires more antigen on the cell surface. That means there's the potential for the tumors to escape by down-regulating the expression of that antigen,” Gregory said. “We've been working on architectures that increase the sensitivity of the CAR-T cell by exploiting the natural regulation and signaling of the TCR itself,” he stated.

“I think that CAR-T cells offer a tremendous platform for the combination [of] a plethora of technologies that exist in oncology; that includes bispecific antibody technologies as well as antibody-based technologies,” Gregory added.