Chimeric antigen receptor (CAR) T cell therapies have shown dramatic results against certain blood cancers and form a key area of investment in approaches that harness the immune system against various forms of the disease. However, biopharma researchers have encountered several challenges as they attempt to develop CAR-T therapies to attack solid tumors. A BIO 2017 panel looked at these challenges and sparked a lively discussion among the panel participants about some of the most promising approaches to designing effective CAR-T therapies in this arena.
Kevin Slawin, MD, Founder of Bellicum Pharmaceuticals, grouped these challenges under several areas: target selection strategy, tumor microenvironment and persistence/durability. The next wave of CAR-T products to treat solid tumors “are going to require much more engineering,” said Slawin. The solid tumor environment is much more inhospitable than that of liquid tumors, and engineered T cells need to be able to penetrate into the tumor. Additionally, because CAR-T therapies target surface molecules, there need to be mechanisms in place to avoid on-target, off-tumor reactions.
The panel generally agreed that it would be difficult to single out the most important challenge to address. These problems are really “a series of hurdles we need to overcome,” according to Jason Litten, MD, Vice President of Clinical Development at Juno Therapeutics. The panel anchored their discussion around questions about efficacy and safety.
While toxicity with regard to CAR-T approaches to treating solid tumors has not been a major concern, David Spencer, PhD, Chief Scientific officer at Bellicum Pharmaceuticals, noted that as biopharma companies engineer T cells to be more effective against solid tumors, “we’re likely also going to increase the toxicity.”
One mechanism to regulate toxicity that each member of the panel agreed is promising are switch technologies that can activate and deactivate the engineered T cells as needed. Dr. Slawin compared the ability to regulate the activity of the engineered T cells in vivo to the ability to regulate the dose of a small molecule medicine. Eric Ostertag, MD, PhD, Chief Executive Officer of Poseida Therapeutics, noted that he does not know of one clinician who would say “No” to having that option.
This section of the panel discussion also honed in on the most important consideration with harnessing the immune system to attack cancer. “The immune system is all about balance,” said Dr. Spencer. All of these factors are going to impact CAR-T therapies, which makes striking the right balance even more complicated.