Immunologist Carl June, the father of CAR T cell therapy
Few people on the planet have changed the world for the better as profoundly as Carl June. A professor at the University of Pennsylvania Perelman School of Medicine and renowned immunologist, June led a team that pioneered the first CAR T-cell therapy to treat certain blood cancers. The therapy works by removing some of a patient’s immune cells, engineering them in a lab to recognize and attack their cancer, and reinfusing the cells back into the body to get the job done.
June treated the first adult patients with experimental CAR T-cell therapy at UPenn back in 2010, and the first pediatric patient in 2012, with astonishing results. Five years later, in 2017, the FDA approved the first T cell therapy drug. There are now six approved such drugs on the market, and around 34,000 patients with blood cancers who have been treated.
“Dr. June’s innovative research and technological contributions have demonstrated that CAR T cells can induce remission and even cure advanced cancer, thereby greatly improving the quality of human life and paving the way for a more equitable and sustainable world for future generations,” said Bruce Levine, a fellow immunologist at UPenn who has worked closely with him for decades. “June’s groundbreaking work has not only revolutionized the care of patients with hematologic malignancies, but also spurred the emergence of a new industry in CAR T cell therapy.”
I had the great honor of speaking to June recently about exactly that. Here are five fascinating insights he shared with me:
1) Glioblastoma Breakthrough
This year will be regarded as an inflection point for the treatment of glioblastoma, a rare and aggressive form of brain cancer that carries a median survival time of around 15 to 18 months. “It’s basically a death sentence,” June said. “[Pediatricians] basically say, ‘Go home, there’s nothing we can do.’”
The treatment options for such patients are limited and haven’t seen significant innovation for decades. But a recent trial from a research group at Stanford showed that repeat infusions of CAR T cells directly into the brains of pediatric patients has benefit. Three other research groups, include June’s own, have since demonstrated benefit from direct CAR T cell infusions into the brains of adult glioblastoma patients, whose tumors are typically more complicated than children’s.
“We published six patients just about a month and a half ago in an ongoing trial with a dual CAR given into the brain,” June said, referring to a T cell therapy that targets two major glioblastoma expressed antigens, to overcome evasion mechanisms. “And all six patients had really quite remarkable imaging changes very rapidly.” He added, “I think about five years down the line, we’re going to have FDA-approved CARs for glioblastoma.”
2) What He Wakes Up Every Day Thinking About
Solid cancer tumors, which are notoriously more difficult to treat with CAR T therapy than blood cancers. That’s because solid tumors have a microenvironment that suppresses immune cells and depletes their potency. June sees hope in so-called “armored CAR Ts,” which are engineered cells that secrete recombinant proteins to modulate the tumor microenvironment or target tumor antigens. “You can have a local benefit, but without the systemic liabilities,” June explained. He is excited for this next-gen type of approach and believes it will be necessary for CAR Ts to tackle solid tumors like pancreatic cancer or glioblastomas.
3) CAR T Therapy Shows Promise For Autoimmune Diseases
This year in February, a team at a hospital in Germany published data on 15 patients they had treated with CAR T therapy to treat their lupus, myositis, and scleroderma. The patients experienced a 100 percent response rate, with remissions lasting for a mean of fifteen months on follow up.
Over ten years ago, “We tried to do that at Penn,” June said, “and we couldn’t get it to happen because our regulatory framework is different than what’s in Germany.” There, one hospital was able to treat patients on a case-by-case basis with local regulatory board approval, rather than requiring permission from their country’s federal oversight agency.
Since the German hospital’s remarkable data came out, excitement has spread, and now there are about 44 trials worldwide recruiting autoimmune patients for CAR T therapy. “It’s going to happen,” June said confidently. “That train has left the station.”
4) Autologous And Allogeneic Therapy
These refer to the two sources of cells that can be used as treatments. “Autologous” refers to immune cells that are taken directly out of a patient’s own body and then are custom manufactured with the synthetic changes that will allow their own cells to tackle their specific disease. “Allogeneic,” on the other hand, refers to immune cells that come from a donor. They each have pros and cons, and many companies are focused on one or the other approach.
Proponents of autologous cell therapy note that they have a strong track record of safety, are unlikely to be rejected by the patient’s body, and they have the ability to persist long term, at least a decade, acting like a living drug. However they are expensive and hard to manufacture, making them difficult to scale.
Proponents of allogeneic cell therapy are bullish about “off-the-shelf” therapies that could treat patients more quickly and affordably, though they may carry more risk of needing immunosuppressants. They also don’t necessarily persist as long as an autologous cell, which can be a good thing – for the right patient.
June says we will need both approaches for the foreseeable future, and that they will have independent uses. Cancer therapy, for example, requires long-term persistence of the CAR T cells, so autologous cells are a better option. But for autoimmune diseases, allogeneic cells may be better because the body only needs them for a few months to reset the immune system: “I don’t think we actually ever want an allogenic cell to persist long-term because they are more of a safety risk.”
5) Ex vivo and in vivo
Ex vivo refers to engineering a patient’s cells outside his or her body, which is how all the cell therapies on the market today are made. While the manufacturing is complex and costly, June says that ex vivo therapy carries a very significant advantage: the ability to do multiplex genetic engineering on the cells with base editing and other techniques, allowing scientists to knock out at least 15 genes at one time and metabolically rewire a whole T cell.
“I think that is going to be necessary in some solid tumors,” June said. “And I don’t see that happening in my lifetime with in vivo engineering.”
That said, in vivo engineering, in which a therapy modifies the patient’s immune cells inside their body, is faster, more efficient, and more affordable. In fact, the first trial of in vivo cell therapy has just gotten underway in patients in Australia by Interius BioTherapeutics.
Capstan Therapeutics, which was co-founded by June and received an investment from my team at Leaps, is another company pioneering in vivo cell therapy using RNA and a proprietary lipid nanoparticle, key technologies in the Covid vaccines.
Based on promising preclinical data, Capstan is advancing their lead program candidate into early clinical proof of mechanism.
“It is Dr. June’s vision together with major advancements in nanotechnology and RNA medicines that led to the current efforts aimed to open this new chapter in medicine,” said Adrian Bot, Capstan’s Chief Science Officer.
We are lucky to live in an era of rapid medical innovation, where our sophisticated tools hold the potential to transform devastating diseases into manageable conditions. Beyond autoimmune diseases and solid tumors, the potential for CAR therapy even extends to regenerative medicine, with theoretical applications for anti-aging therapies, inflammatory dementias, and Alzheimer’s.
It’s clear that the cell therapy revolution is only just beginning.
Thank you to Kira Peikoff for additional research and reporting on this article.
Disclosure: June holds equity in Capstan, as a co-founder and member of the scientific advisory board committee.
