CAR T-Cell Pioneer Plots Technology’s Next Steps

Renier Brentjens, MD, PhD, one of the pioneers in the development of chimeric antigen receptor (CAR) T-cell therapy, is poised to see the technology take its next big leap, with researchers testing new targets and new designs and potentially gaining a foothold in the treatment of solid tumors.

“The ceiling for this technology is incredibly high,” he said. “We’re just now gaining momentum and as some of these next generation designs of CAR T-cells start to show promise, I think that will lead to a flurry of further innovation.” 

Brentjens spent most of his career as a physician-scientist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City but moved to the Roswell Park Comprehensive Cancer Center in Buffalo, New York, in 2021. Now as the deputy director and chair of medicine at Roswell Park Comprehensive Cancer Center in Buffalo, the leukemia specialist is focused on building up the institution’s cell therapy program and making it one of the lead institutes for developing and implementing CAR T-cell technologies and other cellular therapies.

With that goal in mind, Roswell Park recently opened its Good Manufacturing Practices Engineering and Cell Manufacturing (GEM) Facility, the first cell and gene therapy hub in the state of New York. The $98 million facility significantly increases Roswell Park’s cell manufacturing ability, expanding the existing facility from six rooms to 20 and making it the largest GEM facility at any academic institution in the United States.

Brentjens said the facility will allow Roswell Park to open “many more clinical trials,” including for both hematologic malignancies and solid tumors.

Along with running their own investigator-initiated clinical trials and supporting academic researchers at other institutions, Brentjens said they plan to partner with biotech and pharmaceutical companies that have promising products but need facilities and expertise to run trials.

“We think this is the best way that we can optimize this therapy for our patients and the best way to allow our investigators to move beyond lab work to actually testing what the benefit of this approach is for our patients,” he said in an interview.

Early Days of CAR T

Brentjens started his career at MSKCC, where, as a medical oncology fellow, he began preclinical studies that showed the potential clinical application of using autologous T cells that were genetically modified to target the CD19 antigen through the retroviral gene transfer of artificial T-cell receptors.

“When I started working on CAR T-cells in Michel Sadelain’s lab, the term CAR T-cell hadn’t even been created. They called them T bodies at the time,” Brentjens recalled.

The concept of CAR T-cells had been introduced by the immunologist Zelig Eshhar, PhD, about a decade earlier, and impatience was growing in the 10-15 labs around the world that were seeking to get the technology to work in practice. “The concept was attractive, but no one had ever gotten it to the clinic, much less actually gotten it to work reasonably well in preclinical mouse models,” Brentjens noted.

At MSKCC, they were focused on CD19 as a target of interest as the antigen was expressed on many B-cell cancers. Their lab was able to produce some of the first CD19-targeted CAR constructs and in 2003, they were the first to show that these CAR T-cells worked in a mouse model. “That was one of those first eureka moments. But to be honest, back in those days, even trying to write a grant on this technology was very difficult because most reviewers said, ‘We’ve heard about this, but nothing has happened and it probably doesn’t work,’” he said.

When the technology moved to clinical trials in 2006, there was also little idea of how to proceed on initial dosing and other issues because researchers and officials at the US Food and Drug Administration (FDA) had no experience with the novel technology.

After finishing up his fellowship, Brentjens became the principal investigator of his own laboratory at MSKCC and began clinical trials of patients with CD19+ chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia (B-ALL). It was the second trial, published in 2013, among adults with B-ALL, that produced the breakthrough, showing that patients could achieve remission with infusion of CAR T-cells. Once Novartis entered the space, the field “exploded,” Brentjens said.

“It was both cool and bizarre to experience as someone that would have to spend the first 10-15 minutes of every lecture I gave explaining the technology, and now I can get it done in two slides because in the medical world it’s almost kind of a household term and everybody knows about it,” he said. “But back in the day, it was all science fiction.” 

State of the Science 

Although various CAR T-cell therapies are approved in lymphoma, leukemia, and multiple myeloma, patient access has been slow to expand both due to costs and the limited number of centers offering the therapy. One of those patients is Chris Vogelsang, now aged 70 years, who is cancer-free after completing CAR T-cell therapy at Roswell Park in March 2023.

Vogelsang was diagnosed with mantle cell lymphoma in 2009 and had received two prior lines of therapy, including an autologous stem cell transplant and a Bruton’s tyrosine kinase inhibitor, when his cancer returned. His doctors had found a 100% match for a possible next stem cell transplant, but they also told him CAR T-cell therapy was an option.

Vogelsang said he chose CAR T-cell therapy because it offered him the best quality of life after treatment and the process seemed similar to what he had undergone with his first stem cell transplant. While it took about a year to fully recover, Vogelsang said he’s now back to playing tennis and golf and traveling. He continues to take daily antibiotics to prevent infection, and he wears a mask in crowded spaces. “At this point, I don’t feel like it’s an illness. I feel like I’m just taking these along with my vitamins; it’s no big deal,” he said.

Vogelsang, who lives in Buffalo, said he feels fortunate that he was able to access cutting edge therapy so close to home and that his other treatments acted as a bridge to get him to the point where CAR T-cell therapy was available to him. “I’m pretty happy where I am right now. If I can do what I’m doing now for the next 10 years, I’ll be happy.” 

While success stories like Vogelsang’s are becoming more common, Brentjens said there’s still room to improve in the use of CAR T-cell therapy for hematologic malignancies, including better designs of CAR T-cells, learning the optimal type of T cell, and examining different targets. 

“There’s a lot of work that still needs to be done with blood cancers. But when we got those first patients into remission, the big question was, is this a novel approach to treatment in blood cancers or is this a proof of principle that all cancers could be susceptible to this type of therapy?” Brentjens said.

Blood cancers make up a minority of cancer diagnoses, but the much more common solid tumors have been difficult to tackle with CAR T-cells for many reasons. The targets are more difficult to find than CD19 on B-cell cancers, and even if researchers can identify a good target that is safe to attack using CAR T-cells, chances are that about half of the cells in the tumor don’t express it. This target antigen heterogeneity means that even a CAR T-cell therapy with two or three targets results in immune escape.

Another significant obstacle is the immune-suppressive tumor microenvironment in many solid tumors. “Tumor cells scaffold themselves with other cells that suppress the immune system or, in the case of fibroblasts, inhibit properly targeted T cells from being able to infiltrate into the tumor,” Brentjens said.

Future of Armored CARs 

That’s why Brentjens and other researchers are focused on the idea of creating more potent CAR T-cells that can overcome some of the issues in solid tumors. If the original CAR T construct was a Model T Ford, Brentjens said a next-generation CAR T-cell construct would be comparable to a Ford Mustang.

“What we found, actually reasonably early on, is that you could further endow these CAR T-cells to become more potent if you engineer them with additional genes, for example cytokine IL-12 [interleukin-12],” Brentjens said. “It’s where we first came up with the term armored CAR T-cells.” 

IL-12 is proinflammatory and these cytokines can modulate the suppressive tumor microenvironment. At the same time, the cytokines recruit a patient’s own nonengineered immune cells to recognize the tumors, reducing the impact of the target antigen heterogeneity.

Over the last 5-10 years, most of the work has been about identifying solid tumor targets, essentially trying to take the approach that worked for blood cancers and applying that same CAR T construct in solid tumors. But none of those trials have yielded meaningful clinical improvement. Now, attention is shifting to addressing the differences between blood cancers and solid tumors and whether an armored CAR can overcome those limitations. “We kind of had a false start with just using CARs alone for solid tumors,” he said.

At Roswell Park, they have recruited both basic scientists and clinicians with experience in CAR T-cell therapy to move forward the science of armored CAR T-cells. Over the next several years, they expect to launch a half dozen clinical trials testing this approach, including an investigation of an armored CAR T-cell therapy targeting the antigen DLL3 in small cell lung cancer as well as CAR T-cell therapy targeting the CD83 protein in acute myeloid leukemia.

Brentjens said he is hopeful that there could be FDA approved CAR T-cell therapies for solid tumors in the next 5-10 years. “Understanding the biology and then meticulously trying to target what the limitations are through further engineering gives me a great deal of hope,” he said.

Brentjens had licensed intellectual property to and collects royalties from BMS, Caribou, and Sanofi. He had received research funding from BMS and is a consultant to BMS and Atara Biotherapeutics Inc.