SAN DIEGO, CA – At the 2026 American Association for Cancer Research (AACR) Annual Meeting, Verismo Therapeutics unveiled early data that could reshape CAR T-cell design. Built on a novel “KIR-CAR” platform, the experimental therapy SynKIR-310 uses a multi-chain, split-signaling architecture that mimics natural immune receptors, enabling T cells to stay active through repeated tumor attacks while potentially reducing exhaustion and safety risks that have long limited conventional approaches.
In preclinical studies, SynKIR-310 delivered potent anti-tumor responses in B-cell cancer models, including 100% survival in treated mice. The therapy targets CD19 using a canine-derived binding domain and is now being tested in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in the Phase I CELESTIAL-301 trial.
Early clinical findings included a 70-year-old patient with follicular lymphoma who achieved a complete response just 28 days after receiving the lowest dose, an outcome still holding at six months. While preliminary, the results suggest that reengineering CAR T-cell biology itself may unlock more durable responses with fewer toxic side effects, tackling two of the field’s toughest challenges.
Two decades of rethinking CAR T
Verismo’s presentation of the data at AACR itself was understated, unfolding among rows of posters and quiet conversations. In the eyes of Laura A. Johnson, PhD, it was the culmination of a nearly two-decade-long scientific journey. It all began as a postdoc in the lab of immunotherapy trailblazer Steve Rosenberg, MD, PhD, who is currently chief of surgery at the National Cancer Institute, among several other appointments.
Johnson, who is chief scientific officer and chief operating officer at Verismo, told Inside Precision Medicine, “My postdoc project was literally taking, finding, and choosing an antigen; finding a shared antigen T cell receptor; subcloning it; and making it into a T cell. Not a CAR drug, but a TCR engineered drug that worked so well in the first year that they used to have money on tap there, turned it into a clinical trial, and then put me as an academic in charge of overseeing the clinical trial, the making of the drug, and getting to go and visit and shake the patient’s hands. In the four years since then, we saw literally pounds of tumor fall off these patients when we visited them in the clinic.”
That dramatic and deeply personal experience showed Johnson the promise and limitations of immune-based cancer therapies. Even as she saw tumors regress in ways that seemed almost implausible, she saw that those responses were not universal or durable and that toxicity could complicate even the most striking successes.
She continued to gain experience and try out different things, eventually leading her to the University of Pennsylvania (UPenn) with CAR T-cell therapy pioneer Carl June, MD. Working with June at UPenn, Johnson expanded CAR T-cell research rapidly, supported by industry investment and a mandate to investigate engineered immune cells’ effects on a variety of cancers. It was during those “great five years” that Johnson began to tackle solid tumors with CARs. Even as the field struggled with relapse, toxicity, and solid tumor efficacy, she led the way in clinically implementing experimental therapies.
Johnson’s subsequent move into industry, including a leadership role at GlaxoSmithKline (GSK), broadened her perspective further. “At the time, I did not see myself as an industry kind of person,” said Johnson. “I didn’t know what that was, but I did go to GSK for five years. It was amazing. I learned so much there. You know how to run clinical trials across the globe for registration. These huge teams of support. It was great.”
Johnson added, “I also had a sponsored research agreement with GSK, which was then exploring cell therapy, and after a year of that, they decided to open up a whole cell therapy unit and invited me to come and lead the group.”
By the time she returned to academic collaborations, she had seen the field from multiple angles—scientific, clinical, and operational—and had developed a growing sense that the limitations of CAR T therapy might be rooted in something more fundamental than incremental improvements could fix.
The origins of KIR-CAR
That realization sharpened when she reconnected with colleagues at UPenn, including Carl June and Michael Milone, PhD, MD, the co-inventors of Kymriah, the first-ever approved CAR T, who had already begun questioning the underlying design of conventional CAR T systems. “Back then, Mike and Carl already saw that it worked, but they felt something was not right about it. You know that patients can have recurrences of cancer, and it doesn’t work in solid tumors, no matter what they do. So they were already in the background trying to tinker and figure it out.”
The success of Kymriah had proven that engineered immune cells could be transformative, but it had also exposed persistent problems that could not be ignored. “At the time, Mike had a great idea that the artificiality of the single-chain CAR T was causing these problems because it was not evolutionarily selected for. It’s not natural. Maybe this has something to do with it.”
That insight led Milone to revisit the basic biology of immune receptors, examining how natural systems separate recognition from activation rather than fusing them into a single, continuously active structure. “They all have the same receptor format to bind to the target on the cell’s outside. The receptor is anchored in place by a neck in the cell membrane, while a completely separate internal signaling mechanism is also anchored by a neck in the membrane and is activated from the inside. And these two actually don’t interact. They have nothing to do with each other unless and until that target is found unbound, which brings the two together.”
From this observation emerged the concept of KIR-CAR, a multi-chain system inspired by natural killer (NK) cell biology that attempts to restore a more controlled and conditional activation process. “T cells, their main job, is actually not to kill you but rather to kill bad things, so they try and shut everything down,” Johnson explained. “So, we said, ‘Let’s use NK cells.’ They’re the other main lymphocyte that attacks tumors, and they’re innate. Maybe they won’t have the same problems with shutting down. Let’s throw it at the wall and see what sticks.’”
The resulting design combined elements of NK cell receptors with T-cell machinery, creating what Johnson describes as a more natural on-off switch. The combination of the killer immunoglobulin receptor (KIR), which acts as the outside binder, with existing intracellular signaling machinery used for CARs resulted in the name KIR-CAR. “A chimera has the head of a lion, the body of a goat, and the tail of a snake,” said Johnson, using the hybrid from Greek mythology in describing a traditional CAR. “We’ve un-Frankensteined them and put them back. What we end up with is just a more natural on/off switch. Why would we think we can do better than a million years of evolution at figuring out a way to trigger and turn off these cells to get rid of bad things?”
Early signals of efficacy and safety
In early preclinical experiments, KIR-CAR cells were compared to single-chain CAR T cells, showing subtle differences in vitro but greater differences in complex systems. By the time Johnson presented SynKIR-310 at AACR, those differences had become a consistent pattern across preclinical studies and early clinical observations, suggesting that the KIR-CAR approach may improve tumor control without the toxicity of conventional CAR T therapies.
Johnson said, “It’s been surprising, but great news. Our preclinical team has reversed the process, gone back to mice, and successfully reproduced the same findings. Not only is the KIR-CAR superior at eliminating tumors, but it also has a shorter duration of interferon gamma. In contrast, the single-chain CAR T cells that everyone else on the planet is using appear to be frighteningly toxic because they go off script.”
Johnson vividly described that uncontrolled activation. “If you do any assay with them, presumably including in vivo, lasting more than a day, they start killing everything around them,” she said. “They start spitting out interferon gamma. They infect every cell they come into contact with; they proliferate; they produce cytokines; they cause lysis; and they have many other harmful off-target effects.”
That behavior aligns with her broader description of how conventional CAR T cells can become overactivated and exhausted. Johnson elaborated, “The CAR T cell is hyperactivated, and it’s going down. It knows it’s exhausted, but it also detects an activated state, so it sets off fireworks and hopes the grenade response will take out whatever is bad too.”
In contrast, biomarker data from SynKIR-310 suggest a more controlled and physiologic immune response. “When we look at the biomarkers, they’re not making a ton of interferon or TNF alpha,” said Johnson. “Even from the first dose we used, we showed clearly biological activity where the T cells go in; as of day seven, you start to see interferon pickup. It peaks out at about ten days.”
Johnson continued, “Then it’s textbook as for how a T cell activates when it sees its target; this process is crucial for the immune response. It showed that it’s very clearly encountering a target, activating and doing what it’s supposed to do. However, the blood levels we observed were significantly lower than expected due to hematologic malignancies, which involve widespread tumors throughout the body, including the bone marrow and blood.”
Clinical observations, though limited, reinforce that pattern. “The results were announced today for the first nine patients. It’s a basket study for both ovarian cancer and cholangiocarcinoma. So, there are three very high unmet and urgent needs for patients. Most of these have one line of approved therapy, or maybe two, and once they become advanced refractory or metastatic, there’s nothing for these patients. Overall survival is measured in weeks, not months.”
Within that context, even modest responses carry significance. “Four of the nine showed measurable tumor reductions and the last patient treated, the last one in cohort three, had a response that continued past our data cutoff and keeps going. So, it’s very good news.”
Perhaps most striking, however, is the KIR-CAR’s apparent safety profile. “The biggest thing they were worried about is toxicity. Everybody knows that CAR causes cytokine release syndrome (CRS), and interferon gamma causes neuropathic disease, leading to brain damage and other severe symptoms. It’s got a bad rap. I think they got a headache one night that was called ‘CRS.’ That was gone the next morning. That’s it.”
A broader vision for cancer treatment
For Johnson, the significance of these findings lies less in any single result than in their consistency across different models and targets, reinforcing her belief that the KIR-CAR platform reflects a fundamentally different—and potentially more effective—approach to engineering immune cells. “You can want something to work as much as you want, but if it doesn’t, it doesn’t, and you accept it,” said Johnson. “So it’s okay that the data was the same for both our platform assets, the CD19 and mesothelioma KIR-CARs; this result is real.”
That reproducibility has given her confidence to draw comparisons with existing therapies. “When we see the same things again, there are fewer CRS cytokines, less duration of toxicity, and way better treatment. It is better than both Kymriah and Yescarta. We did the in vivo models, but it’s a little better than Kymriah and a lot better than Yescarta.”
At the same time, she remains grounded in the understanding that these are early results, requiring validation in larger trials and over longer follow-up periods, even as they point toward a broader shift in how the field might approach the design of next-generation immunotherapies. Rather than continuing to build increasingly complex artificial systems, the KIR-CAR approach suggests that aligning more closely with the immune system’s natural architecture—its built-in checks, balances, and conditional activation mechanisms—may offer a path to therapies that are both more effective and less toxic.
That idea, rooted in the biology she has spent her career studying, connects her earliest experiences watching tumors disappear in clinical trials to the work she now presents. It formed a narrative for Johnson that is less about a single product than about a way of thinking: that progress in cancer immunotherapy may ultimately depend not on pushing the immune system harder but on understanding it more deeply and working within the logic it has evolved over millions of years to follow.
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