It’s been more than four years since Novartis shook up the CAR-T space with its T-Charge platform. But that’s a lifetime in the fast-moving world of cell therapies.
When the Swiss pharma unveiled the platform in December 2021, the pitch for T-Charge was simple—reduce the time cells spend ex vivo to help preserve the naive and stem cell memory T cells. The theory was that this would reduce manufacturing time as well as lead to better responses, plus improve long-term outcomes and reduce the risk of severe adverse events.
So far, Novartis has one in-house therapy in the clinic that was developed though the T-Charge process. Rapcabtagene autoleucel, also known as rap-cel or YTB323, a CD19-targeted autologous CAR-T, is in phase 2 studies for blood cancers such as B-cell lymphoma, as well as for autoimmune indications such as lupus nephritis and systemic sclerosis.
But while rap-cel has been working its way through the clinic, in vivo options—which use gene editing to generate CAR-T cells within a patient’s body—have become the hottest play in town. Eli Lilly has bought two in vivo biotechs this year alone, joining similar acquisitions by Gilead Sciences, AbbVie, Bristol Myers Squibb and AstraZeneca.
So has T-Charge already been overtaken before it’s even brought a CAR-T to market? Novartis’ cancer chiefs aren’t so sure.
“The in vivo data that we’ve seen so far publicly—it’s encouraging, but I think it’s early, right?” Novartis’ Global Head of Oncology Development, Mark Rutstein, M.D., told Fierce in an interview.
“We see early efficacy that’s promising,” Rutstein continued. “We’ll have to see durability, because one of the hallmarks of … this T-Charge platform is durable efficacy, and so I think we just need to see more data in that regard.”
While acknowledging that in vivo options have “a lot of potential,” Rutstein added that he believes “there’s opportunity for both platforms.”
Another recent development in the CAR-T space has been applying this modality to autoimmune disease. Here, Novartis has remained toward the front of the pack. Rap-cel is in phase 2 development for the likes of lupus nephritis, systemic lupus erythematosus, systemic sclerosis and myositis. In fact, the company is aiming to submit the therapy to regulators for lupus nephritis in 2028.
Despite rap-cel’s origins lying in its potential as a lymphoma treatment, the current timeline for the CAR-T therapy in oncology is slightly less clear. Following interim phase 2 data published earlier this year, Rutstein was only able to say Novartis is “actively discussing next steps” for how to further explore rap-cel to treat cancers.
The two lymphoma studies for rap-cel have so far shown “acceptable safety and competitive efficacy,” said Rutstein. But he was keen to stress that CAR-Ts have potential “beyond the typical hematology setting,” with Rutstein’s neuroscience colleagues also interested in what cell therapies could offer.
At one point, Novartis had been evaluating a second T-Charge candidate, dubbed PHE885, in a phase 1 study for multiple myeloma. But despite execs telling Fierce back in 2022 that the initial clinical data looked “really promising,” Rutstein confirmed that the BCMA-based CAR-T has since been discontinued.
It means that beyond rap-cel, the biggest development in the T-Charge world has come from a hook-up with Legend Biotech. Novartis paid the biotech $100 million back in 2023 for a selection of CAR-Ts.
The therapies all target delta-like ligand protein 3 (DLL3), and include an autologous CAR-T dubbed LB2102 that Legend had already taken into the clinic for lung cancer. The idea was always for Novartis to incorporate T-Charge into the manufacturing process of these therapies, and the pharma is finally ready to put this plan into practice.
“It’s still very early days on that,” Shiva Malek, Ph.D., global head of oncology at Novartis Institutes for BioMedical Research, told Fierce in the same interview. “We are just getting ready to start the clinical studies for that program, but I think in general it’s pretty exciting.”
Malek namechecked the approval in 2024 of Amgen’s bispecific T-cell engager Imdelltra—which targets both DLL3 and CD3—as evidence that “T-cell-targeting approaches should really have benefit in this context.”
The continuing work on T-Charge doesn’t mean that Novartis has no in-vivo strategy, however. The pharma signed a pact in 2024 to use Vyriad’s active targeting lentiviral vector platform to discover and develop new in vivo CAR-T cell therapies.
And while Novartis has been notably absent from the flurry of Big Pharma in vivo dealmaking in recent months, CEO Vas Narasimhan told Fierce recently that even though the company has “no specific plans for any acquisitions,” Novartis will “continue to evaluate that space” and is “very aware of what’s going on.”
For Malek, in vivo is just the latest approach in Novartis’ strategy to “stepwise innovate.”
“We had the traditional autologous CAR-T, then we built the T-Charge platform,” she said. “Then, of course, the next innovation would be in vivo.”
“The power of in vivo is that we would be able to bring this treatment to a broader patient population, because cell therapies as they are right now [are] a challenge to bring to community settings,” Malek continued. “So that would be the hope and the promise.”
“From a patient standpoint, it’s a pretty phenomenal place to be if we can develop agents broadly in the in vivo space,” she added.
