The next phase of Novartis’ CAR-T R&D strategy is well underway. With early clinical data on CD19 and BCMA-directed cell therapies in hand, the Big Pharma is preparing to move into registration trials next year.
Both candidates are made using Novartis’ new T-Charge process, which reduces the ex vivo culture time to about 24 hours and preserves naive and stem cell memory T cells in the final product. Using the new process, Novartis expects to make the primary proliferative potential happen in the patient and minimize the risk of exhausting the T cells during the manufacturing process itself.
Jennifer Brogdon, Ph.D., head of cell therapy research in the Department of Exploratory Immuno-Oncology of the Novartis Institutes for BioMedical Research, set out to explore what the process could mean for patients.
“We think the characteristics of this platform may lead to better and more durable responses, improve long-term outcomes and reduce the risk of serious adverse events. Because we've retained the T cell stemness, we're now able to use a much lower dose when we go into patients, and with this lower dose you see a more gradual expansion of the cells in vivo, and perhaps a reduced risk of some of the acute adverse events,” Brogdon explained.
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Novartis now has early clinical data on candidates made using the T-Charge process. The study of the CD19-directed CAR-T cell therapy YTB323, which has the same CAR transgene as Kymriah, is enrolling patients with B-cell malignancies. At the American Society of Hematology (ASH) 2021 meeting, Novartis is sharing data from the diffuse large B-cell lymphoma cohort.
In the ASH abstract, Novartis reported a response rate of 75%. That is now up to around 80%, with complete responses accounting for the vast majority of the responses. The response rate far exceeds that on the Kymriah label, with the caveat that it is from a small trial, despite Novartis testing a low dose by the standards of conventional CD19 CAR-T therapies.
“We're going in with doses that are over a log lower than what conventional therapies. In that setting, you see a delayed expansion, but you see a robust expansion that's logs higher than what you would see with a more conventional therapy,” Brogdon said.
Novartis is also using the platform in a BCMA-directed CAR-T therapy, putting it on turf targeted by Johnson & Johnson and Bristol Myers Squibb. Again, it is early days for PHE885, with the ASH abstract featuring data on just six multiple myeloma patients, but the response rate at dose level two currently stands at 100%.
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J&J has set a high efficacy bar in the BCMA-directed CAR-T space, but Brogdon thinks PHE885 brings something new to the field, saying she hasn’t seen anything quite like the cellular kinetics Novartis is demonstrating in multiple myeloma.
“Over 75% of the peripheral T cells are CAR positive. We know these patients have the worst characteristics possible—they're very late stage myeloma patients—and yet the stemness of the product is really showing through. We're seeing massive in vivo expansion and retention of some of those stemness characteristics in the patient,” Brogdon said.
It is too early to say much about the durability of responses to either candidate but, with the early data corresponding to Novartis’ expectations for T-Charge, the team already has its sights on sterner tests. “We are well poised to move these into definitive registration trials in 2022,” Jeff Legos, Ph.D., global head of oncology and hematology development at Novartis, said.