AstraZeneca isn’t letting a death in a China trial detract from the potential of its $1 billion in vivo bet, even as the candidate’s safety and efficacy profile have so far failed to separate it from traditional CAR-T therapies.
The British Big Pharma entered the “off-the-shelf” cell therapy space a year ago when it acquired Belgium-based EsoBiotec and its lentiviral vector platform for $425 million upfront and the promise of up to $575 million in milestones payments. At the time, AstraZeneca executives explained that despite “only a few patients” having been treated so far, the data the pharma had already seen “gives us confidence.”
On Wednesday, data from a Chinese phase 1 study of EsoBiotec’s in vivo BCMA CAR-T candidate ESO-T01 in multiple myeloma was published in Nature Medicine. On the good side, the report demonstrated preliminary antimyeloma activity, with four of the five patients achieving objective responses, including three stringent complete remissions by day 60.
The papers’ authors said these findings “provide preliminary evidence on the feasibility and safety of in vivo CAR-T generation using an immune-shielded vector.”
However, the adverse events made for tougher reading. While the paper concluded that the drug was “generally well tolerated” with no dose-limiting toxicities observed, all patients developed grade 3 or higher adverse events. Cytokine release syndrome (CRS)—a potentially serious side effect of immunotherapies that redirect T cells—occurred in four patients, reaching grade 3 in three patients.
The most frequent toxicities were transient cytopenias and reversible hepatic enzyme elevations, and three patients experienced grade 2 infections.
One patient developed grade 1 immune effector cell-associated neurotoxicity (ICANS) and died 19 days after receiving ESO-T01 from compression on his spinal cord related to a lesion, according to the paper. This lesion was extramedullary, meaning it arose far from the bone marrow, which serves as multiple myeloma’s base of operations in the body. There is no standard treatment for extramedullary lesions in myeloma, and patients who develop them are known to have worse outcomes than those who don’t.
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The paper’s authors acknowledged that the swelling on the spine, combined with what appeared to be a “marked decline” in known myeloma biomarkers, “may represent short-lived antitumor activity or immune-related fluctuations.”
However, they also noted that disease progression as the cause could not be ruled out.
The authors said the fatality “underscores the importance of anatomical risk stratification before administering in vivo CAR-T cell therapy to patients with preexisting extramedullary disease.”
CRS and ICANS are common side effects in traditional CAR-T cell therapy, where T cells are taken from a patient, engineered in a lab to target cancer, and then reinfused. The authors noted that the in vivo approach’s cases of CRS and ICANS was consistent with traditional CAR-T, but “the timing and sequence of toxicities suggest different underlying biology.”
An undifferentiated safety profile may spell trouble for ESO-T01, since Johnson & Johnson and Legend Biotech’s traditional CAR-T therapy Carvykti is already approved for relapsed and refractory multiple myeloma and Kite’s highly anticipated anito-cel is also set to debut in the indication this year.
A key question for ESO-T01 and other in vivo candidates will be the durability of their cancer eradication. While the AstraZeneca asset has scored a 60% complete response rate at two months in this small patient sample, anito-cel’s mark rose over time from the high 60s to 74% complete responses after 15.9 months.
While acknowledging to Fierce this morning that “every death is a tragedy,” an AstraZeneca spokesperson pointed out that all five patients on the study had multiply relapsed, refractory and aggressive forms of multiple myeloma.
The phase 1 trial was launched before AstraZeneca acquired EsoBiotec, the pharma noted. Overall, the studies of ESO-T01 have “demonstrated that in vivo cell therapy is feasible without lymphodepletion of patients and demonstrated clinical responses, validating this off-the-shelf approach.”
“AstraZeneca is now working to further develop in vivo treatments based on these results,” the spokesperson added.
EsoBiotec had previously published data from four patients in a separate cohort last July, which included similar details of CRS and ICANS cases. In that earlier study, the researchers found that ESO-T01 could seemingly eradicate extramedullary disease. No signs of spinal cord compression from an extramedullary lesion were seen in that earlier cohort, the authors noted in Wednesday’s paper.
Since AstraZeneca jumped into the in-vivo space, Big Pharma interest has only increased, with Eli Lilly buying Orna Therapeutics for up to $2.4 billion last month.
While AstraZenca was relatively late to the in-vivo game, EsoBiotec touted ESO-T01 as the first BCMA CAR-T candidate to enter the clinic back in 2024.
