Key Takeaways
- AstraZeneca’s in vivo CAR-T candidate ESO-T01 shows preliminary efficacy but has faced safety concerns in trials.
- The death of a patient raises questions about anatomical risk stratification in multiple myeloma therapies.
- Despite challenges, AstraZeneca remains committed to developing in vivo therapies amid increasing industry interest.
AstraZeneca Pursues In Vivo CAR-T Development Amid Safety Concerns
AstraZeneca is maintaining its commitment to the development of its in vivo CAR-T therapy, ESO-T01, even after a patient death was reported during a phase 1 trial in China. The candidate, intended for treating multiple myeloma, is part of AstraZeneca’s $1 billion investment following the acquisition of Belgium-based EsoBiotec.
Recent data published in Nature Medicine indicates that ESO-T01 demonstrated promising results, with four out of five patients achieving positive responses, including three achieving stringent complete remissions within 60 days. The authors of the study stated that the findings reflect both the feasibility and safety of in vivo CAR-T generation with the immune-shielded vector used in ESO-T01.
However, the trial results also highlighted significant safety concerns. Although the drug was generally well tolerated without dose-limiting toxicities, all participants experienced grade 3 or higher adverse events. Cytokine release syndrome (CRS), a serious side effect associated with immunotherapy, affected four patients, with three reaching grade 3. Other frequent side effects included transient cytopenias and heightened hepatic enzyme levels, alongside grade 2 infections in three patients.
Tragically, one patient developed grade 1 immune effector cell-associated neurotoxicity (ICANS) and later died from spinal cord compression linked to an extramedullary lesion—an area beyond the bone marrow where multiple myeloma typically thrives. The authors indicated that the fatality emphasizes the need for anatomical risk stratification when administering in vivo CAR-T therapies, particularly in patients with preexisting extramedullary conditions.
While CRS and ICANS are not unusual in traditional CAR-T therapies, the authors noted that the sequence of toxicities in the in vivo approach may suggest differing underlying biological mechanisms. This uncertainty about safety could jeopardize ESO-T01’s competitive edge against already approved therapies like Johnson & Johnson’s Carvykti and Kite’s upcoming anito-cel, particularly since they demonstrate higher response rates over extended periods.
AstraZeneca acknowledged the challenges during this early trial, which began prior to the company’s acquisition of EsoBiotec. The spokesperson emphasized that ESO-T01 has shown efficacy without requiring lymphodepletion, validating the off-the-shelf approach it employs.
Despite the setbacks highlighted by the patient’s death, AstraZeneca remains optimistic about the potential of in vivo treatments, working to further innovate based on the initial results. Notably, EsoBiotec had previously reported similar adverse events in earlier cohorts while also suggesting the potential for extramedullary disease eradication.
Interest in the in vivo cell therapy space continues to grow, evidenced by Eli Lilly’s recent acquisition of Orna Therapeutics for $2.4 billion. Though AstraZeneca entered the field later than some competitors, it promotes ESO-T01 as a pioneering BCMA CAR-T candidate, which commenced clinical trials in 2024. This strategic focus on advancing innovative therapies amidst safety and efficacy concerns reflects the evolving landscape of cancer treatment.
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