Lyell Reports Early CAR T Trial Death, High Response Rate

Lyell Immunopharma has released encouraging initial Phase I data for its experimental CAR-T therapy, LYL797, though safety concerns cast a shadow over the findings. Among the participants, one patient succumbed to grade 5 respiratory failure on the 41st day of treatment. The company has yet to confirm if this fatality was directly related to the therapy.

The early-stage data involved 20 patients, with 16 suffering from triple-negative breast cancer (TNBC) and the remaining four from non-small cell lung cancer (NSCLC). All patients had metastatic disease that was either relapsed or refractory, having gone through an average of six previous treatment regimens.

Adverse events were prevalent, with over 60% of patients experiencing cytokine release syndrome, though most instances were mild. Additionally, 22% of the patients developed pneumonitis, an inflammation of lung tissue not caused by infection. This was the most frequent toxicity of grade 3 or higher, particularly in TNBC patients with lung metastases. To address this, all patients are now receiving prophylactic dexamethasone therapy.

Despite these complications, Lyell remains hopeful regarding LYL797’s safety profile, noting that no dose-limiting toxicities were identified in patients without lung involvement. The company also highlighted the absence of immune effector cell-associated neurotoxicity syndrome linked to the therapy.

David Spigel, Lyell’s Chief Scientific Officer, emphasized the occurrence of pneumonitis, calling it a known side effect of treatments like radiotherapy and various approved cancer therapies including immune checkpoint inhibitors and antibody-drug conjugates. He expressed confidence in the steroid protocol implemented to manage and monitor these events.

LYL797 is designed to target the ROR1 protein, which is crucial for cell migration and survival, and is often overexpressed in many cancers, indicating a poor prognosis. Lyell has enhanced this CAR-T therapy using anti-exhaustion genetic and epigenetic reprogramming technologies to increase its effectiveness.

The Phase I study, while raising safety concerns, also demonstrated promising efficacy for LYL797. In TNBC patients treated with a 150 x 10^6 cell dose, the objective response rate was 40%, and the clinical benefit rate (CBR)—defined as achieving stable disease, partial response, or complete response—was 60%. Across all dosage levels, the therapy achieved a CBR of 38%.

Lyell plans to continue developing LYL797, and is exploring higher doses, specifically a 300 x 10^6 cell dose for patients without lung involvement. Patients with lung metastases will be treated with a lower 75 x 10^6 cell dose of LYL797.

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