Shares of Adaptimmune slid 12% yesterday morning after the company updated its TCR therapy to include fludarabine, which was linked to deaths in Juno’s CAR-T trials.
Despite optimism that T-cells are the key to cancer cures, the field has taken a number of hits this year. Most recently, the FDA put a partial hold on the clinical development of Adaptimmune‘s lead program last August after it proved ineffective in Phase I/IIa trials for a rare form of cancer. Adaptimmune is attempting to fix the problem by preconditioning future patients with fludarabine, the chemotherapeutic agent linked to the deaths in Juno’s CAR-T therapy trials.
In these trials, fludarabine was faulted for three fatal cases of cerebral edema and one of lethal neurotoxicity. Despite its infamy, John Carroll at Endpoints notes that fludarabine remains a “vital part of the preconditioning regimen” in cell therapies, because it allows cells to proliferate and kill off their cancerous counterparts. Indeed, Adaptimmune believes patients did not respond to its therapy as a result of omitting this drug and instead relying upon cyclophosphamide alone.
We hope that, as previously observed in synovial sarcoma, this lymphodepleting regimen will enable anti-tumor immune responses mediated by NY-ESO SPEAR T-cell therapy in these patients with advanced chemotherapy relapsed or refractory ovarian cancer.” Dr. Rafael Amado, CMO of Adaptimmune.
Unfortunately, fludarabine also kills healthy cells and in a high enough dose, it can lead to death, as was demonstrated in the cautionary tale of Juno. As with most things medical, moderation is key: the trick is to tune the fludarabine dosage to avoid causing death. Investors have reacted to its inclusion with skepticism, as the stock price plummeted to €5,53 yesterday morning after closing at €6,56 on Tuesday evening.
Even so, Adaptimmune is steadfastly forging ahead with plans to enroll another 10 patients in an updated trial. The company has an additional 5 other therapies in Phase I/II trials for different cancers (synovial sarcoma, multiple myeloma, ovarian cancer, melanoma and non-small cell lung cancer). T-cell therapies represent a less crowded field than the rest of those in immuno-oncology; while this setback isn’t a competitive catastrophe for Adaptimmune, it could give one of its rivals an advantage the company could come to regret.
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Figure 1: Juan Gaertner/shutterstock.com