Adaptimmune in the clear over latest patient death

Adaptimmune has survived two scares with patient deaths in trials of its engineered T-cell receptor therapies in the past, and it looks set to survive a third, reported just this week.

The death, on November 13, concerned a lung cancer patient in a safety study of Adaptimmune’s TCR against the Mage-A10 antigen, and came to light because the patient and his family had detailed his progress on a blog and Facebook page. Adaptimmune tells EP Vantage that the trial’s investigator has deemed the death to be unrelated to T-cell therapy, a finding confirmed by a safety review committee that includes external experts.

According to the Facebook entries the patient appeared to have suffered pulmonary failure, with fluid building up in his healthy lung, having been admitted to intensive care on October 29 – just 12 days after receiving the TCR-modified T cells. He died two weeks later, 27 days after cell infusion.

No clinical hold

Independent verification that this was not a treatment-related effect should allay fears of another clinical hold for Adaptimmune, and explains why the company has not issued a formal statement about the death.

However, the circumstances around the fatality are relevant for a number of reasons. Most importantly, the relatively quick death seems at odds with the trial’s recruitment criteria; the study specifically aims to enrol subjects with ECOG performance status 0-1, implying relative health, and an expected life expectancy of over three months.

Moreover, this is a safety trial, which as its primary endpoint measures pulmonary function as one of a number of potential dose-limiting toxicities.

On the other hand, Adaptimmune states that its studies “are recruiting patients with advanced disease, who present a high risk of disease progression that can unfortunately lead to death”. Indeed, recruitment criteria aside, the patient in question was a non-smoker with NSCLC, which tends to imply particularly aggressive disease.

Adaptimmune's engineered TCR work – not plain sailing
Project Indication Date Issue Resolved?
Mage-A3 TCR Melanoma & multiple myeloma 2011/12 Two patient deaths of heart failure Asset redesigned
NY-ESO-1 TCR Gastro-oesophageal cancer Aug 2015 One treatment-related death leading to clinical hold Hold lifted after 4 months
NY-ESO-1 TCR Myxoid round cell liposarcoma  Oct 2016 Clinical hold after US FDA request re chemistry & manufacturing controls Hold lifted after 1 month
Mage-A10 TCR NSCLC 13 Nov 2017 One patient death Deemed not treatment-related

That said, toxicities are a major focus of therapies involving the adoptive transfer of cell therapies including engineered TCRs and CARs, whose effects on the immune system are still not entirely understood.

In CAR-T cytokine release syndrome and neurotoxicity have led to fatalities, while patient deaths due to cerebral oedema caused Juno to scrap development of JCAR015 and gave Kite a scare in the pivotal Zuma-1 trial of Yescarta (Spotlight – Putting a number on CAR-T deaths, June 26, 2017). A study of Cellectis's UCART123 has only just come off clinical hold after the death of its first enrollee. 

Adoptive cell therapies represent cutting-edge science for late-stage patients with advanced diseases, so safety will continue to be a live issue.

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