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.

Figure 1. T-cells

Figure 1. T-cells

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 sarcomamultiple myelomaovarian cancermelanoma 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.


Featured Image: Tefi/shutterstock.com
Figure 1: Juan Gaertner/shutterstock.com

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  • Dieter Hovekamp

    Better do your homework:
    1) T-cell therapies are all flavors — including CAR-T — what is difficult and not that crowded is TCR T-cell therapies like Adaptimmune’s SPEAR® method
    2) the partial-hold was NOT related to Adaptimmune’s own clinical trials, Juno use of fludarabine, or any other safety issues but for CMC-manufacturing questions from the FDA before (!) a newly planned pivotal study can enroll patients in the clinic
    3) lymphodepleting regimes including fludarabine are a standard before giving an immunotherapy.
    Juno added fludarabine to its regime in JCAR015 trial after it found positive evidence elsewhere (see http://www.bloodjournal.org/content/126/23/3773?sso-checked=true )
    and got the sad death that FDA ordered a halt for.
    Juno’s quick fix by removing fludarabine from the protocol again to get a lift of the clinical hold by the FDA has nothing to do with the scientific finding Adaptimmune received by explicit study they did in a cohort without fludarabine (see update at ESMO http://ir.adaptimmune.com/phoenix.zhtml?c=253991&p=irol-newsArticle&ID=2210294 ).
    As planed by Adaptimmune earlier this year these findings now let to the modification of the protocol and cohort extension in ongoing trials as reported for Ovarian Cancer here.

    • Thanks for your comment! As much as I enjoy being patronised, I suggest rereading the article for clarification re: 1) and straightening out 2) and 3) so that they don’t contradict each other re: the reasons for Juno’s clinical hold. I suspect the concern you expressed in these last two points would be resolved by, you guessed it, rereading the article.

      • Dieter Hovekamp

        Thanks for the update – and sorry for the harsh tone in my comment.

        Your article just happened not to be the first that mixes using fludarabine in preconditioning and Adaptimmune partial hold with safety issues in Juno clinical hold.

        Maybe my points were not clear either – so I’ll try it simple again:

        1) T-cell therapies are crowded – TCR (!) T-cell therapies less so.

        2) Adaptimmune and FDA try to align on a planned pivotal study with manufacture and design changes – not safety issues.

        3) There is new hope for patients with therapy resistant or refractory metastatic ovarian cancer that TCR T-cell therapy might finally work for them with the amended protocol.

        This is supported from the Juno scientific findings AND Adaptimmune’s systematic study outcome in Sarcoma patients that fludarabine should NOT be avoided in preconditioning!