In 2016, five patients died from complications of CAR-T (Chimeric Antigen Receptors T cell) therapy in JUNO’s Rocket trial.
JUNO, to its credit even after retiring the CAR-T used in that trial, went back to look at what they could learn from the tragedy to lower risks and to improve CAR-T therapy going forward. This reports on the data they found by studying what went wrong and how they could improve going forward with a new CAR-T product.
Related recent publications are also reviewed.
If you are not familiar the basics of CAR-T, please see these two interviews with Dr. Porter from U Penn: Part 1 and Part 2 to get you started. Those interviews were done before we really recognized the significance of the rare, but potentially fatal brain inflammation that is investigated in this article.
A more detailed scientific explanation aimed at physicians is available from JUNO here:
Key Take Aways:
- CAR-T therapy has the potential to be lifesaving in chronic lymphocytic leukemia and other cancers for patients who have run out of options.
- Five of 38 adults with a difficult to treat dangerous leukemia, ALL (acute lymphoblastic leukemia) died in the ROCKET trial studying JCAR015.
- JCAR015 is now a “retired” a CAR-T therapy that is no longer being used.
- The brain swelling and inflammation what lead to the deaths was not anticipated.
- A high level of IL-15, a marker of inflammation, is associated with neurotoxicity.
- In this this article and this one, both from ASH, it appears that factors that leads to rapid expansion of CAR-T cells may be the trigger of neurotoxicity and CRS (cytokine release syndrome). CRS is a systemic inflammatory flare caused by release of excessive cytokines.
- This rapid expansion in turn is associated with elevated levels of cytokines (inflammatory enzymes).
- This leads to vascular instability, capillary leakage, causing the low blood pressure and possible organ failure with CRS and the increased permeability of the blood-brain barrier (BBB) leading to the brain inflammation. The more permeable BBB allows the cytokines into the brain where they can cause their damage.
- Both CRS and neurotoxicity can be fatal.
- This article from AACR lists factors associated with neurotoxicity:
- Higher dose of CAR-T cells.
- Earlier and more severe CRS (rapid expansion of CAR-T).
- Younger age, pre-existing neurological disease and a high tumor burden.
- JCAR017 is a newer very different CAR-T product that may cause less severe CRS and neurotoxicity.
- It is ill advised to assume what applies to CAR-T in ALL will also be true with CAR-T in CLL. That remains to be proven, but all information is helpful.
- CLL trials in CLL are ongoing and new ones will be opening in 2018.
It is only because of this kind of risky but groundbreaking research that we can move closer to a cure.
I am reminded of the deaths from TLS (tumor lysis syndrome) in the early trials of ABT-199, now known as venetoclax. Trials were halted for many months, and eventually restarted in a safer manner that eventually led to the approval of Venclexta, a life-extending drug for many with CLL.
CAR-T therapy is moving forward now and has the potential to be the same kind of sea change that happened in chronic lymphocytic leukemia with the introductions of the small molecule B-cell receptor blockers.
This progress only happens because of the courage and ultimate sacrifice of some in those early trials. We are all in their debt. And I for one am also grateful that there is a deep post-mortem being done on what when wrong and how we can improve.
Here is the link to Xconomy take on JUNO’s dive into the data.
Brian Koffman, MD 11/29/17