Putting A Number On CAR-T Deaths

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Includes: JUNO, KITE, NVS
by: EP Vantage

The toxicity of CAR-T therapies took on fresh importance with the discontinuation of Juno's (NASDAQ:JUNO) Rocket study of JCAR015 owing to deaths from cerebral edema. Little wonder that when Novartis (NYSE:NVS) presented its update of the Eliana trial of CTL019 one spotlight fell on safety.

The good news, according to Saturday's update at the European Hematology Association meeting, is that there were no new unexpected deaths, and no cerebral edema. How this plays out will be important: precise safety data are hard to pin down, but an exhaustive EP Vantage search of various sources has yielded a definitive list of CAR-T deaths not due to disease progression (see tables below).

This involves not just CTL019, but all of the three leading players' CD19-targeted projects. One little-appreciated finding is there have been seven deaths - two from cerebral edema - in trials of Juno's JCAR014. This has resonated little with investors, likely because Juno has long maintained that it does not intend to pursue JCAR014 to registration.

However, the close similarity with Juno's lead - JCAR017 differs from JCAR014 only in a manufacturing step - should push CAR-T followers to pay close attention to this issue. That said, reported deaths on JCAR017 have been substantially lower, the data show.


18 Juno study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
JCAR017 (Juno/Seattle Children's Hospital)
Lymphoma Transcend NCT02631044 Diffuse alveolar damage (subject refused mechanical ventilation) Yes Asco 2017
Lymphoma Transcend NCT02631044 Multiple organ failure No Asco 2017
JCAR015 (Juno/Memorial Sloan Kettering)
Adult ALL MSKCC study (Jae Park) NCT01044069 Severe hypotension, (ventricular arrhythmia?), CRS Yes Juno S-1, Dec 2014
Adult ALL MSKCC study (Jae Park) NCT01044069 Status epilepticus, CRS (history of neurotox w prior CAR-T)* Yes Juno S-1, Dec 2014
Paed/adult ALL MSKCC study (Kevin Curran) NCT01860937 Survived CRS, died 4mth later from multiviral pneumonia No Report to GTSAB
Adult ALL MSKCC study (Jae Park) NCT01044069 Sepsis, multi-organ failure Yes Ash 2015
Adult ALL Rocket NCT02535364 Neurotox, later specified as cererbral edema Yes Juno Q3 2016 SEC filing
Adult ALL Rocket NCT02535364 Cerebral edema Yes Juno 7 Jul 2016 call (revised)
Adult ALL Rocket NCT02535364 Cerebral edema** Yes Juno 7 Jul 2016 call (revised)
Adult ALL Rocket NCT02535364 Cerebral edema Yes Juno Q4 2016 SEC filing
Adult ALL Rocket NCT02535364 Cerebral edema*** Yes Juno Q4 2016 SEC filing
JCAR014 (Juno/Fred Hutchinson)
Adult ALL Hutch study NCT01865617 CRS Yes Juno S-1, Dec 2014
Lymphoma Hutch study NCT01865617 Encephalopathy and pontine haemorrhage Yes Ash 2015
Adult ALL Hutch study NCT01865617 Cerebral edema Yes 7 Jul 2016 call (revised)
CLL Hutch study NCT01865617 Pulmonary aspergillosis after severe CRS No Ash 2015
Lymphoma Hutch study NCT01865617 CRS or neurotox Yes Juno Q4 2016 SEC filing
Adult ALL Hutch study NCT01865617 CRS or neurotox Yes Juno Q4 2016 SEC filing
CLL Hutch study NCT01865617 CRS, cerebral edema Yes Juno Q4 2016 SEC filing
Note: patient exposure numbers are undisclosed for JCAR015, JCAR017 or JCAR014. CRS=cytokine release syndrome.*FDA-imposed clinical hold. **Second FDA-imposed clinical hold. ***Voluntary clinical hold, leading to discontinuation of JCAR015.

The toxicity of CAR-T therapies has been problematic ever since the first signs of truly robust activity were seen - it is known that cytokine release syndrome and neurotoxicities correlate with efficacy and tumor burden.

However, nurses have become very skilled at dealing with these types of toxicities, and several important centers have developed detailed plans to minimize their effects. Nonetheless, the specific finding of cerebral edema posed very serious questions, and ultimately did for JCAR015, which until recently was Juno's lead.

The issue also hit Kite's (NASDAQ:KITE) KTE-C19, a construct very similar to JCAR015, and this group's stock took a tumble last month when a patient died from cerebral edema in a safety extension cohort of the pivotal Zuma-1 lymphoma study (Kite investors see an uncomfortable parallel with Juno, May 8, 2017).


Nine KTE-C19 study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
Lymphoma NCI phase I-IIa trial, group 1 NCT00924326 Influenza pneumonia 18 days after receiving CAR No Kite S-1, Dec 2014
Lymphoma NCI phase I-IIa trial, group 2 NCT00924326 Unknown cause 16 days after receiving CAR, presumed heart arrhythmia No Kite S-1, Dec 2014
Lymphoma Zuma-1, phase I NCT02348216 Gr 4 encephalopathy & CRS, gr 5 intracranial hemorrhage & severe thrombocytopenia No Ash 2015
Lymphoma Zuma-1, phase II NCT02348216 Hemophagocytic lymphohistiocytosis Yes Ash 2016
Lymphoma Zuma-1, phase II NCT02348216 Cardiac arrest in setting of CRS, later specified as anoxic brain injury Yes Ash 2016, FR doc 2017-07800
Lymphoma Zuma-1, phase II NCT02348216 Pulmonary embolism No Ash 2016
Adult ALL Zuma-3 NCT02614066 Hypotension, heart failure, hypoxemia, acidosis in dose expansion, organ failure & CRS Yes Ash 2016
Paed ALL Zuma-4 NCT02625480 Fungal infection No Ash 2016
Lymphoma Zuma-1, safety expansion cohort NCT02348216 CRS, multi-organ failure, leading to cerebral edema Yes Q1 2017 call
Note: ~300 subjects have been dosed KTE-C19, including NCI studies. CRS=cytokine release syndrome.

The data need to be seen in the context of several important caveats. Firstly, they comprise all disclosed CD19-directed CAR-T trial deaths that were not due to disease progression, whether these were deemed to be due specifically to the CAR-T cells or not - a subjective decision made by the specialist in question.

Early deaths on trials of KTE-C19 and JCAR015 were in the academic setting, and will have involved academic rather than commercial manufacturing. In evaluating the frequency of deaths the total number of patients treated must be borne in mind - though this is a number Juno has never disclosed.

And of course it must be remembered that subjects on CAR-T studies are very ill, so are already at high risk of death. While this does not reduce the need for clinical rigor, several sources have commented to EP Vantage off the record that Juno might - scientifically if not reputationally - have been rash to discontinue JCAR015.

Extreme care must also be taken in extrapolating JCAR014 deaths to JCAR017; the deaths caused Juno to continue its ALL trial only with the lowest JCAR014 dose (2x105 cells/kg), and to scrap two higher levels. Juno has yet to choose a dose of JCAR017 to take into its pivotal lymphoma trial.

All that said, taking into consideration the caveats the data should speak for themselves.

After EP Vantage compiled the lists Kite and Juno cooperated fully in confirming the data as accurate. Novartis, however, did not respond to requests for clarification; as such, it is possible that there have been more deaths on CTL019 trials, and the list comprises only the two that came to light in scientific presentations.


Two CTL019 study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
Lymphoma Penn study (Stephen Schuster) NCT02030834 Encephalitis Yes Ash 2015
Paed ALL Eliana NCT02435849 Cerebral haemorrhage Yes Ash 2016
Note: 283 subjects have been dosed CTL019.

Across CAR-T projects, the cerebral edema deaths tally with those reported at December's meeting of the US Recombinant DNA Advisory Committee, which additionally detailed two non-fatal cerebral edema cases, one in a multiple myeloma study of an anti-BCMA CAR.

Several of the other neurotoxicity-related deaths disclosed - brain hemorrhage, for instance - sound uncomfortably close to cerebral edema. But it should be stressed that after the JCAR015 incident most groups went back and reanalyzed all previous toxicities to ascertain whether cerebral edema might have been involved, and to rule out such a possibility.

Mechanistic mystery

Meanwhile, it is one of the many mysteries of CAR-T therapy that there is still no agreement on what precise mechanism might be responsible for causing cerebral edema, though it is largely accepted that, being a cytokine-mediated event, it is something that arises from cytokine release syndrome.

Some doctors have told EP Vantage that this likely involves activated CAR-T cells crossing the blood-brain barrier, and then undergoing some kind of secondary activation event in the cerebrospinal fluid. However, many dismiss the simple answer that this results from expression of CD19 in the CNS.

An even deeper mystery is what aspect of CAR-T therapy might give rise to this kind of stimulation. Some have suggested the role of the co-stimulatory domain that each construct uses, others the manufacturing process, others still the indication studied, but given that all the CAR constructs differ in multiple ways, and that the numbers are still small, there is no way to be sure.

The FDA is separately compiling its own database of CAR-T toxicities. The provisos notwithstanding, investors should at the very least be aware of the numbers as they emerge.