Brief Background on Anti-CD19 CAR-T Immunotherapy
So far, CAR-T immunotherapy has been most successful against CD19-positive tumors such as(specifically B-ALL). CD19 is a cell surface molecule mainly expressed by mature B cells, meaning anti-CD19 CAR-T targets B cell tumors but also normal B cells. Despite considerable differences in CAR-T constructs used in different studies ( , , , ), specifically
- different short-chain variable fragments, scFv (the anti-CD19 antibody variable domain) that would be expressed on the CAR-T cell surface to bind to the CD19 expressed by the B cell tumor, and
- different stimulating elements (CD28 or 4-1BB +/- CD3 ) that would get inserted into its cell membrane to signal within,
so far anti-CD19 CAR-Ts have yielded impressive anti-tumor responses in relapsed or refractory populations. This is interpreted as a considerable advance since these were patients who’d failed standard therapies.
Reversible Neurotoxicities as also Fatalities have occurred in various Anti-CD19 CAR-T Immunotherapy Trials
Since such studies began, different groups, including Juno, Novartis and Kite, testing CAR-T immunotherapy for B cell cancers have reported severe side effects including CRS orand neurotoxicity as well as fatalities.
- CRS ranged from low-grade to high-grade fevers, muscle pain (myalgia) and severe hypotension ( ).
- CNS ( ) involvement is striking and unexpected since it occurred even in patients without disease in CNS. Neurotoxicity symptoms ranged from (lack of coordination), confusion and delirium to speech loss (aphasia), hallucinations, headaches, seizures ( , , , , 8, 9).
- While different studies reported anti-CD19 CAR-T associated-neurotoxicities in 13 to 53% of patients ( ), they were reversible with speedy admission into critical care and aggressive management.
Juno’s ROCKET trial: Too Many Fatalities, All from Cerebral Edema. Why: Patient selection criteria and/or CAR-T construct and/or dose?
Juno’s ROCKET trial was different because it had far more fatalities and all from the same cause, cerebral edema, something previously unreported. Juno Therapeutics first reported 3 fatalities among enrolled patients with resistant/refractory B-ALL ().
Some additional background is necessary at this point. Early in tests of CAR-Ts, scientists observed that depleting patients of lymphocytes (aka lymphodepletion or conditioning) seemed to improve clinical response. Speculation is reducing patient’s own circulating lymphocytes prior to infusing them with CAR-Ts reduces competition for cytokines such as IL-7 and IL-15 that CAR-Ts need to survive and expand. Accordingly, patients in Juno’s ROCKET study also received conditioning consisting of/ , a nucleoside analog and an alkylating agent, respectively.
FDA put this trial on hold after 3 patients died but then lifted the hold in a record short time, allowing it to resume after removing Fludarabine alone, implying it was the source of increased neurotoxicity. However, two more deaths occurred even after this modification in the conditioning regimen, which led to the FDA stopping this trial.
It’s difficult to decipher what led to these fatalities since all the relevant factors aren’t (yet) in the public domain. However, comparing variables between different trials helps narrow down options (see below from) to patient selection and CAR-T construct and dose.
Specifically, was there something different about their patient selection criteria and CAR-T construct, and did they use a different perhaps larger dose? This is because
- Conditioning regimen of Fludarabine/Cyclophosphamide is commonly used in such trials with no reports of similar problems so that’s out as a probable cause.
- Juno used autologous CAR-T cells (derived from patients themselves) as did Novartis and Kite.
- Juno used a similar CAR-T construct to the one currently being used by Kite in its anti-CD19 CAR-T trial ( ). However, Juno tested it for ALL while Kite’s ongoing trial is against non-Hodgkin’s lymphoma (NHL). Safe in NHL (at least as of Aug 2017) but not in ALL patients would be an obvious speculation, and determining what the difference entails would be an obvious question to explore.
- Novartis (
) and Fred Hutchinson Cancer Research Center ( ) are using a different CAR-T construct against ALL.
- Key difference is the signaling domain in their CAR-T is derived from 4-1BB while Juno and Novartis use one derived from CD28 (see below from ).
- Studies suggest the CD28 signaling domain enhances anti-tumor activity ( ) while the 4-1BB signaling domain confers longer persistence ( , ).
- Though the Novartis ( ) and FHCRC ( ) trials are still ongoing, they already report high percentages of 82 (24 of 29) (18) and 93% (27 of 29) ( ), respectively, complete response, which is disappearance of all clinical evidence of disease. No reports yet (as of Aug 2017) of fatalities due to cerebral edema.
- Unfortunately, patient selection criteria and CAR-T dose Juno used in their ROCKET trial aren’t yet available in the public domain (as of Aug 2017) so conclusions about their role can only be speculative.
- Dose is an especially interesting consideration since one FHCRC study ( ) done in collaboration with and funded by Juno showed a correlation between CAR-T cell dose and time of peak CAR-T expansion.
- What was additionally interesting about this study is that even though they infused CD4 and CD8 CAR-T cells at a 1:1 ratio, they found higher absolute numbers of CD8s at the peak of expansion.
- Since activated CD8 are presumably the effector cells that actually kill the tumor cells, whether dose-dependent expansion of this type of 2nd generation CD8 CAR-Ts could contribute to cerebral edema in relapsing/refractory B-ALL at the dose Juno used in its ROCKET trial is a possibility to consider.
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