【近期，国际肿瘤免疫细胞治疗领域热门话题之一无疑是CAR-T细胞治疗巨头JUNO公司的JCAR-015产品在ROCKET II/III临床试验中出现3例患者因严重CNS毒性而病逝，其中最近的2例死亡事件更直接导致该临床试验被FDA hold，尽管现在FDA已经接受JUNO的解释 - Flu+Cy预处理方案是导致3例患者死亡的主要原因，并同意JUNO的提议-采用去除Flu而仅采用Cy的预处理方案继续临床试验，但马念相信该事件仍然没有完全结束，本文仅交流一下笔者对该事件粗浅的理解】
Deep Dive into 3 Death -Homeostatic Proliferation May Explain
by MA Nian
26 -July- 2016
FIRSTOF ALL, it is very difficult to draw a conclusion on the exact reason andmechanisms underlying the death at this stage, since I do not have as enoughinformation as both JUNO and FDA have, but we could make a personal “rational speculation”. ：）
JUNO has listed the possiblefactors in the slides submitted to FDA soon after the death, includingconditioning regimen, patient characteristics, toxicity management, cell dose,product/CMC attributes… and then in the conference call, JUNO was pointing the combinationof the more potent pre-conditioning regimen with flu and cys with the JCAR015 thatprompted the deadly events. and although with the approval of FDA, JUNO willcontinue the ROCKET trial with the new protocol with cy only aspre-conditioning regimen now.
JunoTherapeutics, Inc. Corporate Presentation – July 2016 submitted to FDA
BUT NOT CONVINCING TO ME…
INSTEAD, I PERSONALLY THINK, THE T-CELL RELATED CELL EXPANSION MAY BE THE FIRST CHOICE OF ‘CHIEF CUPRIT’ FOR THE CAR-T CELL THERAPY RELATED SIDE EFFECTS INCLUDING sCRS AND NEUROTOXICITY, AND PRE-CONDITIONING REGIMEN (WITH FLU + CY) IS JUST ONE OF FACTORS AFFECTING THE DIFFERENCE IN T CELL EXPANSION.
Cy or Cy plus Flu as pre-conditioning regimen, have been widely used in cell therapy, for example, TIL based tumor therapy by Pro. Rosenberg, with good safety, even in combination with TBI sometime;
Severe CRS and neurotoxicity were also reported in clinical trials without cy or flu plus cy involved, such as BLINCYTO, a bispecific antibody drug by Amgen; TGN1412, an anti-CD28 antibody; and OKT3, an anti-CD3 antibody. However, one of the common features among all these products or trials is that their effacy is mainly dependent on the strong expansion of T lymphocytes;
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Again in JUNO’s conference call, the KOL highlighted for a few time that the big difference with flu + cy regimen is the “rate of increase” of T cells, while not only the expansion and persistence of T cell in vivo; BUT the mechanism for this remainsnot clear according to JUNO, although several hypotheses offered;
JunoTherapeutics, 8K , July 2016
BUT in fact, from my personal point of view, there is another possible mechanism underlying the benefit of lymphodepleting pro-conditioning regimen, Homeostatic Proliferation, which may be able to explain the difference in T cell expansion and relevant side effects. Homeostatic Proliferation, is a special kind of T cell expansion only happed in the situation of lymphopenia, such as drug induced strong lymphodepletion, in which the residual T cells in vivo after depletion or T cell infused will proliferate automatically independent of antigen stimulation, and differentiate preferentially into memory-like cells. That is to say, the few T cells in the body could try to recover both quantitalively and qualitatively by rapid proliferation to recover the protection role ASAP. So CD19-CAR-T cells will experience both antigen independent homeostatic proliferation and CD19 antigen dependent expansion in vivo in case of lymphodepleting pre-conditioning. And this is consistent with the findings that more expansion and persistence in CAR-T trial when with cy plus flu as pre-condition.
Royalsocietypublishing 2005
Trends in Immunol 2009
BUT, the happening and extent of Homeostatic Proliferation are dependent on many factors, including but notlimited to, the cell number of residual T cells and infused T cells, cell differentiation status, the in vivo level of cytokines such as IL-7, IL15, IL-21... While, in clinic, all these factors after the lymphodepleting treatment and CAR-T cell infusion are very different in different patients, which could obviously lead to a big difference in Homeostatic Proliferation in different patients. In case some patients happen to undertake a super-strong Homeostatic Proliferation soon after the infusion of the CAR-Tcells, the super neurotoxicity, for example fatal cerebral edemain in JUNO, esp, when toxicies not well-managed in time, could consequently happen.
The hypotheses about Homeostatic Proliferation could also explain another two death in ALL patients and two deaths in NHL patients happened in JCAR014 trial.
SO FROM MANIAN’S PERSONAL POINT OF VIEW, REMOVAL OF THE FLU FROM PRE-CONDITIONING REGIMEN WILL NOT COMPLETELY ELIMINATED THE POSSIBILITIES OF SEVERE EVEN FATAL NEUROTOXICITY IN CAR-T CELL TRIALS IN THE FUTURE.
Again, of course, other possibilities cannot be rule out, such as on-target off-tumor effect, toxicity management…. which I am going to discuss in next article
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