NorthWest Biotherapeutics Inc (NWBO)

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Take your time - and anyone else that cares to weigh in. I am curious to see if others agree, or can find something I missed.

Please note, I'm writing this as if to the NEJM. Obviously I'm not writing it to them, at this time.

If you are interested in looking through this, you will need to read the article, look at the supplements, etc.
You will not hurt my feelings if you're able to point out where I'm wrong... I'll appreciate it, as this was my reaction to the article, and I could certainly be in error. This is certainly not what I do for a living, so I'm ready to see what others might think.

https://www.nejm.org/doi/full/10.1056/NEJMoa1610497
Journal article

Have at it.

:)


I’m writing to point out various problems with your article entitled “Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy” dated December 29, 2016. I believe there are two prominent problems with this article, and they concern the timing of the diagnosis of “multifocal leptomeningeal disease” with the patient, as well as the 7.5 month dramatic clinical response time claimed.

Initially, and in the “Case Report”, the 50 year old patient presents with glioblastoma in the right temporal lobe. There is no mention of this patient having multifocal leptomeningeal disease when he originally presented in the “Case Report”. The patient is then enrolled into the IL13Ra2-targeted CAR T study, but does not begin treatment as the CAR T cells are being manufactured. During this time, the patient participates in a different study (clinical trial NCT01975701) for BGJ398, an FGFR inhibitor.

clinical trial: BGJ39
https://clinicaltrials.gov/ct2/show/NCT01975701?cond=NCT01975701&rank=1


While still in the “Case Report” section of your article, it is implied that after enrolling in the BGJ398 trial, the patient’s disease progressed rapidly with the development of multifocal leptomeningeal glioblastoma in both cerebral hemispheres, because as you can read in the excerpt below, the sentence beginning with “However, the disease progressed rapidly during treatment, with the development of multifocal leptomeningeal glioblastoma involving both cerebral hemispheres” immediately follows the sentence about how the patient began treatment in the BGJ398 trial. This is extremely misleading as it becomes evident when looking at the data in this article that the multifocal leptomeningeal GBM began after the treatment in the clinical study for CAR T (clinical trial NCT02208362) began.

While the IL13BB?–CAR T cells were being manufactured, the patient participated in an investigational clinical trial (ClinicalTrials.gov number, NCT01975701) at a different institution (Fig. S2A in the Supplementary Appendix). However, the disease progressed rapidly during treatment, with the development of multifocal leptomeningeal glioblastoma involving both cerebral hemispheres (Figs. S3 and S4 in the Supplementary Appendix).

This passage clearly reads and implies that the disease progressed rapidly and the patient developed multifocal leptomeningeal glioblastoma while in clinical trial NCT01975701 and while on treatment BGJ398; after which, the patient THEN began to receive treatment from clinical trial NCT02208362, the CAR T therapy.

In fact, the article even assures the reader that the multifocal leptomeningeal glioblastoma occurred before treatment began in the CAR T therapy. Looking at the “Clinical Response” section, it states that “At the time of treatment, the patient presented with a highly aggressive recurrent glioblastoma with features indicating a poor prognosis, including multifocal leptomeningeal disease (Figs. S3 and S4 in the Supplementary Appendix)”, indicating that the patient “presented” with the spinal tumors.

However, when looking at the S3 and S4 figures that the article refers the reader to as proof this multifocal leptomeningeal disease (as evidenced by the spinal tumors - specifically T8) presented at time of treatment (and not after treatment), they do not present any MRIs for any spinal tumors which is what multifocal leptomeningeal disease is represented by. Figure S3 indicates Tumor 1, T2, and T3, and there are no spinal tumor MRIs present. Figure S4 B indicates MRIs for T1, T2, T3 again, and then adds T4, T5, T6 and T7, and again, there are no spinal tumors MRIs presented. Figure S4 A indicates tumor T8 (the spinal tumor) as a large 18mm tumor with along with multiple small spinal tumors, however, in the article we learn that tumors T6 and T7 occur later and after CAR T treatment begins. Table S3 also indicates with an asterisk that tumors 6 and 7 were not diagnosed prior to the treatment cycles 4-6, and while the number 8 always follows 7, in this article, somehow the 8th tumor was diagnosed prior to the 7th. Additionally, there is no asterisk by tumor 8 in Table S3 to indicate it to be a “new lesion arising during Cycles 1-6”, implying, of course, that it is was present before CAR T treatment began. Table S3 also indicates that the Spinal tumor was ND “imaging was not done”, until some time POST the 6th cycle, when the spinal tumors were suddenly present and measuring a full 270 mm!

And again, I’d argue that the NEJM article implies that ALL of the tumors shown in Figures S3 and S4, including T8, which is not shown, occurred while the patient was enrolled in the BGJ39 trial and before receiving CAR T IL13BB? treatment.

Continuing in the Case Report section, even though I’d argue that the article initially read as if tumors 6 and 7 (along with 8) were already present when the CAR T treatment began, we learn that that tumors T6 and T7 are new, and were discovered AFTER treatment with IL12Ra2 began, as indicated below, and by the asterisk shown on Table S3. Still, how on earth can tumor T8, the eighth tumor, the CNS tumor, and the evidence of multifocal leptomeningeal glioblastoma disease, have already been present BEFORE the patient even began treatment with IL12Ra2, when tumors 6 and 7 began AFTER treatment with CAR T IL13BB??

Although the local treated site (tumor 1) remained stable during this treatment phase, with no evidence of disease progression, two new lesions (tumors 6 and 7) appeared near the previously resected frontal-lobe tumors (tumors 2 and 3), and the nonresected tumors (tumors 4 and 5) continued to progress.

One can only argue strongly that the CNS tumor did not occur BEFORE the CAR T treatment began, as the authors would like you to believe, and the fact that there was no MRI scan presented, AND NO IMAGING DONE is simply more proof of this. How could they know there was evidence of multifocal leptomeningeal glioblastoma disease if no MRI was performed to indicate this?

In the “Results”, and under the “Clinical Response” section, the authors claim that during the first 6 weekly intracavitary infusions (cycles 1-6), tumor T1 remained stable. The MRIs also indicated that tumors T4 and T5 in the left temporal lobe (that were not there when the patient first presented before beginning the trial employing BGJ39 - only the T1 in the right temporal lobe was present) were progressing. MRIs also revealed the two new tumors - T6 and T7 - that were located near the resected areas of T2 and T3. And these two tumors, 6 and 7, occurred AFTER the CAR T treatment began, and were also progressing.

It is also after the first 6 weeks of treatment that the authors eventually admit in the article that the large 18mm tumor known as T8, along with multiple smaller tumors, were revealed in the spine, when they state that they were “detected”, despite having written throughout most of the same article that the patient presented with these tumors before beginning CAR T treatment.

In addition, new metastatic lesions in the spine causing leg numbness, including one large tumor that was 18 mm in diameter and several smaller tumors (≤4 mm), were detected (Figure 2C, and Fig. S2A in the Supplementary Appendix).

So despite having written the article to indicate that the T8 spinal tumor occurred prior to CAR T treatment, it seems instead quite evident that it was discovered after the 6 weekly intracavitary infusions of the CAR T treatment. I believe this to be a critical error because while GBM is known to recur, and almost always does, for it to have metastasized to the spine would be considered to be a rare occurrence. It is also very painful, often resulting in severe back pain, paraparesis, and bladder-bowel incontinence, and is usually considered to be fatal as well. In fact, a study by Vertosick FT and Selker RG, entitled “Brain stem and spinal metastases of supratentorial glioblastoma multiform: a clinical series”, indicated that of 600 patients, only 2% developed symptomatic CSF tumor dissemination.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075830/#ref7

And yet, one of the first GBM patients to ever be treated with a CAR T treatment develops a very large tumor, and multiple other tumors in the spine in the first 6 weeks of the CAR T treatment. And following that, the authors present this case in the New England Journal of Medicine as if this spinal tumor instead occurred BEFORE the IL12Ra2 CAR T treatment began. I’d argue that with so many eyes on CAR T as a promising possible treatment in solid tumors, and with thus far so little published hope being offered patients in the treatment of glioblastoma, this was a serious miss on the part of those conducting any peer review of this paper.

I believe it is evident that the spinal tumor T8 was a result of the CAR T IL13BB? given, as this tumor was discovered AFTER the CAR T IL13BB? had been given, and I also believe that the authors intentionally tried to hide this fact. Additionally, and certainly of interest, is that Table S3 from the supplementary indicates that even after the first 3 CAR T cycles, there was no imaging even performed or provided of the spinal tumors. And I’d argue that had there been any spinal tumors present, the MRIs would have been done on them. By the time that the 4th and 5th CAR T cycles were completed, the T8 tumor in the spine, as well as the multiple smaller tumors also present in the spine, equaled a total of 270mm in size. The patient was complaining about leg numbness, which is likely why they took an image of the spine, and lo, there the spinal tumors were, after 6 cycles of the CAR T.

I had also earlier indicated that I felt it was wrong to describe the 7.5 month “dramatic” clinical response. The authors state it was “sustained for 7.5 months after the initiation of CAR T-cell therapy”, but I’d argue differently as this is not a correct representation of the time that any “dramatic” response was achieved.

I believe it is evident that in the first 6 weeks of the intracranial treatment, at least three new tumors developed (T6, T7, T8), including one that was a full 18mm in size; therefore that first month and a half can hardly be considered to have offered any type of “dramatic” clinical response except to result in developing additional tumors, including the very rare, large T8 in the spine.

At this point, the investigators chose to change directions and instead of continuing with the intracavitary infusions, they decided to directly infuse the CAR T into the patient intraventricularly; which they did by infusing the CAR T directly into his right lateral ventricle. They argued that they had adopted this new approach because they believed that while the CAR T cells were preventing tumor recurrence locally, the intracranial infusions were not sufficient enough to control tumor progression at distant sites.

Quote is somewhat of a repeat, but it's there to make my point:

In addition, new metastatic lesions in the spine causing leg numbness, including one large tumor that was 18 mm in diameter and several smaller tumors (≤4 mm), were detected (Figure 2C, and Fig. S2A in the Supplementary Appendix). These results suggested that although intracavitary administration of IL13BB?–CAR T cells may have prevented tumor recurrence locally (at the tumor 1 injection site), these infusions were not sufficient to effectively control tumor progression at distant sites.

Except, of course, that the tumors located on the spinal column - the “distant site” - were likely not new (and had begun with the first course of Car T therapy), so not only were they not controlled, they had instead developed due to the Car T treatment.

So at least 6 weeks had passed on the intracranial treatment, or a month and a half of the 7.5 month process for the first 6 infusions. They then stopped with the intracranial infusions, and began administering ten intraventricular infusions into the patient. On the 3rd treatment intraventricular treatment, on day 133, or around 4.4 month of the 7.5 month process, they observed a dramatic reduction in size of all the tumors. And by the fifth of the ten intraventricular infusions, on day 190, they noted that all the tumors (1 -8) had decreased by 77 to 100%, which is, of course, arguably dramatic. Please note that day 190 would be about 6.3 months into the 7.5 described trial timeline. Finally by the 16th cycle of CAR T treatment, on day 228, or 7.6 months later after the initial CAR T treatment had begun, the patient’s disease recurred, and while the first 8 tumors had not recurred (yet), there were four additional new tumors present. So between day 190 and day 228, which is basically 38 days, four new tumors, T 9 - T12, became evident with T12 being located in the spine.

So to state, as the authors do, that the”dramatic clinical response was sustained for 7.5 months after the initiation of CAR T-cell therapy” is wholly incorrect. The “dramatic clinical response” was “sustained” from day 133 (4.4 months) to day 190 (6.3 months), 57 days, or almost two months. And at that time, I’d argue that it stopped being dramatic and instead became recurrent GBM.