NorthWest Biotherapeutics Inc (NWBO)

[biosectinvestor]

The reasons are likely not clear rather than a failing of the study. My understanding is there are various other studies that have found that 30-40% of nGBM patients receiving the standard of care convert from unmethylated to methylated MGMT status. But it's still an area being studied. Meaning we don't absolutely know what happens to patients receiving the standard of care, but the nature of their tumor tissue may change.

We know that methylated MGMT patients with DCVax-L have a much higher rate of survival than the same patients in the external control arm, the mOS being just over 30 months, rather than 21 months for the placebo arm, an increase of 142% for the median patients receiving DCVax-L so categorized. That is very possibly going to extend survival for a good chunk of those patients with DCVax-L substantially, but it's not an absolutely known factor, something that is being studied and upon which this study was not focused.

https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847

Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P?=?.03). . . In patients with nGBM with methylated MGMT, mOS was 30.2 (95% CI, 23.7-33.9) months from randomization (33.0 months from surgery) in 90 patients receiving DCVax-L vs 21.3 (95% CI, 18.3-25.1) months in the 199 patients in the ECP (HR, 0.74; 95% CI, 0.55-1.00, P?=?.03)."

if rGBM patients are converting at a high rate, you're going to see a souped up response to DCVax-L, I'd expect and I think anyone rational would also expect.

The only new factor is their receiving DCVax-L after those patients had recurrence. There is no indication that after recurrence, without some additional intervention, patients live longer. It's a late event. But with DCVax-L, we know that these patients did live longer, and they can show that both with the placebo arm and the various statistical studies, MAIC included, that consistently confirm the results are statistically quite significant.

And we know from ATLnsider's DD that UCLA is working on a technology or tactic for actually making unmethlated patients convert to methylated.

https://link.springer.com/article/10.1007/s11060-023-04531-z

dCas9/CRISPR-based methylation of O-6-methylguanine-DNA methyltransferase enhances chemosensitivity to temozolomide in malignant glioma
Research
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Published: 15 January 2024
Volume 166, pages 129–142, (2024)
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Journal of Neuro-Oncology
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Serendipity Zapanta Rinonos, Tie Li, Sean Thomas Pianka, Terry J. Prins, Blaine S. C. Eldred, Bryan M. Kevan, Linda M. Liau, Phioanh Leia Nghiemphu, Timothy F. Cloughesy & Albert Lai

Background
Malignant glioma carries a poor prognosis despite current therapeutic modalities. Standard of care therapy consists of surgical resection, fractionated radiotherapy concurrently administered with temozolomide (TMZ), a DNA-alkylating chemotherapeutic agent, followed by adjuvant TMZ. O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylated lesions from tumor DNA, thereby promoting chemoresistance. MGMT promoter methylation status predicts responsiveness to TMZ; patients harboring unmethylated MGMT (~60% of glioblastoma) have a poorer prognosis with limited treatment benefits from TMZ.

Methods
Via lentiviral-mediated delivery into LN18 glioma cells, we employed deactivated Cas9-CRISPR technology to target the MGMT promoter and enhancer regions for methylation, as mediated by the catalytic domain of the methylation enzyme DNMT3A. Methylation patterns were examined at a clonal level in regions containing Differentially Methylation Regions (DMR1, DMR2) and the Methylation Specific PCR (MSP) region used for clinical assessment of MGMT methylation status. Correlative studies of genomic and transcriptomic effects of dCas9/CRISPR-based methylation were performed via Illumina 850K methylation array platform and bulk RNA-Seq analysis.

Results
We used the dCas9/DNMT3A catalytic domain to achieve targeted MGMT methylation at specific CpG clusters in the vicinity of promoter, enhancer, DMRs and MSP regions. Consequently, we observed MGMT downregulation and enhanced glioma chemosensitivity in survival assays in vitro, with minimal off-target effects.

Conclusion
dCas9/CRISPR is a viable method of epigenetic editing, using the DNMT3A catalytic domain. This study provides initial proof-of-principle for CRISPR technology applications in malignant glioma, laying groundwork for subsequent translational studies, with implications for future epigenetic editing-based clinical applications.

Epigenetic aspects of a tumor, with the use of new tools, may be significant events and may, with help the help of DCVax-L, extend the survival of patients generally. But the Phase 3 study is the study. It did not set out to measure or prove any of this. What they have are mOS results that are amazing and beat anything else out there that is truthfully measured. Your attempts to undermine by raising questions, I do not think, will do more than frustrate you and the interests you represent. No one wants to send them back to the salt mines because we have not yet figured out every angle of tumor evolution in treatment. No other study has such a hurdle, and this one won't either. And as for your speculation, which is all it is, the problem is, you're expecting your vague speculation to overturn the statistics of the trial because there is no explanation for the exceptional results, in your mind. I expect they do have explanations and have taken a deep dive into the data. But I expect that conversation is only for regulators until they have broader data to back up assertions to the wider world, perhaps in new studies on recurrent patients and their response rates.

But requiring that they explain every aspect of their exceptional results or they are "invalid", is not necessarily a thing. They have adequate explanations for how the treatment works generally, and like I said, they likely have done a deep dive on recurrent patients as well, but not for publication, for discussion with the regulator. The reality is, DCVax-L is not harmful, it has beneficial effects for nGBM and rGBM and especially methylated MGMT biomarker patients, and likely with other biomarkers as well that they are still reviewing. But they have solid data, it has been teased and teased with all kinds of statistical reviews and efforts to ensure it is valid, and nothing has disturbed it. So your speculation here on the edge of things is not likely to do you much good.