1. FDA unveils trio of new draft guidances to help cell and gene therapy developers (thanks pgsd and Peter Brit 🙏🏻)
2. FUD ORR continues
Why that helps a DC-vaccine developer like NWBO
1) Trial designs for small populations just got clearer - and more permissive.
FDA’s draft on innovative trial designs for CGT products in small populations explicitly endorses approaches NWBO already uses or plans to use: single-arm, externally controlled, adaptive, Bayesian, and master-protocol designs, with the goal to “simultaneously expedite drug development and generate data necessary to demonstrate substantial evidence of effectiveness.” That language supports compact Simon two-stage studies, use of high-quality historical controls, and Bayesian borrowing to cut sample size.
Why this matters to NWBO:
It validates a lean Phase 2 for DCVax-Direct or Kalinski aDC1 programs in indications with limited eligible patients (e.g., brain mets subsets), while keeping the evidentiary bar clear and pre-negotiable with FDA.
2) A refreshed fast-path for regenerative therapies (RMAT) with examples that fit IO. FDA’s updated Expedited Programs for Regenerative Medicine Therapies draft (which will replace the 2019 guidance) spells out what “preliminary clinical evidence” can look like for RMAT - e.g., a first-in-human, open-label autologous cell immunotherapy that shows an objective response rate above historical chemotherapy - and it stresses that early-phase product quality controls must be in place during early clinical development.
Why this matters to NWBO:
• A vaccine-driven ORR under iRECIST that exceeds credible historical benchmarks can support an RMAT request for a DCVax-Direct Phase 2.
• The guidance highlights manufacturing comparability: if the product used to generate early evidence differs materially from the product heading to approval, that early evidence won’t support expedited designation. This aligns with NWBO’s push to lock process via Eden/automation and show comparability to any prior lots.
3) Post-approval data expectations are now spelled out for CGT.
The post-approval methods draft tells sponsors how to capture long-run safety and effectiveness for CGT using EHRs, claims, and registries, emphasizing long-term follow-up because trials treat few participants and effects can persist.
Why this matters to NWBO:
It sets the blueprint for a DCVax post-approval registry and RWE plan from day one. Building those pipelines before pivotal data reads saves time later and strengthens any expedited review discussion.
What NWBO should do next (tactical moves)
1. Pre-IND meeting package that cites the innovative-designs draft and proposes a single-arm, Simon two-stage study with:
• iRECIST reads and central imaging,
• objective endpoints (ORR, DCR, DoR) plus survival follow-up,
• an externally controlled benchmark and, if appropriate, Bayesian borrowing.
2. RMAT readiness: map the planned DCVax-Direct endpoints to the RMAT draft’s examples and lock CMC comparability now—same cell inputs, maturation conditions, release assays, and potency metrics from early cohorts through pivotal.
3. Real-world data plan: stand up an LTFU registry and EHR/claims strategy that matches the post-approval draft. This can double as supportive evidence in expedited pathways and satisfy long-run safety expectations.
And now … the ORR FUD.
In lack of better option the FUD Brigade from InvestorVillage has chosen the DCVax-Direct phase 1 trial and the talk of ORR endpoints as their new bullshit operation.
Let’s simply talk about relevance in Phase 1:
The DCVax-Direct Phase 1 was a single-arm, dose-escalation safety/feasibility study. The peer-reviewed publication of Phase 1 did not compute or report an ORR, and Table 3 in that paper is not an ORR table; it lists week-8 SD/PD and biomarker data.
• Where the “ORR” talk came from:
1. Outside commentary that misread Table 3 and inferred “ORR=0” even though no ORR was calculated in the paper.
2. Company SEC filings that discuss future Phase 2 plans to inject multiple tumors, give more doses, and use tumor response (ORR) as a practical primary endpoint - for Phase 2, not Phase 1.
So, ORR was not an endpoint for the Phase 1 trial; the term entered the DCVax-Direct conversation mainly via external misinterpretations of the publication and via company plans for Phase 2, where ORR makes operational sense.
Of course you can just read this and you have a debunk manual on all the BS the FUD Brigade could possibly bring up.
Mind you though, none from the Brigade is interested in discussing that, so they make up a couple of sentences daily to keep the kettle warm.
So let’s just debunk Jondoeuk’s claims from yesterday.
Claim 1
“It was a Phase I/II (N=60). The only objective efficacy measure was response rate, assessed by RECIST/irRC. So the trial was an efficacy failure.”
iRECIST
IRECIST … IRECIST … IRECIST
The “i” Bubbe!!!! It MEANS something.
Facts
What is RECIST?
Think of RECIST as the ruler doctors use to measure cancer on scans.
• If tumors shrink a lot (30% or more), that’s counted as a “response.”
• If tumors grow a lot (20% or more, or new ones appear), that’s “progression.”
• If the change is in-between, it’s called “stable.”
This is simple and works well for chemo or targeted drugs, where tumors usually shrink quickly if the drug works.
Why RECIST doesn’t always work for immunotherapy
Immunotherapy is different. When the immune system floods into a tumor, it can make the tumor look bigger on scans before it gets better. Sometimes new tiny spots show up as the immune system wakes up.
This is called pseudoprogression - it looks like the cancer is worse, but really it’s the immune system doing its job.
If we stick to the old RECIST ruler, these patients would be marked as “treatment failed” and taken off therapy - even when the treatment was working.
What is iRECIST?
iRECIST is the updated measuring tape made just for immunotherapy.
• The first time a scan shows “progression,” doctors don’t immediately call it failure. Instead, it’s marked as “unconfirmed progression.”
• The patient stays on treatment (if they’re otherwise stable) and comes back in about a month for another scan.
• If the tumor really keeps growing, then it’s confirmed progression. If it shrinks or stabilizes, it’s reclassified as a response or stable disease.
When to use which?
• RECIST: Use for old-school chemo or targeted drugs - they kill cells directly and tumors usually shrink right away.
• iRECIST: Use for immunotherapy - vaccines, checkpoint blockers, cell therapies - where tumors can swell before they shrink.
Bottom line
• RECIST is a quick yes/no ruler: smaller = good, bigger = bad.
• iRECIST adds a second check: don’t throw away a working immunotherapy too soon, give it time to show if the swelling is real cancer growth or just the immune system at work.
• Phase and size.
The published study you’re referencing is the Phase 1 portion:
A single-arm, dose-escalation safety/feasibility study with ~40 patients (39 evaluable). It was designed conservatively: one tumor injected per patient; most got 3 injections over 2 weeks (some a 4th at week 8). That is straight from the company’s annual reports describing the Phase 1 stage and regimen.
• No published ORR; Table 3 DOES NOT EQUAL ORR.
The peer-reviewed Clinical Cancer Research (CCR) 2018 paper did not compute ORR, and Table 3 shows week-8 SD/PD status and cytokine data, not a trial-level ORR. Calling “ORR = 0%” is an inference, not a reported result.
• Multiple objective measures beyond shrinkage were positive.
• Stable Disease (SD) at week 8 in ~62% of patients, and SD predicted longer overall survival (pre-specified week-8 first scan).
• Biopsy-proven tumor necrosis (no viable tumor cells) in 3/9 injected lesions that looked larger on scans - classic pseudoprogression.
• Intratumoral immune activation: increased CD4+/CD8+ T-cell infiltration in 15/27 (˜55%) with systemic clonal expansion.
• Product potency <-> outcomes: In Phase 1, patients whose dendritic cell vaccines made more IL-12 lived significantly longer (p=0.028). In other words: higher IL-12 -> better survival.
• Why shrinkage alone is the wrong yardstick in Phase 1 immunotherapy.
Early immune infiltration can enlarge lesions (pseudoprogression), so modern immune criteria (e.g., iRECIST) confirm progression before counting failure - exactly to avoid miscalling active immunotherapy as “non-responsive.”
Conclusion:
Phase 1 succeeded on its purpose (safety/feasibility) and showed objective biological/clinical activity. Labeling it an “efficacy failure” because CR/PR were rare at week-8 misstates both the design and the data.
Claim 2
“Why don’t you just say there’s no improvement in OS?”
Facts
• In a single-arm Phase 1, you cannot claim comparative OS benefit vs standard of care. That’s true for any early safety study.
• What you can do (and what CCR 2018 reports) is show objective links between on-study outcomes and survival:
• Patients with SD at week 8 lived longer than those with PD.
• Patients whose dendritic cell vaccine batches produced more IL-12 tended to have a longer overall survival.
Conclusion:
The Phase 1 paper reports statistically significant survival correlations tied to treatment biology. That is exactly the kind of signal Phase 1 is meant to detect.
Claim 3
“Without a control arm, there is no way to objectively assess survival.”
Facts
• Comparative improvement vs SOC needs a control arm; agreed. But it is incorrect to say there’s no objective assessment in a single-arm study.
• The trial made objective, internal assessments
• Week-8 SD <—> longer OS (radiology-to-survival link).
• The strength of IL-12 produced by the vaccine was linked to how long patients survived.
• Pathology-confirmed necrosis despite early enlargement (resolving “is it progression?” with tissue).
Conclusion:
You can objectively evaluate survival signals and their biological underpinnings in Phase 1; what you cannot do is make a comparative claim without a control. This study did the former, correctly.
Extra context
• Company filings on Phase 2:
NWBO’s 10-Ks/10-Qs repeatedly state Phase 2 would proceed “when resources permit,” with a more intensive regimen (inject multiple tumors; more doses) - not that Phase 1 “failed an ORR hurdle.”
• Why ORR can be used going forward:
With iRECIST confirmation and stronger dosing/combination strategies, ORR becomes a sensible primary endpoint for new trials; the plan explicitly contemplates iRECIST-confirmed ORR and biomarker-supported designs.
That the FUD brigade is actually spending so much time on this, shows how little they have left to BS about.
AI
