Replies to post #185913 on NorthWest Biotherapeutics Inc (NWBO)

[jondoeuk]

''Merck really has no idea how to increase response rates to Keytruda, without introducing further toxicity.''

That's debatable.

''Do you know how many Keytruda combo trials are planned or ongoing?
Hundreds..''

I knew that.

''So they are just employing a scattergun approach, in the hopes that something works. PDL-1 is a very inaccurate biomarker.''

PDL-1 is a limited biomarker. Others will be needed. But this is already known.

''The Moderna link-up may well come to nothing.''

We know that responses to neoantigens drive checkpoint inhibitor
efficacy http://science.sciencemag.org/content/348/6230/69.long and you can vaccinate against them https://www.nature.com/articles/nature22991 https://www.nature.com/articles/nature23003 They key challenges for the future are the selection and delivery methods. Gritstone Oncology seems to be getting both the former http://cancerres.aacrjournals.org/content/78/13_Supplement/5722 and latter right http://cancerres.aacrjournals.org/content/78/13_Supplement/724 So the combination of a neoantigen based vaccine and checkpoint blockade should increase the depth and duration of responses.

''And it is not even the only neo-antigen based vaccine, they are partnering with. (Neon Neo-PV-01 being the other.)''

Again, I knew that. The only reason I didn't add any links is due to no financial terms being discussed. I assume that Keytruda is being provided for free and/or certain costs of the trial are being paid for.

''Over the full range of histologies, the ICI's have average response rates of about 20%. And that could mean just a couple of months without tumor growth, before treatment effect peters out. And disease progression resumes..''

Apples and oranges. For each type you need to take into account ORR, DCR, PFS and OS.

''And ICI's accelerate disease progression (and death), in perhaps 10% of all patients.''

The percentage depends on what papers you look at. The mechanisms underlying hyperprogression after checkpoint blockade are still poorly understood. A number of clinical variables including older age, regional recurrence in an irradiated field and specific genomic alterations (MDM2 family amplification and EGFR aberrations) have been found to be associated with it.