NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

I've tried to explain that to her before. A scan showing possible progression to treatment --even if the treatment is simple standard of care -- does not mean the patient progressed. Patients who do not progress are called pseudoprogression. Patients who are unclear but not yet crossed progression threshold but yet flagged for possible progression early on under immunotherapy are called Indeterminates, this term falls under RANO criteria for surgical resected patients.

Immunotherapy

Nonspecific imaging changes can also occur after immunotherapy. Inoculation of genetically engineered T cells in a murine model of glioblastoma multiforme has been shown to cause T1 gadolinium enhancement and T2 hyperintensity 24 hours after treatment, followed by decreased enhancement 2 to 3 days after treatment.61 Intratumoral administration of proinflammatory cytokines can cause prolonged increases in enhancement that can take up to 3 months after treatment to resolve.62,63Accordingly, new enhancement after immunotherapy should be confirmed on follow-up imaging, with the timing of the follow-up imaging possibly dependent on the type of immunotherapy.


Retrospective Assessments of Disease Progression Should Be Permitted in Clinical Trials

As discussed above, there are no validated imaging modalities that reliably distinguish treatment effects from tumor progression, and the clinical management often involves serial imaging studies to determine the persistence of the radiographic changes. In many patients, serial imaging evaluation will show that the extent of new enhancement has regressed without clinical intervention, and these patients are considered to exhibit “pseudoprogression.” 64,65 Others will show persistent progression of imaging changes and will be considered cases of true disease progression. Accordingly, an imaging-based response classification scheme must allow a retrospective categorization of a patient as having disease progression based on the results of serial radiographic imaging. When progression is suspected but treatment-related effects remain a valid possibility, the response should be called indeterminate. If subsequent evaluation proves that the changes reflect true progression, the time of progression should be retrospectively corrected to the first time at which an indeterminate response was noted.

Because blinded independent central review will be used to guide decision making in individual patients in real time, there will be a requirement for the technological ability of all sites to transfer images to central review without delay. Furthermore, there will need to be acceptance of the idea that participating investigators will cede final determination of a patient's status to the central review body and will allow retrospective identification of pseudoprogression as described above.

https://academic.oup.com/neurosurgery/article-lookup/doi/10.1227/NEU.0b013e318223f5a7


The CUA also makes it clear that suspected progression patients needed a follow-up scan, a requirement of MacDonald. Again from the 55 Compassionate Use Informational Arm abstract, what we know as fact that the first progression scan does not = confirmed progression. It by default removes Psuedoprogression response.

"Patients re-imaged at Month 2 after Baseline Visit to confirm either actual disease progression or pseudo-progression (patients categorized by independent medical imaging company)

 
Methods: Disease progression (recurrence) was determined through MRI imaging at the Baseline Visit and at Month 2 thereafter. All images were reviewed and analyzed by an independent specialized medical imaging company. Each image was reviewed separately by two independent reviewers, and any material differences were resolved by a third independent reviewer. Reviews were conducted using both RANO and McDonald criteria.
OS data is available for all 51 patients. Baseline and Month 2 images are available so far for 46 of the 51 patients.

Based on comparison of the Baseline and Month 2 images, the independent medical imaging company classified the 46 patients into the following 3 groups. The other 5 patients were unclassified, due to lack of available images.

* 20 Rapid-Progressor Patients: A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
* 25 Indeterminate Patients: Stable disease, modest progression and/or regression, or measurements still unclear
* 1 Pseudo-Progressor: Month 2 image showed resolution of most of the prior appearance of tumor growth"

http://www.nwbio.com/NWBT_ITOC_poster_3-25-15.pdf