Replies to post #94489 on NorthWest Biotherapeutics Inc (NWBO)

[md1225]

Thank you senti, highway and RK excellent research I'm learning everyday with you guys. I'm more confident then ever the FDA will approve DCVAXL.

[Rkmatters]

Keep in mind Senti, immune checkpoints work well when the immune system is at advance stage disease. Those PFS low medians, particularly relates to pseudo progression incidents in the presence of existing tumor. In advance stage disease -- as reported with DCVax-Direct, as well -- immunotherapy inflammatory response can causes tumors to grow before they shrink. There are several sections within that conference that cover that phenomena. That is progression under old RECIST standards, but it doesn't mean patients failed imunotherapy, which you know. The immune cells gather within the mass, but considering in all those trials tumor existed, thus size thresholds were crossed relatively quickly. That low response for PFS are affected by the mechanism of action that correlates with that later stage of disease -- with tumor. I remind you that pseudoprogression in the NO MEASUREABLE disease setting, GTR environment, and essentially at earlier stage (as in newly diagnosed GBM) cause the same TIL. Patients are not necessarily being removed for Psuedoprogression as BBB changes do not mean "tumor" swelling. They are affectively finding ways to monitor the immune cell infiltration with other imaging modalities to keep patient who have not progressed by RANO measure (FLAIR does not have an initial size at start of treatment) within the studies. See attached.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337341/pdf/fneur-06-00033.pdf


"TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination.

Hsu MS1, Sedighim S2, Wang T3, Antonios JP4, Everson RG2, Tucker AM2, Du L5, Emerson R6, Yusko E6, Sanders C6, Robins HS7, Yong WH8, Davidson TB9, Li G10, Liau LM11, Prins RM12.


Abstract: Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate-pulsed dendritic cell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response. Cancer Immunol Res; 4(5); 412-8. ©2016 AACR.

Neuro Oncol. 2016 Mar;18(3):368-78. doi: 10.1093/neuonc/nov153. Epub 2015 Sep 1."

That same paper above, also found that there is a correlation with longer survival for patients who have higher TCR overlap, regardless of whether TIL. And so TIL was best responders, but all patients who have responses are still deriving survival benefit. :)

Some important points, off RANO papers about FLAIR:

"RANO also advocates retrospective analysis of FLAIR signal intensity change and backdating time of progression to the first time point in which progressive nonenhancing tumor is suspected.” -- RANO paper

“In addition for FLAIR signal intensity change, RANO does not specify what degree of increase qualifies as tumor progression, only that it must be “significant” or “unequivocal.” Thus, it could be the case that although a 25% increase in bidimensional measurements for enhancing tumor is categorized as progression, a smaller amount of change in size of abnormal FLAIR signal intensity also may be defined as progression.” -- RANO

http://www.ajnr.org/content/32/5/794.full

"Patients with nonmeasurable enhancing disease whose lesions have significantly increased in size and become measurable (minimal bidirectional diameter of = 10 mm and visible on at least two axial slices that are preferably, at most, 5 mm apart with 0-mm skip) will also be considered to have experienced progression. The transition from a nonmeasurable lesion to a measurable lesion resulting in progression can theoretically occur with relatively small increases in tumor size (eg, a 9 × 9 mm lesion [nonmeasurable] increasing to a 10 × 11 mm lesion [measurable]). Ideally, the change should be significant (> 5 mm increase in maximal diameter or = 25% increase in sum of the products of perpendicular diameters of enhancing lesions). In general, if there is doubt about whether the lesion has progressed, continued treatment and close follow-up evaluation will help clarify whether there is true progression." RANO criteria

http://wp.vcu.edu/radres/wp-content/uploads/sites/2550/2013/10/Updated-Response-Assessment-Criteria-for-High-Grade-Gliomas.pdf



"When new enhancing lesions appear at 3-6 months after TMZ, differentiation between true progression and pseudoprogression is not possible on the initial MRI. The definite diagnosis of pseudoprogression is made with RESOLUTION of the lesion on follow-up imaging [Figure 3]. The only useful sign for true progression on initial MRI is subependymal enhancement; although the specificity of this finding for the diagnosis of true progression is high (93.3%), it has low sensitivity (38.1%) and modest negative predictive value (41.8%).[23] According to the modified RANO recommendations, true progression on initial MRI must be reported only if there is new enhancement outside the radiation field (beyond the high-dose region or 80% isodose line) or if tumor is seen on histopathological sampling."

What do ICON state about RANO criteria as it relates to Psuedoprogression [mine]:

"Pseudoprogression:

--Enhancement that simulates tumor growth, most often caused by radiation (whole brain or focal).
--Growth of existing lesions or appearance of new lesions [BRAD] within 12 weeks of completion of radiation therapy may be the result of treatment effects rather than growth of tumor.
--Continued follow-up imaging can determine whether initial lesion growth was true progression or pseudoprogression.
--If lesion continues to enlarge, the initial growth is called true progression
--If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression
-- In such cases, the baseline SPD is no longer included when choosing the nadir value for the purposes of determining when progression occurs [baseline nadir is measurement used in this Phase III trial]
-- Diffusion weighted imaging can help distinguish pseudoprogression from
true tumor growth, but its use is still experimental. The use of MR perfusion and spectroscopy is also being explored. [this trial allows other imaging used to confirm new lesion is progression]. " - ICON

FYI, ICON is the imaging specialist for this trial.

[flipper44]

Thanks for all the synthesis you provided. The quotes from the video are very helpful.

FDA applies flexibility regarding the evidence required to support approval to address particular challenges posed by each disease. -- panel presenter

Now, just for the fun of it, I would remind you of a paper that ASCO, which is an society I'm a member of, published recently, indicating that every drug that achieves a hazard ratio below .80 for survival should be made available to the public. So keep that in mind. -- panel presenter

Kind of makes you wonder if one possibility is that, in her previous presentation, Dr. Liau was indirectly talking about Hazard ratios as one (of many) possible solution(s) -- if necessary.

Here's a video by Terry Shaneyfelt on hazard ratios explained for the laymen.

[Astavakra]

Good work Senti, HIGHWAYMAN and RK. I sense you're very warm and getting warmer.