Replies to post #59087 on NorthWest Biotherapeutics Inc (NWBO)

[longfellow95]

Thankyou RK.

[flipper44]

Thanks RK. Very new and interesting.

It will be interesting to see how the combo trial (aka: PD1 inhibitor + DCVax-L) affects this type of analysis, particularly in what otherwise would be the "low-low" group. I bet researchers' will broaden their conclusions as to what patients are good candidates for immunotherapy. Perhaps everyone will respond.

One thing they did not appear to discuss is what correlations they'd find with immunotherapy alone (aka: No SOC, No radiation, No temodar).

In the meantime, this demonstrates DCVax therapy can produce results in certain patients above and beyond SOC -- chemoradiation.

[longfellow95]

My first thought is whether or not TIL content is adversely affected by prior RT and Temodar.
And my second thought is, perhaps they are not using UCLA Phase 3 subjects in this study, as TIL content would be predictive in terms of patient outcome.

[flipper44]

From a skeptical perspective, one might read the latest UCLA article (767: TCR sequencing can identify and track tumor-specific T cell populations and is a predictive biomarker of response to DC vaccination in glioblastoma patients) and say, "hey, UCLA only used 6 patients from standard of care to determine if TIL made a difference for survival in GBM."

The answer in the UCLA paper is that TIL count in SOC patients' tumors did not make a difference in survival.

I found UCLA to be confirmed in a 2013 paper in Clinical Cancer Research.

TILs are not associated with prolonged with survival (171 patient cases reviewed)

TILs were not associated with prolonged survival in univariate analyses. We compared the survival of cases with absent (0) lymphocytes, present (1+) and abundant (2+) lymphocytes using a log-rank test (p>0.05) (Figure 3). We found patient age was a highly significant predictor of survival (p<0.001); however, lymphocytes did not vary according to age. The mean age of patients with absent (0), present (1+) and abundant (2+) lymphocytes was 56.9 (SD ± 14.6), 57.3 (SD ± 12.1) and 54.8 years (SD ± 13.1), respectively (p>0.05). TILs were not a significant predictor of survival in an age-adjusted Cox proportional hazards model (data not shown) (p>0.05). If tumors belonging to the classical transcriptional class were excluded, there were no survival differences according to TILs among proneural, neural and mesenchymal tumors (p>0.05). Similarly, if mesenchymal tumors were excluded, there were no survival differences according to TILs among proneural, neural and classical tumors (p>0.05). www.ncbi.nlm.nih.gov/pmc/articles/PMC3865611/

In other words, I think the UCLA paper and this paper together demonstrate TIL count does not make a difference in GBM when treated with SOC.

I don't know if many people know this, because SOC can make a difference in other types of cancers to one degree or another that have high TIL counts.

While this does not remove all questions, I think it helps confirm.

[flipper44]

"We showed that an increased estimated TIL content prior to therapy was associated with prolonged TTP and OS. All very long-term survivors in this trial had estimated TIL content in the top quartile. The correlations between estimated TIL content and TTP and OS argues that estimated TIL content in the initial tumor specimen may be used to select patients for DC vaccination and may be applicable to other immunotherapies as well. In contrast, TIL content was not associated with survival in patients who were not treated with immunotherapy. Thus, our data suggests that the use of TCR sequencing to predict such survival indices may be directly relevant only for patients undergoing immunotherapy treatments such as DC Vax." -- Cancer Immunol Res. 2016 May;4(5):412-8. doi: 10.1158/2326-6066.CIR-15-0240. Epub 2016 Mar 11

http://www.ncbi.nlm.nih.gov/pubmed/26968205