NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

RK, Two questions
1. How many Glioma cells do you think the average patient will have on the day they receive their first vaccination? (If you want to further break it down separating those who did and did not achieve GTR and those who did and did not respond to chemorad) -- AVII

Great question! This is going to be a long post, brace yourself. Note, I started and stopped writing it so if it’s broken in thought, sorry about that. I will highlight parts of articles that I think is pertinent to establish how I came to my answer. Hopefully you will see why I'm long. Hoping you go long, eventually. :)

Let’s just recap:

An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%). On average, radiotherapy after surgery can reduce the tumor size to 107 cells.

Here is where I found my facts on tumor cell loads in case anyone want to verify:
Philip Lawler Glioblastoma Foundation: http://philiplawlerbraincancerfoundation.com/treatment.html
(I’ve also seen it confirmed on either Glioblastoma sites, so it is accurate.)

It’s honestly a two part question, as the tumor volume before surgery will count as well. Pre-surgery affects Post-surgery:

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

The difficulty of combating an established disease is partly founded in fundamental Darwinian principles. Statistically, the cellular heterogeneity within a tumor becomes relevant when the tumor accumulates one billion (10(9)) cancer cells, in man and in mouse, equivalent to a tumor with a diameter of 1 cm.2,3 At this point, the accumulation of cancer cell variants results in miniscule probability that all cancer cells are susceptible to a single chemotherapeutic agent.2,3 This statement is based on models of chemotherapy, but there is nothing to suggest that immunotherapies cannot be modeled in the same way; for example, antigen-loss variants can be considered analogous to drug-resistant mutants. The relevant variables that could be considered are innumerable, but the nature of the problem is fundamentally the same in both cases.

www.tandfonline.com/doi/full/10.4161/onci.1.2.18311

And this shows that prior studies mostly have not seen high GTR, and that most hospitals are only going to going to leave residual tumor behind even with 5-ALA. The operating room matters!

Extent of Resection and Survival in Glioblastoma Multiforme: Identification of and Adjustment for Bias

journals.lww.com/neurosurgery/fulltext/2009/06000/extent_of_resection_and_survival_in_glioblastoma.33.aspx

An observation that constitutes a “byproduct” of this study is interesting. The tumor could be completely removed in only 65% of the patients even with 5-ALA, whereas the remaining patients had residual tumor with a volume of up to 25.7 cm3 (2). Patients who did not have a contrast medium-uptaking tumor on postoperative MRI scans had a distinctly longer MST than patients with residual tumor (16.7 versus 11.8 months, P < 0.0001) (3). This corresponds to a prolongation of MST by nearly 5 months (about 30% longer than the MST after standard therapy). This is much more than could be achieved by all previous chemotherapy protocols and even with the use of 5-ALA

And so size of pre-operative mass will matter. I do believe that the Philip Lawler numbers takes into account that not all patients will qualify for GTR in their average.

DCVax-L will not be give to patients with residual volumes of average patients. They will be able to go in and take out the extra 20%.

Linda Liau had to state about iMRI in 2005 at Immunotherapy for Brain Tumors Conference

https://www.youtube.com/watch?v=ZLsOthpPv7k


Intra-operative MRI (minutes 45:15 onward)

"Acquiring an MRI during surgery allows for updating the neuro-navigation systems."

“After taking out half of an 8 centimeter tumor, the brain has shifted. And there’s quite a bit of distortion, so you can’t really use your pre-operative MRI, especially if you want to be in a millimeter of accuracy ”

"The radiologist is able to look at the scans right then and there."

"And the reason that is important is because, if you ask your neurosurgeons, I’m sure they’ve had a lot of these cases. i know I have in the past. Whereby, you know you take out majority the tumor, you think you're done, but there’s a little left behind. That extra 20%. And usually we close up, and we tell the patient, “we weren’t able to get that last 20%”. Well a lot of times it’s because we couldn’t see it. And what this inter-operative MRI allows us to see before closing. And you can see, this patient, the skin flap is still open, when we got that MRI scan. And oh, I thought I got all the tumor out, there’s a little bit left. Went back in and took it out and essentially got a complete resection."

"So, i think this will hopefully make a difference in terms of patient survival in the future. i know there’s been contraversal as to how useful surgery is for something like a gliomablastma, but I don’t think we have in the past, this kind of precision in terms of surgical resection."

"So in conclusion, neuro-surgerical technicals has advanced to allow safer, more complete surgeries for patients with brain tumors. And surgery, like I mention, is the first step in patient center team approach to these tumor. I’d like to I think the future of brain tumor therapy is going to be a combination of all these things."

This is a patient of mine with a large tumor. I don’t think a tumor like this is going to go away with just vaccine therapy or targeted molecular inhibitors. We need to do is first take it out so that you have very few residual tumor cells. Then treat the residual cells with radiation, and then drug therapy, whether it be Temodar or more targeted agents in the future. And then the role of immunotherapy will be, t cell, or the immune response to attack the cell sin those fingers, that we can’t see and can’t surgically take out. “ -- LINDA LIAU in 2005; minutes 47:50 - end).

“Patients must have a surgically accessible, unilateral tumor for which surgical resection, with intent to perform a gross total or near gross total resection, is indicated.” — Phase III Criteria


I think we can agree that the Phase III recruitment criteria is highly selective, and does not reflect those found in routine clinical practice. Their study will not be the typical tumor burden, it's unilateral tumors only and, no metastases. Their tumor volume will be less before surgery, since it's only unilateral tumors that qualify for entry. And as you know, there will be less tumor burden behind as the sites they use are the state of the art equipment, so there will less likely be Tumor load behind. It's going to be residual cell loads that immunotherapy can manage.

And here is rates on FGG:
http://www.ncbi.nlm.nih.gov/pubmed/20607351/

And here is rate of ioMRI:
Impact of intraoperative high-field magnetic resonance imaging guidance on glioma surgery: a prospective volumetric analysis.
http://www.ncbi.nlm.nih.gov/pubmed/19487886/

As a reminder they recruit at the sites that qualify them for a GTR, using techniques, like brain mapping and ioMRI that I researched and shared over at IV:

http://www.investorvillage.com/smbd.asp?mb=6543&mn=3518&pt=msg&mid=15407625
http://www.investorvillage.com/smbd.asp?mb=6543&mn=3586&pt=msg&mid=15413433

And here is a DC study that used EoR of a qualifying entry, and should serve as an example what to expect:

Main limitation for entry is that FGS surgery must achieve residual tumor less than 1 cc.

Dendritic cell vaccination in glioblastoma after fluorescence-guided resection

In 2009, we started a phase-II trial for patients with newly-diagnosed GBM based on immunotherapy with ex-vivo tumor lysate-pulsed, autologous dendritic cells (DC) following fluorescence-guided surgery (FGS) using 5-aminolevulinic. After resection, immunotherapy was used as up-front therapy in combination with standard therapy. We hypothesized that the more extensive resection possible with this surgical technique[8,9] would create the best situation to begin immunotherapy, and that immunotherapy itself could be more useful as a front-line strategy. To avoid the potential selection biases shown in other immunotherapy trials[5-7], we aimed at including a wide population of patients and enrolling them right after surgery. Main limitation for entry is that FGS surgery must achieve residual tumor less than 1 cc.

In this report, we present 5 previous cases that constitute a pilot group of this clinical trial.

I’l summarize what they found:

Mean age was 66 years, median KPS was 70, four patients were RPA class V and one was class IV. MGMT promoter was unmethylated in one and methylated in four cases. Mean preoperative tumor volume was 54 cc (34-112) Resection was total in three cases, while the other two cases had 0.25 cc and 0.27 cc residual tumor.

The 5 patients median age was 67 years old. AGE and KPS scores is a significant prognosis factor. Here is the chart of the 4 patients (the unmethylated patient removed). Notice how this small group overall survival improves (OS: 27 mo, 27.5 mo, > 36, > 32)? Notice two were still alive (as of late 2012)?

Patients characteristics
Patient Age(yr) KPS(%) RPA Sex MMSE score Tumor volume (cc) MGMT promoter Tumor location PFS (mo) OS (mo)
1) 69 70 5 M 28 111.8 Methylated right frontal 19.5 27.0
3) 50 80 5 F 26 12.9 Methylated left temporal 3.2 > 36.0
4) 67 60 5 F 28 68.3 Methylated right frontal 16.1 27.4
5) 71 90 4 F 30 44.8 Methylated right frontal 20.3 > 32.0

Five patients were screened and included: www.ncbi.nlm.nih.gov/pmc/articles/PMC3536842/table/T1/

MGMT methylation patients:
Patient #1, 19.5 mo. PFS and OS 27.0
Patient #3 3.2 mo. PFS (early progressive event, indicative of distance mass, confirmed not to be a psPD) and OS > 36.0 (patient remains alive)
Patient #4 16.1 mo. PFS and OS of 27.4
Patient #5 20.3 mo. PFS and OS > 32.0 (though patient on Avastin care).

GIVEN AGE and KPS are significant prognosis factor, these patients did well:

Patient #1 was 69 years old male, and had a KPS of 70.
Patient #3 was 50 years old woman, and had a KPS of 80
Patient #4 was 67 year old woman, and had a KPS of 60
Patient #5 was 71 year old woman, and had a KPS of 90

This pilot comes from their larger study. Both are referenced here:

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=122652331

The study’s conclusion:

“Despite the small number of cases, the survival time is clearly unexpected for a group with these characteristics. MGMT promoter methylation was the only positive prognostic factor, and yet the cohort with methylated MGMT promoter in the EORTC-NCIC shows a median OS of 23 mo, while all of our 4 methylated patients have lived longer than 27 mo, with two still alive. The median OS in our group exceeds the OS expected using the EORTC nomograms by almost 15 mo (27.0 to 12.3). Even with the intrinsic limitations of the small sample size, we conclude that this DC-based immunotherapy is likely to have added to the results of standard of care and provided an OS clearly superior to the expectations, suggesting a strong benefit from immunotherapy in an unfavorable group of patients. “

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536842/

But I already know what you will tell me, you’re going to state it has to do with their MGMT promoter status, and the amount of adjuvant chemo they received.

Elderly Patients With Glioblastoma Live Longer With Chemoradiation Using Temozolomide. But we are talking in terms of months, and GTR do not produce anything near as well as this DC study did.


https://www.asco.org/about-asco/press-center/news-releases/elderly-patients-glioblastoma-live-longer-chemoradiation-using

A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677).


Background: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly diagnosed glioblastoma (GB) showed increased overall survival (OS) with concomitant and adjuvant temozolomide (TMZ) added to radiotherapy (RT). Pts were 18-71 (median 56) years; however, a trend of decreasing benefit from the addition of TMZ with increasing age was noted. Recent RCTs in elderly GB detected non-inferiority of 40 Gy/15 v 60 Gy/30 RT and superior survival was noted for MGMT-methylated pts treated with TMZ alone. However, whether the addition of TMZ to RT improves survival in elderly pts remained unanswered. Methods: We conducted a global randomized phase III clinical trial for patients ≥ 65 yrs with histologically confirmed newly diagnosed GB, ECOG 0-2, randomized 1:1 to receive 40Gy/15 RT v 40Gy/15 RT with 3 weeks of concomitant TMZ plus monthly adjuvant TMZ until progression or 12 cycles. Stratification was by centre, age (65-70, 71-75, or 76+), ECOG 0,1 vs 2, and biopsy vs resection. Results: 562 pts were randomized, 281 on each arm; median age 73 yrs (range 65-90), male 61%, PS 0/1 77%, resection 68%. RT+TMZ significantly improved OS over RT alone (median 9.3m v 7.6m, HR 0.67, 95%CI 0.56-0.80, p < 0.0001) and significantly improved PFS (median 5.3m v 3.9m, HR 0.50, 95%CI 0.41 – 0.60, p < 0.0001). Tissue from 462 pts was provided and adequate for MGMT analysis in 354 to date. In MGMT methylated patients (n = 165) OS for RT+TMZ v RT was 13.5 m and 7.7m respectively (HR: 0.53 (95% C.I. 0.38, 0.73, p = 0.0001). In MGMT unmethylated patients (n = 189) OS for RT + TMZ v RT was 10.0m vs 7.9m respectively (HR 0.75 (95% C.I. 0.56 – 1.01, p = 0.055). QoL analyses showed no differences in functional domains of QLQC30 and BN20 but were worse in the RT/TMZ arm for nausea, vomiting, and constipation. Systemic therapy after PD was reported in 39% on RT+TMZ v 41% on RT. Conclusions: The addition of concomitant and adjuvant TMZ to hypofractionated RT for elderly pts with GB significantly improves OS and PFS in all patients and is well tolerated. Patients with MGMT methylated tumors benefit the most from the addition of TMZ to RT where median OS is nearly doubled. Clinical trial information: NCT00482677

It’s as I stated before has to do with chemotherapy synergies:

The inventors' studies support the notion that clinical outcome is significantly improved by the specific combination and sequence of vaccination plus chemotherapy in GBM patients. Stated more generally, it is believed that anti-tumor immunity directly impacts GBM chemosensitivity. Vaccinated patients receiving subsequent chemotherapy exhibited significantly delayed tumor progression and longer survival relative to those receiving vaccinations without subsequent chemotherapy or to those receiving chemotherapy alone. Improved clinical outcome appeared dependent on the specific combination and sequence of therapeutic vaccination followed by chemotherapy. These observations suggest a substantial therapeutic slowing of GBM progression and extension of overall survival for GBM patients. These clinical benefits appeared to markedly surpass those in previous vaccine studies as well as those in even the most hopeful analyses of GBM chemotherapy. See. e.g., R. Stupp et al., "Recent developments in the management of malignant glioma," J. Clin. Oncol., 1091-9118:779 (2001). Moreover, the more favorable clinical outcome conferred by post-vaccine chemotherapy did not appear to be confined to younger subgroups of patients. As such, this supports the notion that this specific treatment combination conferred clinical improvement to a majority of treated cancer patients, which is believed to be unique for a vaccine-based therapy.

I showed you it’s feasible to go after residual cells, but now how many do I think there will be… Using another trial criteria for nGBM to answer your question:

Assessment of extent of tumour resection before vaccination
Complete resection was defined as the absence of any residual tumour mass on early postoperative MRI or CT scan performed with and without contrast within 72?h after surgery. Any resection leaving a measurable residual tumoral mass <1?cm3 and <10% of the initial tumour volume was considered subtotal. All solid residual tumor of a measurable size ?1?cm3 or removal of <90% of the tumour volume was classified as partial resection.

Okay, let me break down my response:

Doctors measure cancer in millimeters (1 mm = .04 inch) or centimeters (1 cm = .4 inch).
A tumor reaching the size of 1 cm(3) (approximately 1 g wet weight) is commonly assumed to contain 1 x 10(9) cells (=1,000,000,000 cells).

Radiological levels of detection. The crucial point is the minimal detection level of radiologists. This was experimentally tested by Spratt and coworkers [17], who placed lucite balls having a radiopacity approximating that of solid tumors and ranging in diameter from 1.6 to 12 mm randomly upon the posterior and anterior thorax of patients. Radiographs were taken and examined by a group of radiologists. The conclusions were: ‘‘Radiologists could distinguish 10–12 mm diameter balls regard- less of their location; 6 mm balls could be detected when the shadow was in a favourable site, and 3 mm shadows could only be found when the radiologist was shown precisely where to look. Radiopacities smaller than 3 mm were indistinguishable.’’ For mammography, the lowest level of detection is stated to be 2.1 mm [41].

https://visualsonline.cancer.gov/details.cfm?imageid=7278

The measurable phase of a cancer is said (2 × 10(7)–10(11) cells), as such, I do not think they be treating the patients at the 10 (11) cells.
A large tumor (10 cm in diameter) contains about 1012 cells (1 kilo). In GBM, that is likely to be cancer that extends into other parts of the brain, and not a candidate for this study.

Pre-surgery tumor = 100 grams is 10 (11) = 100,000,000,000; post surgery 10 (9) = 1,000,000,000 cell
Pre-surgery tumor = 10 grams is 10 (10) = 10,000,000,000; post surgery 10 (8) = 100,000,000 cells
Pre-surgery tumor = 1 gram is 10 (9) = 1,000,000,000; post surgery 10 (7) = 10,000,000 cells
Pre-surgery tumor is 10 (8) = 100,000,000; post surgery = 1,000,000 cells.
Pre-surgery tumor is 2x 10(7) = 2 x 10,000,000 = post surgery = 200,000 cells.

But DCVax-L need 2 grams of lysate. So the ideal patient would be a patient with 2 - 10 grams tumor. But at the same time, if a GBM surgery is considered GTR, then it should not fit into the classification of what qualifies for pre-surgery, at the post surgery point, and so I suspect that even before any log kill patients will have < 20,000,000 cells.

GTR: < 20,000,000 cells post surgery;
STR < 20,000,000 cell but up to 1,000,000,000 cells (1 cc). And .25 cc would be 250,000,000 cells.

Keep in mind even if post surgery of a 5 - 10 gram tumor I speculated would leave remnants of > .5 cc tumor and so that would likely to be a range of what is considered tumor burden of 500,000,000 cells; and therefore, I going to guess that would show up on an MRI.

If patients are unresponsive to radiotherapy and to chemo, then within the three months, the patients tumor would likely grow; eliminating them from main arm enrollment.

I imagine one could respond to 1 but not both (chemo or radiation); and even unMGMT derived benefit on TMZ, as most tumors have varying degrees of methylation. And MGMT promoter status is a positive factor of TMZ benefit, it isn’t a predictive factor to TMZ response. In case you’re wondering, even with the Stupp unMGMT group, the combination of TMZ-RT was better than RT alone.

New data from the EORTC trial support the perception that the methylation status of MGMT is mainly a positive prognostic factor rather than a predictive factor that is relevant to treatment.

Patients who had tumors with methylated MGMT status had longer median and 2-year survival independent of treatment (see Table 2 in the article by Stupp et al1). Even patients who received radiotherapy only lived longer than patients who had unmethylated MGMT status after combined treatment (median survival, 15.3 months vs 12.6 months, respectively; 2-year survival rate, 23.9% vs 14.8%, respectively). If MGMT methylation status were a strong predictive factor with which to identify patients who may benefit from temozolomide, then patients who have tumors with unmethylated MGMT would not experience an advantage from combined therapy. However, the 2-year survival rate in this group of patients was 14.8% compared with 1.8% for patients who received radiotherapy only.

onlinelibrary.wiley.com/doi/10.1002/cncr.24950/full

Again, getting back to the topic, with an iMRI, and the like scanning procedures; to be detectable as “partial, the cells can be detected between 2.1 - 6 mm (see above extent of tumor resection). In that study, and in others I’ve seen, if they are able to detected .25 cm tumor and call that STR.

Majority of their case will have absence of any residual tumour mass on early postoperative MRI to < 1 cc of tumor after surgery. And none of the above takes into account that tumors are not made up of entirely cancer cells. The vaccine will be given to patients with the least amount of disease, as I imagine the trial will maintain a large percentage of GTR in the main arm. Patients whose tumors are growing quickly will be removed at baseline. And, any patients who dies from complications from surgery, or fails eligibility criteria (lower KPS score), will not make it into the study. Majority of patients would likely fall in these ranges:

GTR: < 20,000,000 cells post surgery; but there would also be cells in the fingers that the surgeon couldn’t see. I’ll guess that could double the number. <40,000,000 cells
STR (up to .5 cc mass) > 40,000,000 - < 500,000,000 cells post surgery

Then log kill of radiation and chemotherapy can bring it down by 10(-2), 10 (-1), respectively. Later cycles of chemotherapy can bring it down more, but you asked about Day 0 of the vaccine.
Final answer for best to worse case main arm patients residual cell loads on DAY ONE of DCVax-L:

If patients respond to both radiation + chemotherapy: 4,000 - 500,000 residual cell
And if the patients only responds to one of the two therapies: 40,000 - 5,000,000 residual cell
And yes, I know the immune system can only actively move 10,000 cell to cure.

Such an interesting question, so I did dig before answering. It is still too much for the immune system to get rid of it immediately, but over time it could with further cycles of chemotherapy it could keep the disease stable and subsequent rounds of chemotherapy will help. Plus, I believe I already proved without a shadow of a doubt that manufacturing has been reduced from and 10 day batch to and an 8 day, likely to incorporate TFF, which will make it a more potent biological product.

Survival with only surgery and radiotherapy combination being grim makes sense when you account for things like growth rates of tumor. The average GBM are said to double ever 49 days, and those that are of low oxygen would fall main arm (true rapid progression).

And then, that leads us to discuss the tumor growth of the remaining mass:

Growth dynamics of untreated glioblastomas in vivo.

“The median specific growth rate of the tumors was 1.4% per day, and the equivalent volume doubling time was 49.6 days. Exploring 3 different tumor growth models showed similar statistical fit for a Gompertzian growth model and a linear radial growth model and worse fit for an exponential growth model. “

www.ncbi.nlm.nih.gov/pubmed/25758748

It become clear that less mass, extends survival, and why I argued placebo arm with advanced surgical care, on Stupp protocol, will do very well in this study.

Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma.

www.ncbi.nlm.nih.gov/pubmed/25192475

And so, next step is what they will have afterwards, the proliferation and growth rate will be depending on how well established the disease was in the first place.

Trajectory of tumor Gompertizian growth (obviously the less mass, means chemotherapy works better):

www.orchidcancercentre.com/images/curve.jpg

But we would have to go into kinetics and the Norton-Simon Hypothesis and why I think vaccine and chemotherapy are turning out to be so synergistic.

KINETICS OF CLINICAL RESPONSE AFTER THERAPEUTIC VACCINATION

The Chemotherapy Source Book (see log kill pages 8, onward; and laddering, as in the Norton-Simon method):

https://books.google.com/books?id=CDADMzS0TKUC&pg=PA1&source=gbs_toc_r&cad=3#v=onepage&q&f=false

“The reduction which is constant is in common accordance with the first order of kinetics representing it's peculiar rate of production. Applying this principle, it's just as easy to we juice 1 million cancer cells to 10,000 as it is it is to reduce 100 cancer cells to one both situations represent a 99% reduction.”

"Mathematical models for tumor-immune interactions have a long history dating back at least to Stepanova’s classical paper [13] in which a system of two ordinary differential equations was proposed to describe the main interactions between cancer cells and the immune system. Great ad- vances have been made since then in the understanding of the workings of the immune system in connection with research on HIV, yet the main premises of this model remain valid: for small cancer volumes, the immune system can be effective in the control of cancer (immune surveillance), but the tumor overwhelms the immune system for large cancer volumes [4], [15]. Tumor-immune system interactions play a significant role in the development of the disease when both a benign (microscopic) and a malignant (macroscopic) stable equilibrium exist. The regions of attractions of these two locally asymptotically stable behaviors are separated by the stable manifold of a saddle point and, geometrically, the aim of therapy can be formulated as to move an initial condition in the region of attraction of the malignant equilibrium point into the region of attraction of the benign equilibrium [8], [9]. In this paper, we consider this problem for a combination of chemo- and immunotherapy when a bilinear pharmacokinetic model for the therapeutic agents is included in the model."

We considered a mathematical model for combination of cancer chemotherapy with immunotherapy in form of a boost to the immune system that included pharmacokinetic models for the therapeutic agents as a multi-input optimal control problem. Administrations along intermediate dose rates given by singular controls satisfy the strengthened Legendre-Clebsch condition and thus are expected to be at least locally optimal, but the exact determination of optimal concatenation sequences generally is a challenging problem. In this paper, examples of optimal controls and corresponding trajectories have been computed numerically that confirm optimal administration of the chemotherapeutic agent at dose rates determined by singular controls [5], [6]; in the scenarios considered here, the immune boost is given over a single interval at maximum dose.

www.siue.edu/~uledzew/papers/CDC2012immune.pdf

BUT, it then will also BENEFIT the vaccine, as will reduce the cells to a level that with Effect of Vaccination on Chemotherapeutic Treatment of GBM Tumors

Impact of tumour volume on the potential efficacy of therapeutic vaccines
J.L. Gulley md phd,* R.A. Madan md,* and J. Schlom phd*

www.ncbi.nlm.nih.gov/pmc/articles/PMC3108875/pdf/conc-18-e150.pdf

And so, chemotherapy and vaccine therapy will be VERY effective on OS in this trial:

Research on Chemo-effect:

Wheeler CJ, Das A, Liu G, Yu JS, Black KL: Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 2004, 10:5316-26. clincancerres.aacrjournals.org/content/10/16/5316.long

As a reminder, NW Bio was sued by IMUC because they felt the cross over arm conflicted with their patent. Effect of Vaccination on Chemotherapeutic Treatment of GBM Tumors:

http://investorshub.advfn.com/boards/replies.aspx?msg=119725260

"Importantly, 2-, 3- and 4-year survival was also unique for patients receiving chemotherapy after vaccination. Whereas chemotherapy or vaccination alone resulted in 2-year survival within the established range for GBM (8%; FIG. 5), post-vaccination chemotherapy resulted in a substantial increase (42%; FIG. 5) in 2-year survivors (P<0.05; binomial distribution). Similarly, no 3-year or 4-year survivors were evident after chemotherapy or vaccination alone, but such survivors persisted in post-vaccine chemotherapy patients (P<0.01 for 3-year survivors; binomial distribution)."

"Moreover, the more favorable clinical outcome conferred by post-vaccine chemotherapy did not appear to be confined to younger subgroups of patients. As such, this supports the notion that this specific treatment combination conferred clinical improvement to a majority of treated cancer patients, which is believed to be unique for a vaccine-based therapy."

That elder pilot study came from this study, the overall abstract:

IMMUNOTHERAPY WITH TUMOR LYSATE-PULSED DENDRITIC CELLS FOR NEWLY-DIAGNOSED GLIOBLASTOMA FOLLOWING FLUORESCENCE-GUIDED RESECTION Ricardo Diez Valle1, Sonia Tejada1, Sauna Inoge ´s1, Miguel Angel Idoate1, Ascensio ´ n Lopez Diaz de Cerio2, Jaime Espinos1, Javier Aristu1, Jaime Gallego1, Javier Perez Calvo1, and Maurizio Bendandi1; 1Clinica Universidad de Navarra, Pamplona, Spain; 2CIMA, Pamplona, Spain

BACKGROUND: Immunotherapy is a promising therapy for glioblastoma, however, different strategies and potential selection biases make it difficult to evaluate efficacy. We hypothesized that treatment with tumor lysate-pulsed autologous dendritic cells would be effective when added to gross total resection and standard radio-chemotherapy in newly diagnosed glioblastoma. We designed a trial recruiting patients from the time of surgery to avoid selection biases.

METHODS: All patient candidates for re- section during the study period were screened, and an attempt at maximum resection was made in every case using fluorescence-guided surgery; less than 1 cm2 residual tumor and glioblastoma pathology were required for entry confirmation.

Adjuvant treatment included radio-chemotherapy with temo- zolomide up to 12 cycles. Vaccines were prepared as soon as possible after surgery using autologous dendritic cells pulsed with tumor lysate and matured ex vivo. The vaccination calendar started before radiotherapy. Overall survival was compared to a historic cohort and to European Organization for Research and Treatment of Cancer (EORTC)-published nomograms. RESULTS: We screened 32 patients and included 31 (96.9%); one was excluded because of the presence of residual tumor. The mean age was 58.6, and Karnofsky performance status score was 90-100 in 28% of the patients, 70-80 in 65%, and 60 in 6%; 10% of the patients were in RPA III, 42% RPA IV, and 48% RPA V. Immunotherapy was well tolerated and induced specific immune responses. Median overall survival at the moment of this writing is 27.4 months versus 14.7 months in patients treated with the control (p 1/4 0.003). Median survival in RPA class V patients is 26.9 versus 10.7 (p 1/4 0.007). Compared to EORTC nomograms, 23 patients have lived longer than predicted, 3 have lived shorter, and 5 do not have enough follow-up information (p , 0.001, binomial distribution). In multivariate analysis, vaccination was the most significant variable (p 1/4 0.012, odds ratio 2.7; 95% confidence interval: 1.24-5.77). CONCLUSION: Tumor lysate-pulsed, autologous dendritic cell vaccination is safe and effective when added to standard therapy after gross total resection in glioblastoma.

This above study, did not do any patient selection bias, other then EoR, and it clearly shows how well the above DC trial went after what I described is becoming to be much more well know occurrence with GTR, recurrent patterns happen outside the RT field, and so they come later, but DC vaccines go after those cells:

I bring this up as I believe "multicentric" lesions is in part the reason DC technology is having success. With RESECTIONS rates on the rise, longer PFS rates have been recorded. But the extended time before first progression at initial site of surgery does not translate to longer survival because BCS are resistance to chemo and radiation cells, and therefore they escape and migrate and a new lesion is born elsewhere. Well immunotherapy as we all know, stops the spread of metastases. And in the brain, the GTR rates of multicentric growths go down with the introduction of immunotherapy, but have gone up considerably in GBM with chemo and radiation (longer PFS, but death still occurs around 18-22 months). And if the means that recurrences tend to be local to the initial tumor site if and when it shows up in immunotherapy. And that does translate to longer survival. A sort of abscopal affect as radiation makes new tumors more susceptible to immunotherapy.

And pattern of cancer recurrences will change as surgical GTR precision goes up; and chemotherapy is introduced to a lower residual environment:

Analysis of Recurrence Pattern, in MGMT methylation:

Recurrence Pattern After Temozolomide Concomitant With and Adjuvant to Radiotherapy in Newly Diagnosed Patients With Glioblastoma: Correlation With MGMT Promoter Methylation Status

To our knowledge, the present study could be the first in literature to evaluate the recurrence pattern after the administration of TMZ as a radiosensitizing agent concurrent with RT19 and, as a cytotoxic drug, in the maintenance setting. Because of strict inclusion criteria, there may have been the possibility that a selection bias exists, and the generalizability is therefore applicable only to patients who are ≤ 70 years of age and who undergo resection. We observed a failure pattern shift from local/marginal to distant, recurrences outside the RT field occurring in approximately 20% of cases. Furthermore, distant recurrence occurred significantly later than local recurrence, and the recurrence pattern was significantly influenced by MGMT methylation status, recurrences being outside the RT field in 15% and 42% of patients with MGMT unmethylated and MGMT methylated status, respectively (P = .01). Although the factors underlying this phenomenon are not clear, some considerations should be made. It is unclear whether MGMT methylation status alters the motility and migration pattern of GBM cells, or whether the combined chemoradiation approach, by having a synergic effect on MGMT methylated cells,19 can enhance local GBM cell eradication. The latter hypothesis is supported by the finding that the time to recurrence was prolonged in patients with MGMT methylated status,7,20 as was the time to distant recurrence (14.9 months v 9.2 months in patients with local failure). Interestingly, in the present study, after a median follow-up of 18.9 months, 16 patients have not yet had disease progression; moreover, three of these 60 patients (5%) had MGMT unmethylated status and 13 (32.4%) had MGMT methylated status.

jco.ascopubs.org/content/27/8/1275.full

And so, I truly believe they will be getting vaccine going after residual cells; and each treatment being laddered with chemotherapy, will helping keep the disease from establishing in other parts of the brain; and from coming back, if the all the cancer cells end up being removed by log kill.

Stony Brook, NY, October 26, 2015 -- Most cancer drugs are designed to target dividing cells, but a new study by Stony Brook University researchers suggests that targeting invasive cells may be a new strategy to treat metastatic cancer. The approach is based on the finding that cells in C. elegans, a roundworm nematode, cannot divide and invade at the same time. The research, published in the journal Developmental Cell , is the first study to definitively show the dichotomy between cell division and cell invasion.

Uncontrolled cell division is a hallmark of cancer. In the paper titled “Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression,” lead author David Q. Matus, PhD, an Assistant Professor in the Department of Biochemistry & Cell Biology at Stony Brook University, and colleagues found that only when roundworm cells stop dividing can they become invasive. When cells become invasive, it is the most lethal to a host, as they are the cells that escape tumor tissue to travel and form new tumors.

“Our finding changes how we think about cancer to some level,” said Dr. Matus. “While it will remain important to target dividing cells – as cancer is a disease of uncontrolled cell division – we need to figure out how to target non-dividing cells too since they are the invasive ones. 

Well guess what, immunotherapy is going after the non-dividing cells. It will be going after the cells that are begin to formulate the tumors that have not yet been detected. As surgery improves, and check-point inhibitor are added to which will reduce the immunosuppressive macro-environment factors, more and more patient disease will be eradicated.

2. When MD1225 says "treatment begins....literally 6-8 months from the day the patient applied to be in trial.... " do you agree he is off by a factor of two. (and his recent "thanks, I didn't have the energy" response is utter BS. -- AVII

Short answer approximately 3 months.

Off the protocol, which will not have changed:

14.6 months from surgery (95% confidence interval, 13.3 to 16.8; Stupp, 2005). In
the Phase II trial, PFS and survival times will be calculated from time of
randomization, which is expected to occur approximately three months after initial
surgery.

And:

Population:
Patients 18 to 70 years old with newly diagnosed GBM (Grade 4 astrocytoma), who have
undergone surgery, are eligible to enter into screening. Patients in screening who have received
external beam radiation therapy with concurrent temozolomide chemotherapy according to the
Stupp protocol (Stupp et al., N Engl J Med 352: 987-96, 2005), without evidence of disease
progression following radiation therapy, are eligible to be randomized into the study. All patients
must have a Karnofsky Performance Score (KPS) of ≥70, ≥8 week life expectancy, no other
prior
malignancy within the last 5 years, and no active infections. See section 7 for full eligibility
criteria.
These same eligibility criteria, except the requirement for absence of disease progression at
baseline, apply to the patients in the pseudoprogression arm of the study.

Endpoints - Progression free survival (PFS) and overall survival (OS): Time to objective
demonstration of disease progression or death (PFS) or time to death (OS) in patients with
either
no evidence of disease progression after external beam radiation therapy with concurrent
temozolomide chemotherapy, or in patients who show pseudoprogression of disease after
external beam radiation therapy with concurrent temozolomide chemotherapy. Patients with
pseudoprogression will not be treated with DCVax-L until pseudoprogression (no true disease
progression) is confirmed.

And they make sure it's clear, "out of the window" are not accepted:

DCVax-L. Both DCVax-L and the placebo are tested at the contracted manufacturer
prior to release to the study site. Patients for whom sufficient DCVax-L was not
generated are not eligible to continue on this protocol.
All subjects who had a leukapheresis will undergo external beam radiation therapy
(which may include intensity modulate radiation therapy or IMRT) and concurrent
temozolomide chemotherapy as part of standard primary treatment, initiated as soon
as possible, typically 3-4 weeks after surgery (Appendices A & B).
Two weeks after completion of radiation and concurrent chemotherapy treatment,
subjects will undergo the Baseline Visit, during which the final tests to determine
eligibility are performed. Patients who do not have obvious evidence of progressive
disease at the Baseline Visit (as determined by MRI) are enrolled in the main arm of
the study (intent to treat), and are randomized to receive DCVax-L in the treatment
cohort or autologous MNC in the placebo cohort. Randomization and treatment
assignment takes place within 1 week of the Baseline Visit. At the Baseline Visit,
patients must be scheduled to return to the clinic 1 week later to receive their first
immunization. The study drug, containing approximately 2.5 million DC per
immunization (two injections of 1.25 million DC each per immunization, in
approximately 150 µl each), is injected i.d. (not subcutaneously) into a clean area of
the upper arm, alternating arms between visits. Injection volume is patient specific
and the Certificate of Analysis (C of A) should be referenced. Due to the nature of
the disease under study, out of window visits are expected for enrolled patients and
will not require waivers.

See how they have fail screen of rapids at baseline, and then again at baseline 2?

How some say there are no psPD in the CUA do not understand that they need comparison MRIs to make that determination of whether it's "true disease"; and so of course if they confound it with vaccine, it would become "Indeterminate". But I digress.

Patients who do not have unequivocal progressive disease but who otherwise have
evidence of disease progression (possible pseudoprogression) will initiate adjuvant
temozolomide chemotherapy per standard of care, and will be scheduled to return to
the clinic at 10 weeks post completion of initial radiation and concurrent
chemotherapy treatment to undergo a repeat baseline visit, i.e. Baseline 2 Visit.
Patients who do not have progressive disease at the Baseline 2 Visit (as determined
by central review of their MRI) are enrolled into the study (intent to treat), and are
randomized to receive DCVax-L in the treatment cohort or autologous MNC in the
placebo cohort (2:1). Randomization and treatment assignment takes place within 1
week of the Baseline Visit 2. At the Baseline 2 Visit, patients must be scheduled to
return to the clinic 1 week later to receive their first immunization. Patients for whom
disease progression is confirmed by central review of their Baseline 2 Visit MRI will
fail screening and will not be randomized into the study.