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Terça-feira, 31.03.15

GBM Encouraging Survival Results In 51 Glioblastoma Multiforme Patients


  • These 51 patients were screened for the phase 3 trial of DCVax-L, but their cancers progressed before they could be enrolled and they were treated on a compassionate use basis.
  • They received the exact same treatment, from the same institutions, and their data was subjected to the same independent review processes as the patients enrolled in the phase 3 trial.
  • Median overall survival in this open label, non-randomized trial was 15.3 months; rapid progressors showed an increase of 5 to 8 months when compared with historical controls.
  • In this most aggressive stage of glioblastoma, durable effects were seen as 30% of patients were alive after 2 years, and 5 for about 3 years or more.
  • This data increases expectations for the DCVax-L success in the healthier, newly diagnosed patients enrolled in the ongoing, blinded, randomized phase 3 trial.

Executive Summary
Northwest Biotherapeutics (NASDAQ:NWBO) has just presented data on 51 patients whom investigators originally intended to enroll in the ongoing, critically important, 348 patients phase 3 trial of DCVax-L in newly diagnosed glioblastoma multiforme. They became ineligible when their cancer progressed before they could enter the trial. However, they were treated nearly identically to the 348 patients and followed to see how long they survived; the survival data was striking. This increases the expectation for success in the ongoing phase 3 trial.

Glioblastoma multiforme is the most deadly form of brain cancer. If unchecked, it grows rapidly in the narrow confines of the skull and begins to interfere with bodily functions controlled by the brain. In advanced cases, it actually begins to push the brain into the brainstem that connects the brain and spine. The current standard of care is based on surgery removing as much as the tumor as possible and then treating with radiation and chemotherapy. In almost all cases, the tumor begins to regrow and when it does, clinical studies show that 50% of patients die within about 9 months. There is no approved drug that has shown it can increase survival in these recurrent glioblastoma patients. These 51 patients were primarily this type of desperate patient.

There were 20 of these 51 patients who were classified as rapid progressors. Even within recurrent glioblastoma, these patients are probably the sickest of the sick. Half of these patients treated with DCVax-L lived 15.3 months or more, which represents an improvement of about 6 months when compared to median survival seen in historical studies. Generally, a 4 to 5 month improvement in an aggressive cancer like this is considered a major advance.

There was also survival data for another 25 patients who were in a better state than the rapid progressors but still much sicker than the vast majority of GBM patients. Half of these patients lived longer than 21.5 months. To put this in perspective, this is an impressive result even if compared to survival expectations for much healthier newly diagnosed patients whose survival expectation is that half will live more than 15 to 17 months. This is almost as striking as the results seen in the 20 rapid progressors.

Northwest has been completely transparent on the results in this study and has provided charts which show the length of survival and in many cases death for each patient. Obviously, the median survival results are impressive but what is striking to me is the number of durable responses as 30% of these 51 patients were alive at two years. This is the hallmark of other immunotherapy drugs and distinguishes them from chemotherapy. It was a durable effect in about 30% of patients treated with the checkpoint modulators - Bristol-Myers' (NYSE:BMY) Yervoy and Opdivo and Merck's (NYSE:MRK) Keytruda- that sparked such great interest in immuno-oncology. Similarly, the CAR-T immuno-oncology drugs of Juno and Kite have shown spectacular results in refractory cases of B-cell lymphomas and leukemias that don't respond to other drugs. I reasoned in my recent report Immuno-Oncology Promises to be the Next "Big Thing" In Biotechnology that Northwest's dendritic cell cancer vaccine products should be considered in the same light as checkpoint modulators and CAR-T therapy. This has been a view met with skepticism because Northwest is such a small company and because of the long list of failures for previous technologies that sought to develop cancer vaccines. However, with this data I believe that the Company has a data set that is as compelling in highly aggressive glioblastoma multiforme as the CAR-T products in highly aggressive B-cell lymphomas.

There is one other unique aspect of DCVax-L that must be given greater weight with this new efficacy data and that is safety. Opdivo and Keytruda have side effects that are sometimes as severe as chemotherapy. The CAR-T cells produce cytokine storms that result in even more dangerous side effects that can lead to hospitalization and death. DCVax-L has demonstrated to date an extremely encouraging side effect profile. The major side effects are a mild fever of about 102 degrees Fahrenheit that lasts about two days and can be treated with Tylenol and itching at the site of injection. Drugs must be judged not only by efficacy, but also safety. The safety profile of DCVax-L is an extremely important aspect of the drug.

Purpose and Overview of this Report
Northwest's Chief Technical Officer Marnix Bosch made an oral presentation of this new DCVax-L clinical data at the Immunotherapy of Cancer Conference (ITOC) in Munich Germany on March 26, 2015. He discussed survival data on 51 patients enrolled in an information arm outside the phase 3 DCVax-L trial.

The abstract of the paper was available about two weeks ago and was quite encouraging although it was brief. I began preparing this report at that time, but I wanted to listen to the presentation before finalizing it. This was fortunate because the Company issued a poster on March 26th that provided significantly more in-depth data on the 51 patients in the information arm. In a much appreciated display of transparency, they have shown the survival status of all 51 patients

Acronyms Used Frequently in This Report

  • Glioblastoma multiforme - GBM
  • Newly diagnosed glioblastoma multiforme - ndGBM
  • Recurrent glioblastoma multiforme - rGBM
  • Standard of care - SOC
  • Median overall surgery - OS
  • Median progression free survival - PFS
  • Relapsed/ refractory B-cell acute lymphocytic leukemia - r/r ALL
  • Relapsed/ refractory B-cell non-Hodgkin's lymphoma - r/r NHL
  • Relapsed/ refractory chronic lymphocytic leukemia - r/r CLL
  • Complete remission rate - CR
  • Objective response rate - OR

Reproduction of the Abstract Presented at ITOC
I have started this report by reproducing the abstract presented at ITOC virtually in its entirety. After that, I included sections which provide background and context for the abstract. In this section, I have included some of my comments. To distinguish my comments from the exact language of the abstract, my comments are in quotation marks and block letters.

Title of Abstract: Prolonged Survival In Patients With Recurrent Glioblastoma Multiforme Who Are Treated With Tumor Lysate-Pulsed Autologous Dendritic Cells

Authors: Marnix L. Bosch (Northwest Biotherapeutics), Robert Prins (UCLA), Linda Liau (UCLA)

The Abstract

Background: Recurrent Glioblastoma multiform (rGBM) is a life threatening condition, with a mortality rate approaching 100%. Overall survival (OS) in rGBM patients has not materially changed in the past several decades.

We treated 55 rGBM patients with autologous dendritic cells pulsed with autologous tumor cell lysate (DCVax®-L) in an "Information Arm" outside of our Phase III clinical trial. 51 of these 55 patients were not eligible for the trial because they had actual or apparent early progression (recurrence) at a Baseline Visit at the end of 6 weeks of daily radiotherapy and chemotherapy after surgical resection of their brain tumor. 4 of the patients were not eligible for the trial for other reasons (e.g., insufficient doses of DCVax-L).

These rGBM patients received the same DCVax-L product, on the same treatment schedule, in the same medical centers, in the same time period as the Phase III clinical trial, and the data have been collected and maintained by the same CRO managing the Phase III trial.

Aim: To provide compassionate use treatment and to determine OS of these rGBM patients treated with DCVax-L.

Methods: Disease progression (recurrence) was determined through MRI imaging at the Baseline Visit and at Month 2. 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 medical imaging review 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

The following chart shows this categorization of patients.

(click to enlarge)

Analysis of 20 Rapid-Progressors
The results for the rapid progressors are shown in the following waterfall plot. I believe that these patients are probably the sickest of the overall GBM population with extremely poor prognoses. In this group, half of the DCVax-L treated patients lived more than 15.3 months. There do appear to be three patients out of the 20 or 15% that lived two years or more. One patient, who is still alive, has so far survived past 37 months, which is extraordinary.


There was obviously no control group for this study so that historical controls were looked to for judging the treatment effect. The authors cited six studies from the literature that studied rapid progressors. The criteria used to classify these patients as rapid progressors was comparable to that used by the independent imaging company and is shown in the following table along with their determination of median overall survival. The range for median overall survival in these six studies of rapid progressors was 8.3 to 10.4 months.

(click to enlarge)

Analysis of 25 Indeterminate Progressors
The data for the indeterminate progressors showed that half of the DCVax-L treated patients lived for more than 21.5 months. What is very interesting is that 11 patients survived for 27 months or more and, of these, 9 patients are still alive. This suggests that 44% had a very durable response. Two patients are living at more than 40 months which is again extraordinary. This result replicates what seems to be a pattern with immunotherapy drugs that a sub-group of patients have very long, durable responses. Dare we hope that the two patients past 40 months are cured?


Six Other Patients
There is not enough information to comment on the one pseudoprogressor other than to say that the patient is alive at 30 months. For the five patients who were unclassified due to lack of images, one is alive at 26 months, one died at 30 months and three died at 5 to 8 months.

Key Results Highlighted by the Authors
The authors summarized the results as follows:

Overall: The median OS is 18.3 months. 15 of the 51 patients who were ineligible for the Phase III trial due to apparent early recurrence lived beyond 2 years, and 12 of the 15 remain alive.

20 Rapid-Progressors: The median OS is 15.3 months (95% Confidence Interval: 10.5 - 17.2) and the range is 6.7 to 37.1 months. A literature search revealed 6 publications with comparable populations of patients which reported median OS of 8.3 to 10.8 months.

12 of the 20 DCVax-L treated Rapid-Progressors lived beyond 13 months; 10 of the 20 DCVax-L treated Rapid-Progressors lived beyond 15 months; and 7 of the 20 DCVax-L treated Rapid Progressors lived beyond 18 months.

25 Indeterminate Patients: The median OS is 21.5 months, and the range is 8.8 to 40.7 months. 9 of these 25 patients remain alive today at more than 24 months, 6 of these 9 patients remain alive at more than 30 months, and 4 of these 9 patients remain alive at 35-40+ months.

1 Pseudo-Progressor: The OS is 30.1 months to date.

5 Unclassified Patients: The median OS is 9.2 months, and the range is 5.7 to 30.1 months.

Conclusions of the Authors

  • Patients with evidence of disease recurrence immediately following 6 weeks of daily radiotherapy and chemotherapy after surgical resection of their brain tumor appear to survive longer than would be expected based on data in the literature, when treated with DCVax-L.
  • The apparent extended survival of these patients is seen in Rapid Progressor Patients and Indeterminate Patients (as well as the Pseudo-Progressor Patient).
  • The combined data suggest a possible survival benefit for patients with recurrent GBM conferred by the DCVax-L treatment.
  • The ~30% of survivors who have lived beyond 2 years may reflect long term tumor control.
  • DCVax-L treatment (vaccination of patients with autologous dendritic cells loaded with autologous tumor lysate antigens) also continues to have an excellent safety profile.

Separate Survival Data on 8 rGBM Patients Treated at UCLA
The first abstract that was published about two weeks ago discussed a separate group of eight rGBM patients who were treated at UCLA, in prior Phase I trials conducted by UCLA, in which the patients appear to have received fewer vaccine treatments. These patients suffered a recurrence after several cycles of chemotherapy. The poster the Company presented at the ITOC conference omitted discussion of this group, as these patients were not part of the Information Arm. The OS in this UCLA trials group was 13.7 months. The basis for the difference between the UCLA results and the 15.1 month OS seen for the 20 rapid progressors in the 51 patient information arm is unclear. It may be attributable to a difference in the number of treatments.

As a comparator for this group, the authors cited OS results from a study done by Friedman et al. in 2009. This study reported on a comparable group of patients who were treated with Avastin with or without irinotecan. The median overall survival in this group from time of first recurrence was 8.7 to 9.3 months. This suggests an increase in OS in this 8 patient group of about 5.4 to 6.0 months over historical controls.

Providing Clinical and Investment Context on the Abstract

This section of the report summarizes key issues that are important to evaluate results from the informational arm and put them into a clinical and investment perspective.

Design of the phase 3 DCVax-L Trial
Northwest Biotherapeutics is enrolling a 348 patient phase 3 trial of DCVax-L in the most aggressive, fastest growing type of brain cancer, glioblastoma multiforme. The current standard of care (SOC) for this dreadful disease is surgical resection followed by six weeks of daily radiation and the chemotherapy drug temozolomide. After six weeks the patient is treated with six monthly cycles of temozolomide. In this phase 3 trial, at the end of six weeks, the 348 patients are enrolled and randomized; two-thirds receive DCVax-L vaccinations and the others do not.

The primary endpoint of the phase 3 trial is to slow the recurrence or progression of the disease for at least four months. If this endpoint is achieved the trial will be considered a success. Survival is also tracked as a secondary endpoint and will be an important measure of whether the trial is successful. However, when patients who were not initially given DCVax-L see their cancer progress, they will then be given DCVax-L (although they and their treatment will remain blinded). This somewhat confounds the OS analysis.

Importance of progression in glioblastoma multiforme patients
In glioblastoma multiforme, the progression or regrowth of the cancer has dread consequences. This is a fast growing cancer that is confined within the skull and as it begins to grow, it quickly begins to interfere with the critical activities that are conducted by the brain. GBM can actually begin to crowd the brain out of the skull and down the brainstem. This is why perhaps more than is the case with any other cancer that delaying progression of the disease is so clinically significant.

There is obviously a close correlation between progression of glioblastoma and death which has been demonstrated repeatedly. The Stupp trial was a 548 patient trial that defined the current standard of care (SOC) as was described previously. Median progression free survival (PFS) is the time at which 50% of patients have the tumor regrow and median overall survival is the time at which 50% of patients have died. In the Stupp trial PFS was 6.9 months and OS was 14.6 months. The difference between PFS and OS was 7.7 months. This means that half of patients died 7.7 months after the cancer began to regrow or progress.

Roche more recently ran two large trials in which they attempted to show that Avastin added to SOC would improve PFS and OS. They both failed to show that Avastin provided any statistically significant OS benefit but they gave added insight into the relationship between PFS and OS. In the control group of one 978 patient trial, PFS was 6.1 and OS was 15.7 for a difference of 9.6 months from PFS to OS. In a second 637 patient trial, PFS was 7.3 months and OS was 9.4 months for a difference of 9.4 months.

The clear result of these three large trials is to demonstrate that in newly diagnosed glioblastoma multiforme patients, 50% of patients are likely to die 7.7 to 9.6 months after recurrence of the disease. This stage of cancer after progression is referred to as recurrent GBM and the prognosis is much worse than for patients who have not recurred.

The 51 patient information arm of the DCVax-L phase 3 trial
Some of the patients that would have been enrolled in the phase 3 had evidence of tumor progression before they could be entered in the phase 3 trial and consequently were ineligible to enter the trial. Because their tumor had progressed, they would have been counted as failures before they received any dose of DCVax-L. Based on the results of the Stupp trial and the two phase 3 Avastin trials, we might have expected 50% of patients to live about 7.7 to 9.6 months.

There were 51 patients who fell into this category and were considered an information arm outside the phase 3 trial. The (personalized) DCVax-L product had already been prepared and Northwest decided to treat these patients on a compassionate use basis. They were given DCVax-L and managed in the same way as the 348 patients enrolled in the trial. Their results will not be part of the final analysis of the phase 3 trial, but they provide some very important information about how DCVax-L performs in rGBM patients who are much sicker than the ndGBM patients in phase 3.

Rapid progressors experience quick recurrence of GBM
Judgment of tumor progression in GBM patients is made on the basis of analysis of images of the tumors obtained over time through a series of MRI or CT images which are made about every two to three months. In the case of the 51 patients in the informational arm and all 348 patients in the phase 3, these images were read and assessed at a central laboratory. This is critical as assessments by investigators at the clinical sites could vary significantly from site to site and might be more subject to bias.

An image of the tumor is taken immediately after surgical resection at around seven or eight weeks later; this is after a week or two of healing after radiation therapy has ended and before DCVax-L therapy is started. This was followed by subsequent images two months later. Patients were excluded from the DCVax-L trial if the tumor has already begun to regrow in the approximate seven or eight week period since the surgery. Such patients may have a more aggressive form of GBM and are known as rapid progressors; they have a much worse prognosis than other patients.

How do you distinguish rapid progressors from pseudoprogressors?
Determining rapid progressors would seem to be a straightforward determination based on whether the tumor is getting larger over time, but this is not the case. There are some patients whose images show a larger tumor size and brighter image in early scans who are not actually rapid progressors. They are called pseudoprogressors and the appearance of tumor growth in their images following radiotherapy is a false signal, an artifact. It is actually only inflammation or scarring, not tumor. Over time, their inflammation and scarring will heal and resolve, and the appearance of something resembling tumor growth will disappear. There is no good data on survival expectations for pseudoprogressors, but it is generally believed that they do as well or even better than "regular" GBM patients.

Over a period of 8-12 weeks following the initial imaging, the differentiation of rapid progressors from pseudoprogressors can be more accurately determined as rapid progressors will continue to experience growth and they may form new lesions while pseudoprogressors may see the resolution of the inflammation or scarring that had falsely appeared to be tumor growth. It is generally believed that about 20% of patients who initially seem to have evidence of progression are pseudoprogressors and the remainder are rapid progressors or somewhere in between. There are defined criteria that investigators can use to classify patients as rapid progressors. This was laid out in the abstract.

How many of these patients were rapid progressors?
The assessment of who were the rapid progressors was made by the independent central imaging laboratory that is being used to determine the outcome in the phase 3 trial. As might be expected, there is not a crystal clear line between rapid progressors and pseudoprogressors. The lab determined that using the strictest criteria, 20 patients met the generally accepted definition of rapid progression, one met the criteria for pseudoprogression and 25 were somewhere in between and called indeterminate. Five patients could not be evaluated because of missing scans.

How good were results for the rapid progressors?
There was no control group for the information arm which means that the results have to be compared to historical results in other trials. There are always concerns when this is done that we might not be comparing apples to apples. However, in the case of rapid progression there is a wealth of data on patients with characteristics like those in the information arm and they are all consistent with one another in suggesting that median overall survival for rapid progressors is somewhere between 7.7 and 10.8 months.

Going back to the discussion on the Stupp trial and the two Avastin trials we would expect that the median overall survival for these patients would be 7.7 to 9.6 months after their tumors progressed. In the abstract presented by Northwest at ITOC, the Company also cited six smaller studies of rapid progressors in which median overall survival ranged from 8.3 to 10.8 months.

Key opinion leaders generally consider a 4 to 5 month improvement in OS to be a significant advance in an aggressive cancer such as glioblastoma multiforme, but even a smaller improvement can be clinically meaningful - especially in a cancer such as recurrent GBM, in which no treatment to date has achieved any material extension of survival. I previously discussed the Stupp trial; the addition of temozolomide to surgery and radiation improved median overall survival by only 2.5 months but propelled temozolomide to $1 billion of sales. More recently, Medivation's Xtandi and Johnson & Johnson's Zytiga improved median overall survival in metastatic colon cancer (an aggressive cancer) by 4.5 and 4.1 months. Both quickly became billion dollar blockbusters.

Median overall survival improvement for 20 rapid progressors
The median overall survival in Northwest's Information Arm was 15.3 months in the 20 rapid progressors indicating an improvement in median overall survival of 4.5 to 7.6 months when compared to historical controls. These data are suggestive that DCVax-L is a major advance in recurrent glioblastoma.

Comparison to Celldex's results for rindopepimut in recurrent glioblastoma
Celldex (NASDAQ:CLDX) recently reported results for its cancer vaccine rindopepimut in recurrent glioblastoma. Rindopepimut addresses GBM patients who have the EGFRvIII mutation; this is about 30% of the GBM population. DCVax-L addresses all GBM patients including those with the EGFRvIII mutation.

The criteria for enrollment in the Celldex ReACT study were patients whose GBM had progressed and had not yet received Avastin. Avastin helps treat symptoms of GBM, but has not been shown to have an effect on survival. This is similar to the patients in the Northwest 51 patient information arm. There were 37 patients in the Celldex study arm given rindopepimut plus Avastin and 35 who were given just Avastin and constituted a control group. Interim results showed that the rindopepimut arm demonstrated OS of 12.0 months versus 8.8 months for the control arm for a difference in median overall survival of 3.2 months. This was an interim look and some patients were censored; it is possible that these numbers could change slightly and probably in favor of rindopepimut.

The FDA has also granted rindopepimut breakthrough status which is clear indication that they consider the 3.2 month improvement in OS to be very significant. The news on the rindopepimut results has been followed by the stock price doubling from $14 at the time of the announcement in November to $28 currently. The market capitalization increased over $1 billion on this news.

The control group in the Celldex ReACT study showed OS of 8.8 months. This agrees with the estimated OS range of 7.7 to 10.8 months suggested by the Stupp trial, the two Avastin phase 3 trials and the six smaller trials as was previously discussed. We would all prefer to have results from a controlled trial, but there is a great deal of historical evidence to suggest that using expected OS from historical controls provides a sound basis for evaluating the benefit of DCVax-L.

What about the indeterminate group of 25 patients?
These patients partially met most of the criteria for rapid progressors, but they did not meet the criteria as clearly or as fully as the 20 who were clearly rapid progressors. In this group of 25 indeterminate patients, the OS was 21.5 months; there is no clear peer group to compare them to.

Based on all of the available evidence, rGBM patients have much shorter OS than ndGBM. As was previously discussed the OS is about 7.7 to 10.8 months from the time of progression. Judged against the data for rGBM, the OS of 21.5 months for these 25 patients is impressive representing a 10.7 to 13.8 month improvement in OS.

The data remains impressive when compared to OS from the Stupp trial and the two Avastin phase 3 trials in ndGBM patients who are much healthier and are newly diagnosed with GBM (i.e., at an early stage of the disease). The OS expectation in these Stupp and Avastin trials was 14.6 to 16.7 months. Judged against this, the OS of 21.5 months for these 25 patients in Northwest's information arm is still impressive, representing a 4.8 to 6.9 month improvement in OS.

What about the one pseudoprogressor?
This patient remains alive at a little over 30 months. There are some studies which indicate that OS in these patients is somewhere between 16 and 26 months, but this is not as well documented as are rapid progressors.

Summary of all published data on DCVax-L
The published data on DCVax-L until now was based on phase 1/2 results in 20 ndGBM patients. The data was spectacular as it showed OS of 36.4 months and PFS of 25.0 months. This compares to 14.6 months and 6.9 months in the Stupps trial that established standard of care.

Generally, key opinion leaders consider a 4 to 5 month improvement in OS in an aggressive cancer like ndGBM to be a major advance. The Phase 1/2 trial data on 20 patients has all the appearance of a home run, but it has been criticized as being an open label, non-randomized trial done at one medical center and with a small number of patients.

This new data on 51 patients in the information arm provides strong support for the phase 1/2 data. It appears that in a much sicker group of rGBM patients (the rapid progressors) there are OS improvements of somewhere between 4.5 and 7.6 months relative to historical controls.

The data base for DCVax-L is now based on 79 patients from three different data sets which all suggest a highly impressive improvement in OS. I think that there may also be 20 or more patients who have been treated with DCVax-L on a compassionate use basis; these patients suffered from a variety of solid tumors. Results for these patients have never been made public, but I am aware based on anecdotal information of two cases of very significant improvement.

Thoughts about the small trial size and non-randomization of the 51 patients
Critics will be quick to point out that we are dealing with a small patient number of 51 patients broken into smaller sub-groups of 20 rapid progressors, 25 indeterminate patients and 1 pseudoprogressor and of course this trial was not randomized. In comparing to the rindopepimut ReACT trial in rGBM which enrolled 37 patients in the treatment arm and 35 in the control arm, the numbers of treated patients is greater for DCVax-L. However, ReACT has a control group and DCVax-L is comparing to historical controls.

However, if you compare the data set of the informational arm to results for the much-ballyhooed CAR-T companies Juno and Kite the comparisons are eye opening. I use the term ballyhooed because Juno (NASDAQ:JUNO) has a market capitalization of $4.8 billion and Kite (NASDAQ:KITE) is at $2.6 billion. The disease targets for Juno and Kite are relapsed/refractory B-cell lymphomas while DCVax-L is targeted at GBM. These are very different types of cancers; the only thing they have in common is that they are very aggressive cancers with no good treatment options.

Juno is advancing its lead products into phase 2 trials on the basis of 27 patients who were treated in phase 1 open label, non-randomized trials. Kite is advancing its candidate on the basis of 29 patients who were treated in phase 1 open label, non-randomized trials. Neither Juno nor Kite has reported OS in their trials. They are judging results on the basis of response rates.

I think that the data set supporting DCVax-L is certainly as good as and probably better than the data sets that have caused such great excitement with Kite and Juno.

Issues with Informational Arm Data

As was just discussed at length, this paper suggests that the median overall survival for DCVax-L in rGBM is 5 to 8 months longer than median survival with existing treatments. There is also every reason to hope that the results in newly diagnosed and healthier GBM patients that are the subject of the current phase 3 trial will do better, but this remains to be seen. I do note that the available data on 20 ndGBM patients showed 36 months of OS which is 21 months better than the 14.6 months in the Stupps trial.

There are shortcomings of the data that I will now address. I think that we will see an aggressive push back from bears on the stock. Northwest has been the subject of ongoing nasty short selling attacks. There are 9 million shares short for NWBO and perhaps another 4 million naked shorts.

There is no data from randomized trials
The bears will say that the DCVax-L data is based on non-randomized trials which make it much less reliable. It will require a randomized trial to establish that there is a difference between DCVax-L and standard of care in rGBM.

This argument has merit. However, there are six separate studies that suggest that a historical OS is in the range of 8 to 10 months with rGBM. And of course, the rindopepimut study substantiated this as it showed that standard of care produced median overall survival of 8.0 months in the EGFRvIII sub-group. While randomized trial results are more reliable, there is strong evidence that median overall survival in rGBM patients treated with standard of care is in the 8 to 10 months range and DCVax-L is increasing median overall survival in rGBM by 5 to 8 months.

The number of patients is too small to draw conclusions
I agree that we will need to see these results replicated in more patients before we can have strong confidence that DCVax-L is providing a treatment effect. Nevertheless, the body of evidence on data in 79 patients is a very strong signal of activity and is consistently positive.

I would also point out that the ReACT trial of rindopepimut in rGBM had 37 patients on drug and 35 on control. This compares to 59 patients who have been assessed in the informational arm and at UCLA. The number of treated patients is similar, but of course there is no control arm. ReACT was randomized, but its patient numbers are small. I note that despite the small numbers of patients treated with rindopepimut that these results led to a designation from the FDA of breakthrough status. As previously mentioned, the stock price doubled on this news and the market capitalization increased over $1 billion.

The two CAR-T companies, Juno and Kite have been the subject of intense medical interest, and these companies carry multi-billion market capitalizations. Importantly, the data set for both companies includes a small number of patients treated in open label, non-randomized phase 1 trials. In the case of Juno there is only data on 27 patients and for Kite there is data on only 29. Juno has a market capitalization of $4.8 billion and Kite has a market capitalization of $2.6 billion.

Clearly, the market has attributed great value to the Celldex, Juno and Kite data despite the small number of patients treated. In the case of Juno and Kite, investors have not been concerned that the data was created in open label, non-controlled trials. I think that an objective analysis suggests that the Northwest data base is at least as good as that of these three highly regarded companies.

How do we know that pseudoprogressors were not mistaken for rapid progressors?
This argument can't be summarily rejected. However, the criteria used to determine rapid progressors in the informational arm are currently accepted by the GBM investigator community, and the criteria were applied to NWBO's patients by an independent company with specialized expertise in making this judgment.

An Overview of the Data Set for the CAR-T Companies
The data sets for Juno and Kite in refractory B-cell lymphomas have caused such great medical and investor excitement. The key elements of these data sets are discussed in the next sections.


-Cancer Target
Juno is planning on advancing two lead products into phase 2 development this tear; these are JCAR015 and JCAR017. It has decided not to advance a third product JCAR-014 into further clinical trials. Each of these products specifically targets CD19 antigens that are widely expressed on B-cell lymphocytes. The mechanism of action has some similarities to Rituxan, Roche's very successful monoclonal antibody against CD20 on B-cell lymphocytes. All of the JCAR products essentially eliminate both normal and cancer cells that express CD-19. Rituxan does the same with B-lymphocytes that express CD-20. The JCAR products are just more effective.

-Clinical Trial Plans
Juno has not conducted any clinical trials for its products. All of the data was generated in phase 1 trials at NCI and leading academic centers: Fred Hutchinson Cancer Research Center, the Memorial Sloan Kettering Cancer Center, the Seattle Children's Research Institute, and the National Cancer Institute.

Juno plans to begin a phase 2 trial of JCAR015 in mid-2015 in r/r ALL. It plans to continue a phase 1/2 trial of JCAR017 in pediatric r/r ALL that was started at an academic center and it is planning a phase 1/2 trial of JCAR017 in adult r/r ALL and r/r NHL in 2015.

By the end of 2015, Juno plans to have begun phase I testing for at least four additional product candidates using CAR technology and a new phase 1 clinical trial for a fifth clinical-stage product candidate using its TCR technology. In each case, the cancer target is a distinct protein like CD19 that is overexpressed on certain cancer cells.

-Clinical Trial Results
JCAR015 achieved an 89% CR rate in 27 evaluable adult patients with r/r ALL. It compared these results to historical complete remissions in a similar population which it believes to be 10%.

JCAR017 has demonstrated in the phase 1 portion of an ongoing phase 1/2 trial an 85% CR rate in 13 evaluable patients with pediatric r/r ALL.

JCAR014 is not being advanced in clinical trials. JCAR014 in a phase 1/2 trial achieved a 100% CR in 11 evaluable r/r ALL patients and a CR of 60% in 10 evaluable r/r NHL patients.

The number of patients treated by all three products [combined] is 61 patients. In the case of the two products that are being advanced into clinical trials, JCAR015 has phase 1 data based on 27 patients and JCAR017 has phase 1 data on 13 patients. Obviously, these were open label controls with no control group.

-Regulatory Plans
Juno believes that the phase 2 trial of JCAR015 could support accelerated U.S. regulatory approval in r/r ALL in 2016. They believe that the phase 2 trial of JCAR017 in adult r/r NHL could result in approval in 2016 or 2017.

In the case of living cell therapies, the manufacturing process is the product so that the development of the manufacturing process carries nearly the same importance as the clinical data. Juno did not manufacture any of the products used in the phase 1 trials. This was done at the academic centers and NCI.

Very importantly, the side effects of the CAR-T products created by cytokine storms are severe and can require hospitalization.


-Cancer Target
KITE's lead product is KTE-C19. It is a direct competitor of JCAR015 and JCAR017 as it also targets CD 19 on B-cell lymphocytes.

The Company will also begin a large number of phase 1 trials with other products in 2015 and 2016 that target different antigens in both solid and hematological cancers.

-Clinical Trial Plans
The Company has recently enrolled the first patient in a planned 102 patient phase 2 trial in r/r DLBCL, PMBCL and TFL. It will start a phase 2 in r/r mantle cell lymphoma in 1H, 2015 and phase 2 trials in r/r ALL and r/r CLL in 2H, 2015.

-Clinical Trial Results
In trials done at the NCI, there were 17 patients treated with r/r DLBCL and PMBCL. There was a 65% OR and a 35% CR.

In an NCI conducted trial in 7 r/r CLL patients, there was an OR of 86% and a CR of 25%.

In an NCI conducted trial in 5 refractory indolent non-Hodgkin's lymphoma patients, there was a 100% OR and 25% CR.

In total, 29 patients with refractory B-cell lymphomas had an OR of 76% and a CR of 38%.

Severe and life threatening toxicities occurred mostly in the first two weeks after cell infusion and generally resolved within three weeks.

-Regulatory Plans
Kite hopes that the data on the phase 2 trial in refractory DLBCL, PMBCL and TFL will be sufficiently compelling to allow for accelerated approval in 2016. They would then initiate a randomized confirmatory study in refractory, aggressive NHL in 2016 in order to fulfill likely post-marketing clinical study requirements and to convert an accelerated approval to regular approval.

Like Juno, Kite did not manufacture the drug used in the phase 1 trials. This was done at the NCI. Kite's contract manufacturer will be using the same manufacturing process as NCI.

Other Upcoming Catalysts for Northwest
The principal purpose of this report is to discuss the new reported data on DCVax-L. However, I did want to highlight a number of potential upcoming catalysts for the stock:

  • Northwest may complete the process of negotiating reimbursement with ten hospital groups in Germany in the coming months. This will be followed by actual product sales.
  • The Company will begin two phase 2 trials with DCVax Direct in 1H, 2015. There are no approved treatment options in the case of inoperable tumors and the FDA would move swiftly if the data is positive. As in the case of Kite and Juno, these could be the basis of a regulatory submission seeking accelerated approval assuming success. If so, commercialization could begin in 2017.
  • An analysis of the full data set for the phase 1 trial of DC Vax Direct should be released in the next several months. Final data on the last patient may be available in April, 2015. This may not allow enough time for an ASCO presentation in June.
  • The final part of the UK Promising Innovative Medicine designation should be completed and DCVax-L approved for commercial use in the UK in several months.
  • There could be collaboration with one of the checkpoint modulator developers, likely Merck or Bristol-Myers Squibb, to combine their products with DCVax-L or DCVax Direct.
  • The first interim analysis that is triggered by 149 events could be completed for the DCVax-L phase 3 trial at any time. I do not expect the trial to be stopped for efficacy. I think that the data monitoring committee will simply recommend that the trial continue.
  • I expect topline data on the DCVax-L phase 3 study in 1H, 2016.

Risks with the Stock
I do want to emphasize that there is no certainty in the development of new drugs and there is a reasonable possibility that despite the encouraging news on DCVax-L and DCVax Direct, that both drugs could fail in their clinical trials. Data created so far is encouraging but is not sufficient to assure success in ongoing clinical trials that are necessary for approval and commercialization.

The results discussed in this report were from a study in which there was no control group. Such studies are widely viewed as providing important information about a drug. Indeed all of the data for the CAR-T products of Juno and Kite comes from small, uncontrolled phase 1 studies performed at NCI and academic institutions. However, there is always a higher degree of uncertainty in interpreting results of such studies than for randomized trials. There remains a significant risk that the phase 3 trial will not replicate these promising results due to issues such as design of the trial, conduct of the trial, patient selection, etc.

I would advise investors to carefully consider what such a failure would do to their financial status and peace of mind. I have a significant position in Northwest Biotherapeutics and it would be painful if these drugs fail. However, it would not affect my financial or mental status. I would urge other investors to take the same approach. This is a stance that I take with all emerging biotechnology companies in which I invest.

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por cyto às 16:08

Segunda-feira, 30.03.15

Targeting a unique receptor promising for glioblastoma multiforme

Targeting a unique receptor promising for glioblastoma multiforme


Novel therapeutic strategies for glioblastoma multiforme (GBM) are under investigation. These are in the form of targeted therapies against a unique receptor, the interleukin-13 receptor α chain variant 2 (IL13Rα2).

Glioblastoma multiforme (GBM) is one of the most lethal primary brain tumors, with median survival for these patients only slightly more than 1 year.

Researchers at Boston University School of Medicine (BUSM) in Massachusetts collaborated with researchers from the City of Hope in Duarte, California, to publish a review paper in Neuro-Oncology(2014; doi:10.1093/neuonc/nou045). They discuss various targeted therapies against IL13Rα2 and early successes of clinical trials with these therapies in the treatment of GBM. The paper also highlights the need for future trials to improve efficacy and toxicity profiles of targeted therapies in this field.

Targeted therapies, which are drugs that interfere with specific molecules involved in cancer growth, have been successfully used in the treatment of many cancers, including breast and blood cancers. Successful targets for therapies are specific to tumor cells and not found on normal cells.

Selectively expressed on GBM and absent on surrounding brain tissue, the interleukin-13 receptor α chain variant 2 was identified as a potential target for therapy for GBM two decades ago. IL13Rα2 also plays an important role in the growth of tumors. In normal physiologic conditions, IL-13 binds to the receptor IL13Rα1 and helps regulate immune responses. In cancer cells, IL-13 binds to the receptor IL13Rα2 and, through a series of steps, prevents cancer cells from undergoing normal cell death. Increased expression of IL13Rα2 promotes the progression of GBM.

Since its discovery, IL13Rα2 has provided a target for therapies in GBM. These therapies have ranged from fusion proteins of IL-13 and bacterial toxins, oncolytic viruses, and immunotherapies. A phase I clinical trial and a phase III clinical trial have been completed for a T-cell based immunotherapy and IL-13 bacterial toxin fusion protein respectively, both with promising outcomes.

"The field of targeted therapies in gliomas holds a lot of promise, and IL13Rα2 is in an optimal position to materialize these promises," explained corresponding author Sadhak Sengupta, PhD, assistant professor of neurosurgery at BUSM and principal investigator of the Brain Tumor Lab at Roger Williams Medical Center in Providence, Rhode Island. "While early trials are encouraging, we need further research to achieve better targeting of the receptor and improved safety profiles of the treatments."

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por cyto às 16:00

Segunda-feira, 30.03.15

Immune checkpoint inhibitors may work in brain cancers

Immune checkpoint inhibitors may work in brain cancers


New evidence that immune checkpoint inhibitors may work in glioblastoma and brain metastases was presented by Anna Sophie Berghoff, MD, at the European Society for Medical Oncology Symposium on Immuno-Oncology 2014 in Geneva, Switzerland.

The novel research shows that brain metastases have dense concentrations of tumor infiltrating lymphocytes, providing an immunoactive environment. Moreover, both primary and secondary brain cancers often exhibit high expression of the immunosuppressive factor known as programmed cell death ligand 1 (PDL1), which can be inhibited by new treatments, thus activating the immune system.

"Patients with glioblastoma and brain metastases have very few treatment options and usually die within a short period of time," said Berghoff, a resident at the Department of Medicine I, Comprehensive Cancer Centre-CNS Tumours Unit, Medical University of Vienna, Austria.

Immune checkpoint inhibitors are a new group of cancer treatments that work by boosting the patient's immune response to the tumor. The immune system operates differently in the brain in comparison to other organs.

"Our study was designed to find out whether the immune system is activated and working in brain tumors, which would provide the foundation for immune checkpoint inhibitors to work," Berghoff explained.

The study included 117 patients with glioblastoma and 116 patients with brain metastases. Using immunohistochemistry the researchers looked for the presence of T-cells, also called tumor infiltrating lymphocytes, in the tumors and whether they were accentuated in different areas of the tumor. T-cells are the main effector cells of the immune response and can be boosted by immune checkpoint inhibitors. They also looked for PDL1, which is an immunosuppressive protein that influences responses to immune checkpoint inhibitors.

The researchers found that patients with glioblastoma had fewer T-cells, and therefore less activation of the immune system, than patients with brain metastases who had high concentrations of T-cells. They also found that PDL1 was common in both glioblastoma and brain metastases, with glioblastoma showing particularly high PDL1 positivity.

"We saw that these brain tumor types have a different interaction with the immune system. The glioblastoma actively suppresses the immune system and there is little immune response. In contrast the brain metastases do a little less suppression of the immune system and there are a lot more tumor infiltrating lymphocytes," said Berghoff.

Berghoff said the findings demonstrate that the immune system interacts with glioblastoma and brain metastases, which is evidence that immune checkpoint inhibitors may work.

"We have arguments for conducting clinical studies with immune checkpoint inhibitors in patients with glioblastoma and brain metastases. In both tumor types we commonly see high expression of PDL1, an immunosuppressive factor which can be inhibited with new treatments. By inhibiting the suppression you can activate the immune system, which in theory, would work in brain cancers.

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por cyto às 15:59

Segunda-feira, 30.03.15

Immunotherapy delays recurrence for stage III and IV ovarian cancers

Immunotherapy delays recurrence for stage III and IV ovarian cancers


Personalized medicine is getting closer to reality for women with late-stage ovarian cancer. An experimental immunotherapy is in the works that can target an individual woman's tumor and extend the time period between initial treatment and the cancer's return.

"This is cutting edge medicine for ," said Jonathan Oh, MD, a gynecologic oncologist at Texas Oncology, P.A., in Dallas. Dr. Oh presented the results of a preliminary study on the vaccine at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer on March 28 in Chicago.

The phase II study included 31 women with stage III or IV ovarian cancer. Twenty received immunotherapy and 11 did not. The cancer in those who did not receive the immunotherapy returned in a median of 14.5 months. Those who did receive the immunotherapy have not reached the median time to recurrence and the majority is well beyond 14.5 months.

In 2015, there will be an estimated 21,290 women will be diagnosed with ovarian cancer and 14,180 will die, according to the American Cancer Society. Because symptoms are often not noticeable in the early stages, most women are diagnosed in later stages when treatment is less effective, and prognosis—chances of survival—are worse.

The National Cancer Institute states that about 80 percent of women treated for ovarian cancer relapse after their first treatment.

"This immunotherapy may keep the cancer away longer," Dr. Oh said.

The immunotherapy is called "bifunctional" because it works by targeting a biochemical pathway in cancer cells and by helping to stimulate the patient's immune response to fight cancer.

During the initial surgery to remove the tumor, sample cells are taken to develop the personalized. After the initial surgery followed by standard of care chemotherapy, women received either one injection per month for anywhere between four and 12 months or were randomized to standard of care.

"This was a preliminary study with promising results that may give with advanced ovarian cancer an option for a maintenance regimen," Dr. Oh said. "Additionally, the vaccine is very well tolerated."

"The results from this clinical trial suggest that using a patient's immune system to fight advanced ovarian cancer may be a promising avenue to improve outcomes in what has continued to be the most aggressive gynecologic cancer," said Krishnansu S. Tewari, MD, a , professor and director of research at the University of California, Irvine Medical Center, Orange, CA.

Provided by Society of Gynecologic Oncology

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por cyto às 15:57

Segunda-feira, 30.03.15

Study identifies possible new target for future brain cancer drugs

Study identifies possible new target for future brain cancer drugs


A molecule in cells that shuts down the expression of genes might be a promising target for new drugs designed to treat the most frequent and lethal form of brain cancer, according to a new study by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The findings, published in the journal Cancer Research, show that high levels of the enzyme PRMT5 are associated with aggressive growth of the (GBM). The malignancy strikes nearly 14,000 Americans annually. It is a highly invasive form of that is difficult to remove entirely by surgery. Following surgery, chemotherapy and radiation, average survival is still only 15 months, pointing to a critical need for new treatments.

This study shows that inhibiting PRMT5 can significantly improve survival in an of GBM. Blocking the enzyme inhibited the growth, proliferation and migration of GBM cells in laboratory studies, and it increased the number of GBM cells that died by apoptosis.

"Our findings suggest that PRMT5 is a possible prognostic factor and therapeutic target for, and they provide a rationale for developing agents that target PRMT5 in this deadly disease," says co-corresponding author Robert A. Baiocchi, MD, PhD, associate professor of medicine and a hematologist at the OSUCCC – James who is also collaborating on an Ohio State effort to develop a PMRT5 inhibitor.

"Our analyses also helped us identify PRMT5 as a master transcriptional repressor (gene silencer) in this disease, says co-corresponding author Balveen Kaur, PhD, professor of Neurological Surgery at the OSUCCC – James.

"We also learned that PRMT5 inhibition induced the death of glioblastoma cells whether the P53 gene was mutated or not. This has important treatment implications because loss of P53 is associated with a poor prognosis in these patients, so a PRMT5 inhibitor might be particularly important for these patients," says Kaur, who is specializes in glioblastoma research and is chief of Ohio State's Dardinger Laboratory of Neurosciences.

PRMT5 (protein arginine methyltransferase 5) is an enzyme that alters the structure of chromatin to suppress the transcription of genes and the production of proteins. To conduct their study, Kaur, Baiocchi and their colleagues used tumor tissue from patients, cell lines and an animal model. Key findings included:

  • PRMT5 is selectively over-expressed in glioblastoma and the degree of PRMT5 expression correlates with cell growth and patient survival.
  • In GBM patients, PRMT5 expression levels in tumor were significantly associated with lower overall survival;
  • Patients with high PRMT5 tumor expression had shorter overall survival (108 days) compared to patients with medium expression (277 days) and low expression (726 days).


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por cyto às 15:56

Segunda-feira, 30.03.15

Glioblastoma: Study ties three genes to radiation resistance in recurrent tumors

Glioblastoma: Study ties three genes to radiation resistance in recurrent tumors

A new study identifies three genes that together enable a lethal form of brain cancer to recur and progress after radiation therapy.

The findings might lead to new therapies that target , say researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James), who led the study.

The work focused on the glioblastoma multiforme (GBM). It investigated a subset of within those tumors that behave like stem and that sometimes survive. To understand how those cancer stem-like cells survive irradiation, the researchers examined the cancer-related gene EZH2, which is unregulated in GBM and other cancers.

They discovered that in GBM stem-like cells - but not in other tumor cancer cells or in healthy body cells - EZH2 is regulated/controlled by a gene called MELK in combination with a second gene, FOXM1. The interaction of the three genes helps the cells survive therapy.

The findings are published in the journal Stem Cell Reports.

"Currently, GBM is treated surgically followed by radiation therapy and chemotherapy, but these tumors often recur, and patients generally survive less than two years, so we badly need new treatments," says principal investigator Ichiro Nakano, MD, PhD, associate professor in the division of neurological surgery and a researcher in the OSUCCC - James Translational Therapeutics Program.

"Our findings suggest that MELK inhibitors can be applicable to brain and other cancers as a novel stem cell-directed therapy."

In earlier research, Nakano and his colleagues showed that MELK is highly expressed in glioblastoma stem-like cells, and that overexpression is correlated with poor patient survival.

For this study, Nakano and his colleagues used cells dissociated from GBM tumors, a mouse model and the roundworm Caenorhabditis elegans. Key findings include:

  • MELK and EZH2 proteins occur together in a subset of ;
  • Without MELK, GBM cells are more sensitive to irradiation; when MELK is restored, the cells become resistant to radiation;
  • Recurrent GBM tumors have higher numbers of MELK- and EZH2-positive cells than newly diagnosed tumors;
  • MELK and the oncogenic transcription factor FOXM1 form a complex that drives EZH2 expression;
  • Levels of MELK, FOXM1 and EZH2 are strongly linked to patient prognosis.

"Taken together, our data suggest that MELK upregulation after irradiation promotes radiation resistance, and tumor development and progression," Nakano says.

More information: Stem Cell Reports,… -6711%2814%2900383-X

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por cyto às 15:52

Segunda-feira, 30.03.15

Researchers identify protein pathway involved in brain tumor stem cell growth

Researchers identify protein pathway involved in brain tumor stem cell growth

 Glioblastomas are a highly aggressive type of brain tumor, with few effective treatment options. Moffitt Cancer Center researchers are one step closer to understanding glioblastoma development following the identification of a key protein signaling pathway involved in brain tumor stem cell growth and survival. Brain tumor stem cells are believed to play an important role in glioblastoma development and may be possible therapeutic targets.

The neurotrophin protein pathway controls nerve growth, survival and specialization. In an article published in the Feb. 6 issue ofThe Journal of Biological Chemistry, Moffitt researchers reported that the neurotrophin pathway is also involved in the survival and growth of brain tumor stem cells. The stem cells have high levels of neurotrophin receptors called TrkB and TrkC. Cellular signals from normal brain cells can activate TrkB and TrkC on the stem cells and stimulate cell growth. And when scientists inhibited TrkB and TrkC, they found decreased stem cell survival. This suggests that TrkB and TrkC may be possible drug targets for stem cells in gliomas and glioblastomas.

"This work might be a first step in developing new treatment approaches targeting brain tumor stem cells. It may also partly explain why can grow so quickly since proteins from the surrounding normal brain might be used by the tumor to grow even faster," said Peter A. Forsyth, M.D., chair of the Department of Neuro-Oncology at Moffitt.

Researchers also reported a potential reason why several clinical trials targeting a protein called EGFR in glioblastoma patients have failed to live up to expectations. EGFR is frequently activated in glioblastoma, but results from trials using EGFR inhibitors showed little or no patient improvement. Moffitt scientists discovered that TrkB and TrkC maintain brain stem cell survival and growth even when EGFR inhibitors are used. These observations suggest that one reason why EGFR inhibitors may be ineffective in glioblastoma is that TrkB and TrkC are active, thereby bypassing EGFR inhibition and allowing to continue to grow.

This is the first time that scientists have shown that TrkB and TrkC are involved in brain tumor stem. Currently, no drugs that target TrkB and TrkC have been used as brain cancer treatments. Researchers hope that these results might encourage the development of drugs that target both the stem cell compartment and the more differentiated parts of the brain tumor and result in more effective therapies.

More information: J. Biol. Chem. 2015 290: 3814-3824. DOI: 10.1074/jbc.M114.599373

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por cyto às 15:49

Segunda-feira, 30.03.15

Brain tumor patients put on fast track in revolutionary clinical trial

Brain tumor patients put on fast track in revolutionary clinical trial


Brain tumor experts at Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center have launched a revolutionary fast-track approach to cancer research, giving new hope to brain cancer patients. In partnership with The Ben & Catherine Ivy Foundation, the Translational Genomics Research Institute (TGen) and the Barbara Ann Karmanos Cancer Institute, the Barrow studies are the first of their kind.

Called "Phase 0 Trials," these early-phase shorten the evaluation of therapies from an average of five years to only six months at a fraction of the cost. During each single-patient trial, participants are administered an experimental drug already proven to be safe in other types of cancer. Within hours, Barrow neurosurgeons remove the brain tumor and within weeks it is determined if the experimental drug penetrated the tumor and whether it is having a positive effect on the tumor. If the drug reaches the tumor and shows activity, it moves into a Phase 2 clinical trial for patients. If it does not prove to be effective, the patient has the option to enter another study.

"Brain tumors are among the deadliest of all cancers and during the last 30 years, little progress has been made on successful treatments to increase life expectancy," says Nader Sanai, MD, Director of the Barrow Brain Tumor Research Center. "This Phase 0 approach for malignant is a game changer in and our program is the first of its kind in the world."

These studies are called Phase 0 clinical trials because they occur outside of the three lengthy phases that evaluate a drug's safety, effectiveness, side effects and dosage. After years of research and millions of dollars, the vast majority of experimental drugs for brain tumors proves ineffectual and is never brought to market.

One of the major difficulties in treating brain tumors is finding drugs that can penetrate the blood-brain barrier, which buffers the brain from the rest of the body's blood-circulatory system. Located along capillaries, the blood-brain barrier protects the brain from rapid changes in the body's metabolic conditions and minimizes exposure to molecules that are toxic to neurons in the brain.

"The main question answered by these Phase 0 clinical trials is this: Does the drug get to the tumor?" said Dr. Michael Berens, PhD, TGen Deputy Director for Research Resources. "Next, we look at how much of the drug is enough, and if there are any signs of patient benefit."


TGen is using its world-class expertise in genomic sequencing to analyze brain tumor samples and help determine which drugs might work best.

"Because of what is known about how each drug works, we think there are certain genetic mutations that would make certain patients more responsive to the drug," said Dr. Berens, who also is Director of TGen's Cancer and Cell Biology Division and TGen's Glioma Research Lab.

Karmanos is analyzing samples of the resected brain tumors, following surgery, to determine how much of the drug accumulated in the tumor, and what effect, if any, the drugs have on the cancer.

Phase 0 trials were recently introduced by the FDA and have never before been widely used for brain tumor patients. This is the first non-governmental study coalition to push forward with these trials, an initiative that has drawn interest from some of the world's largest cancer therapy developers. The first of these Phase 0 clinical trials was made possible largely through a generous grant by The Ben & Catherine Ivy Foundation.

"The absence of truly effective drugs for brain tumors is one of the medical community's most critical unmet needs," says Catherine Ivy, President of The Ben & Catherine Ivy Foundation. "These Phase 0 clinical trials are part of a much larger research strategy funded by the Ivy Foundation to address this need and give new hope to brain tumor patients worldwide."

Dr. Sanai believes the trials will provide encouragement to brain tumor patients, who often feel abandoned.

"Because of the high cost of developing and testing drugs, there is very little in the pharmaceutical pipeline that has reached brain tumor patients," says Dr. Sanai. "It has just been too expensive for drug companies to develop new therapies for the relatively small number of brain cancer patients. These Phase 0 trials can be the answer. They are safe, cost effective and quick to give us an answer. If a new drug dosen't work, we move to the next one without the patient losing any time. For the first time, I can tell every brain tumor patient, 'I have something new for you'."

Explore further: One dose, then surgery: A new way to test brain tumor drugs

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por cyto às 15:48

Segunda-feira, 30.03.15

Combination therapy found best for low-grade brain tumors

Combination therapy found best for low-grade brain tumors


New clinical trial findings provide further evidence that combining chemotherapy with radiation therapy is the best treatment for people with a low-grade form of brain cancer. This research was published in the International Journal of Radiation Oncology Biology Physics (2015; 91(3): 497-504).

The phase 2 study found that patients with low-grade gliomas and at high risk for tumor recurrence have an overall survival of 73% after 3 years when treated with radiation plus temozolomide, a chemotherapy drug. This is compared with a 3-year survival rate of 54% for historical controls treated with radiation alone.

These findings come from a study co-led by a researcher at Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) in Columbus and researchers at the University of Maryland in College Park and at London Regional Cancer Program in Ontario, Canada.

"The most effective treatment for these rare tumors is currently controversial at best," said Arnab Chakravarti, MD, chair and professor of Radiation Oncology and co-director of the Brain Tumor Program at the OSUCCC – James. Chakravarti is the trial's translational research national study chair.

"Many of these high-risk low-grade gliomas progress to grade III and IV tumors over time, so identifying the best treatment strategy is critical to ensure that patients have the best outcomes," said Chakravarti, who is also the Max Morehouse Chair in Cancer Research at Ohio State.

"Our study reports that combining radiation with temozolomide-based chemotherapy appears to improve clinical outcome compared to historical controls treated by radiation alone. This may prove critical in killing enough tumor cells to prevent progression to stage IV disease, or glioblastoma multiforme, over time."

Low-grade gliomas represent less than 1% of all human tumors in the United States. The average survival times vary depending on the tumor's structural, molecular, and genetic features. (One form of high-risk low-grade glioma has an average overall survival of approximately 5 years.)

The study's 3-year progression-free survival rate was 59%. Grade 3 adverse events occurred in 43% of patients; grade 4 events occurred in 10% of patients.

Chakravarti and his lab are currently conducting molecular studies to identify more specifically which low-grade glioma patients benefit from temozolomide.

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por cyto às 15:42

Segunda-feira, 30.03.15

Radiation plus immunotherapy revs up immune system to better attack melanoma

Radiation plus immunotherapy revs up immune system to better attack melanoma

Treating metastatic melanoma with a triple threat that includes radiation therapy and twoimmunotherapies that target the CTLA4 and PD-1 pathways could elicit an optimal response in more patients. The response will boost the immune system's attack on the disease, suggests a new study published in Nature (2015; doi:10.1038/nature14292).

The study, conducted by a multidisciplinary team of researchers from the University of Pennsylvania's Abramson Cancer Center in Philadelphia, reports for the first time on the response and resistance to radiation combined with ipilimumab (an antibody against CTLA4) in both patients and mice.

"These new immunotherapies are potent treatment options that have generated a lot of excitement in the past few years, but we know that many patients fail to respond, underscoring the need to further improve the drugs' abilities," said senior author Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology. "Anecdotally, we know that combining radiation with immunotherapy can be powerful, so we were very motivated to move forward with both a clinical trial to demonstrate that this combination is a promising route to pursue and with laboratory studies to understand why response happens and why it does not."

Ipilimumab is an FDA-approved, anti-CTLA4 antibody that serves to lift a brake on the immune system, allowing T cells to infiltrate and attack tumor cells. Antibodies that block the PD-L1 pathway, which cancer cells use to hide from the immune system, include pembrolizumab or nivolumab, anti-PD-1 immunotherapies recently approved by the FDA.

Adding radiation is believed to result in a synergistic attack, turning the destroyed tumor cells into a vaccine against the cancer. Irradiated tumor cells are believed to release antigens that help train the immune system to fight other tumors in the body. The treatment has earned the name RadVaxbecause of its vaccine-like qualities.

The impetus for the Penn phase I clinical study was a metastatic melanoma patient in his early 50s who was treated with an anti-CTLA4 antibody at Penn Medicine by co-author Lynn M. Schuchter, MD, chief of Hematology/Oncology at Penn's Abramson Cancer Center. While on an anti-CTLA4 antibody, the patient's condition worsened, and he required palliative radiation therapy. Over the course of many months after both modalities and no further treatment, however, his metastatic cancer started to resolve, and he was eventually deemed nearly cancer free.

Attempting to mirror his treatment experience, the researchers recruited 22 patients with previously treated and untreated stage IV melanoma for a phase I clinical trial that investigated the use of both modalities. The group received stereotactic body radiation therapy (SBRT) to a single tumor followed 3 to 5 days later with ipilimumab every 3 weeks for four cycles.

The team found that 18% of patients had partial response in unirradiated tumors, 18% had stable disease and 64% had progressive disease. The median progression free survival and overall survival for patients was 3.8 months and 10.7 months with a median follow up of 18.4 and 21.3 months, respectively. The group's overall survival rate was 35%. A past, phase III study showed an overall survival rate of 20% in patients taking ipilimumab alone.

The researchers explained that this approach is changing their perspective on radiation, from a strictly local form of therapy to one that might augment a systemic response when given with immunotherapy.

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por cyto às 15:08

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Março 2015