McCain May Benefit from Glioblastoma Tx Advances

barbara

Pioneer Founding member
Treatment landscape altered since pal Ted Kennedy developed disease in 2008

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by John Gever, Managing Editor, MedPage Today
July 20, 2017

The announcement that Sen. John McCain (R-Ariz.) has glioblastoma brought to mind the parallels with his longtime colleague and friend, Sen. Edward M. Kennedy (D-Mass.), who also developed a malignant glioma while major healthcare legislation was being considered.
But treatment options for Kennedy were more limited than they are today. New drugs and devices, and especially new diagnostics and surgical procedures, have become available in the years since Kennedy was diagnosed in May 2008. He survived about 15 months after undergoing surgery followed by chemotherapy and radiation treatments.

MedPage Today asked a number of oncologists about how the treatment landscape has changed since Kennedy was treated.
John Sampson, MD, PhD, of the Preston Robert Tisch Brain Tumor Center at Duke University, was a member of the team that operated on Kennedy, told MedPage Today that "new techniques in minimally invasive, image guided surgery and intraoperative MRI have enhanced our ability to take these tumors out with minimal morbidity."

Also highlighting advances in surgical techniques was Walter J. Curran Jr., MD, a radiation oncologist at Emory University: "There have been substantial improvements in surgical approaches, including new methods of detecting tumor anatomy with special illumination techniques and now MR spectroscopy approaches to defining tumor margins for the purpose of radiation planning," he said, citing the work of several other groups.
Similarly, Susan Chang, MD, of the University of California San Francisco, said the recent approval of a fluorescent dye for identifying tumor cells in situ during surgery has been helpful in assuring more complete excision of malignant tissue.

Progress with drug treatments for gliomas got mixed reviews from the experts we contacted. Curran noted the failures of several drugs in extending survival. On the other hand, he said the new immunotherapies such as pembrolizumab (Keytruda) and nivolumab (Opdivo) have changed the landscape, with "initial promising results" in brain cancer.

And Eric Chang, MD, of the University of Southern California, pointed to the "establishment of temozolomide as standard of care for all patients, including advanced age patients such as Sen. McCain," as an important development. He also cited intensity-modulated proton beam therapy as an enhancement to the clinician's arsenal against brain tumors.

Another rapidly changing area is in molecular tumor analysis. Howard Alan Fine, MD, of Weill Cornell Brain Tumor Center in New York City, said this research has "allowed us to prognosticate and to group patients into more homogeneous groups to allow more rationale choices of treatments and for more scientifically rigorous clinical trials."

A treatment not available to Kennedy was approved in 2011: the Optune "tumor treating fields" electrical device. Susan Chang noted that in one recent trial, it appeared to boost 5-year survival from 5% to 13%.

Finally, there are investigational treatments that could be available to McCain. In addition to the approved immunotherapy drugs, other approaches to harnessing the body's immune system to attack brain cancers are in development. So-called CAR T-cell therapies have attracted significant attention for hematologic malignancies, but could also be helpful for gliomas, noted Eric Chang. And a recent study from Duke found that a vaccine against cytomegalovirus had shown benefit for glioma patients in an early trial.


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California Stem Cell Report
THURSDAY, JULY 20, 2017

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http://californiastemcellreport.blogspot.com/2017/07/mccains-cancer-and-california-stem-cell.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed:+blogspot/QUrJz+(California+Stem+Cell+Report)

McCain's Cancer and the California Stem Cell Agency: The Promising Approaches of Genetic Engineering
City of Hope video on T-cell treatment of glioblastoma

The type of aggressive brain cancer that is now afflicting U.S. Sen. John McCain is a disease that has been long targeted by California's $3 billion stem cell agency.

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), has spent more than $90 million for research dealing with brain cancer, which claims the lives of 13,000 people each year.

Particularly deadly is glioblastoma, the form of cancer involving McCain.

In January, Karen Ring, a stem cell scientist and overseer of CIRM's social media, wrote on the agency's blog about an early stage clinical trial involving glioblastoma, describing it as "a new cell-based therapy that melted away brain tumors in a patient with an advanced stage" of the disease.

The research was conducted at the City of Hope's Alpha Clinic, an effort created by the stem cell agency.

In March, Behnam Badie, who is leading the research, discussed the therapy at a symposium dealing with results from year two of the Alpha Clinic program. Badie, whose father died of brain cancer, described how the use of T-cells beneficially affected the patient, Richard Brady, who was also a surgeon.

In a video presented at the symposium, Badie's colleague, Christine Brown, described T-cells as the "soldiers of the immune system." Brady also appeared in the video, saying,
"I find myself in disbelief that I am here."

On its web site, the agency says,
"Stem cell approaches look promising for treating gliomas. Certain types of stem cell tend to migrate toward the tumor cells wherever they are in the brain. CIRM-funded researchers are trying to genetically engineer those stem cells to produce cancer-killing molecules. Transplanted into the brain, these cells would seek out the cancer cells and deliver their therapy directly where it is needed. This approach could significantly decrease toxic side-effects to normal tissues, preserving or improving the patient's quality of life."

Brady, however, was not cured by his treatment and ultimately succumbed to the spread of the cancer. Ring wrote in January,
"The effects of the immunotherapy lasted for seven-and-a-half months. Unfortunately, his glioblastoma did come back....Patients with advanced cases of glioblastoma like Richard often have only weeks left to live, and the prospect of another seven months of life with family and friends is a gift."


POSTED BY DAVID JENSEN
 

barbara

Pioneer Founding member
Retraction Watch - And there are also disappointments

“We do not want to create false hope”: Authors retract Cell paper they can’t replicate
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http://retractionwatch.com/2017/07/20/not-want-create-false-hope-authors-retract-cell-paper-cant-replicate/

A few years ago, researchers in Sweden had something to celebrate: They thought they had discovered a chink in the armor of the most common type of malignant brain cancer.

In a 2014 Cell paper, the team — led by Patrik Ernfors at the Karolinska Institutet — reported that they had identified a small molecule that could target and kill glioblastoma cells — the cancer that U.S. Senator John McCain was just diagnosed with — and prolong survival in mice with the disease.

Satish Srinivas Kitambi, the paper’s first author, who is also based at the Karolinska Institutet, said the results got the team “really excited:”

We believed we had found a molecule that raised a new therapeutic hope for patients with glioblastoma.

Given the promising results, Kitambi said, “Our [goal] was to use this molecule as a monotherapy.” Unfortunately, their initial excitement soon faded.

The study created buzz. The paper was featured in Research Highlights in Nature Reviews Drug Discovery and in commentaries in Cell and Cell Research, all of which explained why the findings could be important for treating glioblastoma; Cell called the 2014 paper “a true tour de force.”

To carry on the work, the paper’s second-to-last author, Lars Hammarström, told us that the authors performed follow-up studies “to validate the compound’s efficacy” and “to make sure we had a robust response in vivo and to probe minimum efficacious dosing, toxicity etc before proceeding with further preclinical development.”

But when the researchers attempted to test the molecule’s effectiveness in rats and other mouse models of glioblastoma, they could not replicate the original results. Kitambi explained:

We repeated our experiment multiple times and saw that the molecule only extended survival in the animals sometimes, not all the time. That was a cause for concern.

Hammarström, a senior scientist at the Karolinska Institutet, told us:

In the new studies, the control mice lived much longer than we had observed in the initial Cell study.

Hammarström added:

We were puzzled by these results for a long time until we did careful additional histopathological analysis of the brains from the original study, which we fortunately had kept in formalin.

When the researchers re-examined the data from the 2014 paper, for “Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule,” they identified another possible explanation for why the untreated mice didn’t live as long as the treated ones: The control mice had developed a tumor in another location in their brain, called the meningeal compartment, which the researchers believe may have caused the control mice to die more quickly. Hammarström added that the the mice in the treatment group may have also developed tumors in the meningeal compartment, but were “cured” by the compound.

Kitambi said the researchers initially missed this other tumor in the control mice because “We never looked at meningial regions … there was [no] real reason to do at that time.”

When performing subsequent experiments, the researchers modified their protocol to ensure the mice did not develop tumors in the meningeal compartment. As a result, Hammarström explained, “the life expectancy was much longer and overall survival unaffected by the compound.”

Hammarström said that the authors immediately contacted Cell to inform the editors:

We chose to retract the paper so that others would not do any additional study on the compound expecting to repeat the original results.

He added:

It’s of course a pity since the remaining 95% of data, including all in vitro data in the paper have been thoroughly validated by both us and others, but in the end a retraction was the right decision since the in vivo data was the most important piece of the puzzle.

Kitambi agreed that a retraction was “the best way to move forward:”

We feel a high degree of responsibility when it comes to treating patients. We do not want to create false hope.

Here’s the retraction notice:

This article has been retracted at the request of the authors.

Our study reported the discovery of a class of small molecules that induces the massive vacuolization and cell death of glioblastoma cells in vitro, attenuates disease progression, and prolongs survival in a glioblastoma animal model. In the process of generating additional pre-clinical data to support the transition of vacquinol-1 to the clinics, we found that we are unable to replicate the original results showing that vacquinol-1 treatment extends overall survival of mice implanted with glioblastoma cells (Figure 7U in the original paper). Retrospective histopathological analysis of the brains from the original Figure 7U in vivo study indicates that tumor growth in the meningeal compartment of mice in the control group may have contributed to the difference in survival observed between vehicle and vacquinol-treated animals. These results call into question the extent of in vivo efficacy of vacquinol-1 as a monotherapy, and we therefore believe that the responsible course of action is to retract the paper. We apologize for any inconvenience we may have caused.

The 2014 paper has been cited 56 times, according to Clarivate Analytics’ Web of Science.

Hammarström told us:

We are continuing to investigate the mechanism of action of the compound and what is causing the discrepancy between in vitro-in vivo results.

Kitambi hopes the decision to retract the paper will highlight the fact that “retractions are not necessarily a bad thing.” In this case, Kitambi felt that retracting the study and alerting readers to the replication issue would:

…improve what compounds actually reach the clinic and hopefully help researchers engineer more efficient patient therapies. Ultimately, our goal is to help patients.
 
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