Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Vaccine targeting cancer-related antigens in brain tumors appears to prolong survival

15.07.2004


Researchers seeking to direct cancer-killing immune cells against the deadliest brain tumors have three new targets that show promise in laboratory studies and in a Phase I patient trial, according to two articles in the July 15 issue of the journal Cancer Research.

The antigens, previously associated with several other types of cancer cells, were recently found to be expressed in the most common and aggressive type of malignant brain tumor, glioblastoma multiforme (GBM). Scientists at Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute and the National Cancer Institute have generated cytotoxic T lymphocyte clones (cancer-killing immune cells) that recognize GBM cells expressing these antigens.

"In a Phase I clinical trial of 14 patients, we found that our dendritic cell vaccine not only generated an immune response against these antigens but it appeared to play a significant role in prolonging survival in patients with glioblastoma," said Keith L. Black, MD, director of the Institute, the Division of Neurosurgery and the Comprehensive Brain Tumor Program at Cedars-Sinai.



The median length of survival of patients with recurrent glioblastoma whose treatment included the vaccine was 133 weeks – about two and a half years. A similar group of patients receiving the same level of care but not the vaccine had a median survival of only 30 weeks – seven and a half months.

John S. Yu, MD, senior author of the articles and co-director of the Comprehensive Brain Tumor Program, said these findings represent a significant advance in the field of brain tumor immunotherapy.

"This is the first time that a specific response to brain tumor antigens has been demonstrated as the result of an immunotherapy strategy," he said. "These antigens give us specific targets to aim for and they give us potent tools with which to measure immune responses. Therefore, we have a better way of monitoring the progress of patients who undergo vaccination and we have a means of improving these therapies."

In recent years, scientists have identified several tumor-specific antigens that appear to play a role in the development of certain cancer cells. The body’s natural defensive cells, T lymphocytes, have the capacity to attack "foreign" proteins, but cancer cells and the antigens they express typically evade recognition by the immune system. Therefore, cancer researchers search for new antigens that may serve as targets, devise new methods to make the targets "visible" and vulnerable to immune cells, and seek new ways to multiply the number of cancer-killing cells responding to the threat.

"These three antigens – HER2, gp100, and MAGE-1 – have been described since the 1980s but we have only recently found them to be expressed in glioblastoma cells," said Dr. Black.

HER-2 is expressed in a variety of normal tissues, but it is selectively overexpressed in a number of malignancies, including breast and ovarian tumors. Glycoprotein 100 (gp100) is an antigen linked to melanoma. MAGE-1, initially analyzed from melanomas and found to be expressed in a variety of tumor types, became the first identified tumor antigen recognized by the immune system’s protective T cells.

In earlier studies at other centers, a cancer vaccine combining MAGE-1 cells with specially cultured immune system cells was able to produce a tumor-specific immune response among patients with melanoma. Clinical trials using gp100 as a target in melanoma and HER-2 as a target in several types of cancers also demonstrated that the antigens elicit a strong immune response that continues even after the vaccinations have ended.

Since then, researchers have worked to develop a number of therapies that may be used individually or in combination to target malignant brain tumors. Dendritic cell immunotherapy is intended to stimulate a patient’s immune system to recognize and attack glioblastoma cells. Tumor cells that have been removed during surgery are cultured in the laboratory with dendritic cells, also called "antigen-presenting" cells, taken from the patient’s blood. The resulting cells are injected back into the patient, where they are designed to identify brain tumor cells as invaders and stimulate a strong response from tumor-infiltrating T lymphocytes.

In an earlier Phase I trial, tumor cells were grown in culture, and proteins from the cell surfaces were used in preparing the vaccine. In the Phase I trial described in the Cancer Research article, this process was refined.

"Now we take the proteins directly from the surgical specimen, which ensures that we are getting the relevant proteins and not antigens or proteins that are artifacts of the culturing process. This also avoids the technical problems of trying to grow out tumor cells that have been irradiated and undergone chemotherapy," Dr. Yu said. "In addition, instead of just drawing blood to obtain a patient’s dendritic cells, we’re using a process that allows us to get 25-fold more dendritic cells. This may account for the dramatic prolongation of survival that we see compared to our control patients."

Dr. Black said a larger Phase II trial of the dendritic cell vaccine is now being completed and the researchers are preparing to apply for a randomized Phase III trial.

In the lab studies described in Cancer Research, seven established GBM tumor cell lines and cells from 43 GBM tumors removed from patients at Cedars-Sinai were analyzed and compared with normal brain tissue. MAGE-1 was not detected in normal tissue. Although HER-2 and gp100 were detected in normal tissue, this does not preclude their potential usefulness. In previous studies with different tumor types, HER-2 and gp100 were overexpressed in cancer cells, while in normal cells they were expressed at levels below the "threshold" for activation by the immune system.

Furthermore, because healthy neural cells are of a histocompatibility type that does not interact with cytotoxic T cells, the immune system will not launch an attack on normal tissue expressing the antigens. In contrast, however, the surfaces of GBM tumor cells were found to express Major Histocompatibility Complex (MHC) Class I molecules, the type that makes them vulnerable to interaction with cytotoxic T lymphocytes.

The researchers documented that HER-2, gp100 and MAGE-1 are frequently expressed in glioblastoma cells. They generated cytotoxic T lymphocyte clones specific to each antigen and cultured them with GBM cells. The brain tumor cells were able to naturally process the antigens, and the lymphocytes were able to process the antigen-derived peptides or proteins on the surfaces of the GBM cells.

Sandra Van | EurekAlert!
Further information:
http://www.csmc.edu

More articles from Life Sciences:

nachricht Cell Division at High Speed
19.06.2019 | Julius-Maximilians-Universität Würzburg

nachricht Monitoring biodiversity with sound: how machines can enrich our knowledge
18.06.2019 | Georg-August-Universität Göttingen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Successfully Tested in Praxis: Bidirectional Sensor Technology Optimizes Laser Material Deposition

The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.

Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...

Im Focus: The hidden structure of the periodic system

The well-known representation of chemical elements is just one example of how objects can be arranged and classified

The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

A new force for optical tweezers awakens

19.06.2019 | Physics and Astronomy

New AI system manages road infrastructure via Google Street View

19.06.2019 | Information Technology

A new manufacturing process for aluminum alloys

19.06.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>