The current study used mice to show it is possible to shift the delivery path directly to the lymph nodes.Currently all other adjuvants (substances added to vaccines to help to boost the immune response) are thought to enhance immunity at the skin site where the vaccine is injected rather than going to the lymph nodes, where the most effective immune reactions occur.
Monday, 23 January 2012
Vaccines to Boost Immunity Where It Counts, Not Just Near Shot Site
The current study used mice to show it is possible to shift the delivery path directly to the lymph nodes.Currently all other adjuvants (substances added to vaccines to help to boost the immune response) are thought to enhance immunity at the skin site where the vaccine is injected rather than going to the lymph nodes, where the most effective immune reactions occur.
Thursday, 23 June 2011
Improving health assessments with a single cell: Portable microchip for immune monitoring and clinical applications
The scientists reported on their advanced technology in the May 22 online issue of Nature Medicine.
"The technology permits us for the first time to quantitatively measure the levels of many functional proteins from single, rare immune cells," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech and corresponding author of the study. "The functional proteins are the ones that are secreted by the cells, and they control biological processes such as cell replication and inflammation and, specific to our study, tumor killing."
In 2008, Heath -- an expert in molecular electronics and personalized medicine -- led the development of a "barcode chip" that, using just a pinprick's worth of blood, could measure the concentrations of dozens of proteins, including those that herald the presence of diseases like cancer and heart disease. This latest single-cell barcode chip (SCBC) device builds upon the success of that initial design, which is currently being utilized in diagnostic medical testing of certain cancer patients.
The researchers tested the chip by measuring a cancer patient's response to a type of cell-based immunotherapy designed to target and kill tumor cells. The only way to know if the therapy is doing its job is to measure many proteins at the same time from the individual cells that were targeting the tumor. The SCBC aced this test, generating readouts of a dozen secreted biomarkers -- each of which represented a distinct cell function -- and taking those readings from about a thousand single cells simultaneously.
The team was able to conduct a proof-of-concept study by looking at samples from a melanoma patient participating in the immunotherapy trials, and comparing those results to similar samples from three healthy subjects.
"This technology has the potential to be used routinely to monitor immune system performance," says Chao Ma, a graduate student in Heath's lab at Caltech's NanoSystems Biology Cancer Center and lead author of the Nature Medicine paper. "For example, it can be directly used to evaluate the effectiveness of certain classes of therapeutics, such as vaccines and other immunotherapies."
According to Ma, the technology is minimally invasive, cost-effective, and highly informative. The goal, he says, is to help physicians closely track the effectiveness of a therapy, and to rapidly alter or switch that therapy for the maximum benefit of the patient.
"The research fully demonstrates real-life clinical use of our revolutionary technology," Ma says.
The next step for the team will be to systematically apply the technology to clinical studies. The researchers have already begun to test the technology in additional patient populations, and to combine the SCBC with existing assays in order to get a more comprehensive picture of a therapy's efficacy.
In fact, the same study that showed the microchip's efficacy is already helping the researchers better evaluate the specific cancer immunotherapy trial, from which the patient in the study was drawn. "We are doing these same types of measurements on similar patients but at a significantly higher level of detail, and at many time points over the course of the cancer immunotherapy procedure," explains Heath. "It is helping us put together a 'movie' of the patient's immune system during the therapy, and it is providing us with some very surprising but also valuable insights into how the therapy works and how we might work with our UCLA colleagues to improve it."
"Application of this technology provides an unprecedented understanding of the human immune system by allowing an efficient and multiplexed functional readout of immune responses using limiting numbers of lymphocytes," says Antoni Ribas, associate professor of medicine and physician who led the clinical trial portion of the study at UCLA's Jonsson Comprehensive Cancer Center.
The other Caltech authors of the Nature Medicine paper, "A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells," are postdoctoral scholar Qihui Shi; Rong Fan, former postdoctoral scholar; former graduate students Habib Ahmad and Gabriel Kwong; and Chao-Chao Liu, former undergraduate student. Begonya Comin-Andiux, assistant professor of surgery; Thinle Chodon, assistant researcher of medicine; Richard C. Koya, assistant professor of surgery; and Caius G. Radu, associate professor of medical and molecular pharmacology from UCLA's Jonsson Comprehensive Cancer Center also contributed to the study.
The work was funded by the National Cancer Institute, the Ivy Foundation, the Jean Perkins Foundation, the California Institute for Regenerative Medicine, the Caltech/UCLA Joint Center for Translational Medicine, the Melanoma Research Alliance, and the National Institutes of Health.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by California Institute of Technology. The original article was written by Katie Neith.
Journal Reference:
Chao Ma, Rong Fan, Habib Ahmad, Qihui Shi, Begonya Comin-Anduix, Thinle Chodon, Richard C Koya, Chao-Chao Liu, Gabriel A Kwong, Caius G Radu, Antoni Ribas, James R Heath. A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells. Nature Medicine, 2011; DOI: 10.1038/nm.2375Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Sunday, 5 June 2011
Improving health assessments with a single cell: Portable microchip for immune monitoring and clinical applications
The scientists reported on their advanced technology in the May 22 online issue of Nature Medicine.
"The technology permits us for the first time to quantitatively measure the levels of many functional proteins from single, rare immune cells," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech and corresponding author of the study. "The functional proteins are the ones that are secreted by the cells, and they control biological processes such as cell replication and inflammation and, specific to our study, tumor killing."
In 2008, Heath -- an expert in molecular electronics and personalized medicine -- led the development of a "barcode chip" that, using just a pinprick's worth of blood, could measure the concentrations of dozens of proteins, including those that herald the presence of diseases like cancer and heart disease. This latest single-cell barcode chip (SCBC) device builds upon the success of that initial design, which is currently being utilized in diagnostic medical testing of certain cancer patients.
The researchers tested the chip by measuring a cancer patient's response to a type of cell-based immunotherapy designed to target and kill tumor cells. The only way to know if the therapy is doing its job is to measure many proteins at the same time from the individual cells that were targeting the tumor. The SCBC aced this test, generating readouts of a dozen secreted biomarkers -- each of which represented a distinct cell function -- and taking those readings from about a thousand single cells simultaneously.
The team was able to conduct a proof-of-concept study by looking at samples from a melanoma patient participating in the immunotherapy trials, and comparing those results to similar samples from three healthy subjects.
"This technology has the potential to be used routinely to monitor immune system performance," says Chao Ma, a graduate student in Heath's lab at Caltech's NanoSystems Biology Cancer Center and lead author of the Nature Medicine paper. "For example, it can be directly used to evaluate the effectiveness of certain classes of therapeutics, such as vaccines and other immunotherapies."
According to Ma, the technology is minimally invasive, cost-effective, and highly informative. The goal, he says, is to help physicians closely track the effectiveness of a therapy, and to rapidly alter or switch that therapy for the maximum benefit of the patient.
"The research fully demonstrates real-life clinical use of our revolutionary technology," Ma says.
The next step for the team will be to systematically apply the technology to clinical studies. The researchers have already begun to test the technology in additional patient populations, and to combine the SCBC with existing assays in order to get a more comprehensive picture of a therapy's efficacy.
In fact, the same study that showed the microchip's efficacy is already helping the researchers better evaluate the specific cancer immunotherapy trial, from which the patient in the study was drawn. "We are doing these same types of measurements on similar patients but at a significantly higher level of detail, and at many time points over the course of the cancer immunotherapy procedure," explains Heath. "It is helping us put together a 'movie' of the patient's immune system during the therapy, and it is providing us with some very surprising but also valuable insights into how the therapy works and how we might work with our UCLA colleagues to improve it."
"Application of this technology provides an unprecedented understanding of the human immune system by allowing an efficient and multiplexed functional readout of immune responses using limiting numbers of lymphocytes," says Antoni Ribas, associate professor of medicine and physician who led the clinical trial portion of the study at UCLA's Jonsson Comprehensive Cancer Center.
The other Caltech authors of the Nature Medicine paper, "A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells," are postdoctoral scholar Qihui Shi; Rong Fan, former postdoctoral scholar; former graduate students Habib Ahmad and Gabriel Kwong; and Chao-Chao Liu, former undergraduate student. Begonya Comin-Andiux, assistant professor of surgery; Thinle Chodon, assistant researcher of medicine; Richard C. Koya, assistant professor of surgery; and Caius G. Radu, associate professor of medical and molecular pharmacology from UCLA's Jonsson Comprehensive Cancer Center also contributed to the study.
The work was funded by the National Cancer Institute, the Ivy Foundation, the Jean Perkins Foundation, the California Institute for Regenerative Medicine, the Caltech/UCLA Joint Center for Translational Medicine, the Melanoma Research Alliance, and the National Institutes of Health.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by California Institute of Technology. The original article was written by Katie Neith.
Journal Reference:
Chao Ma, Rong Fan, Habib Ahmad, Qihui Shi, Begonya Comin-Anduix, Thinle Chodon, Richard C Koya, Chao-Chao Liu, Gabriel A Kwong, Caius G Radu, Antoni Ribas, James R Heath. A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells. Nature Medicine, 2011; DOI: 10.1038/nm.2375Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Tuesday, 31 May 2011
'I'm a tumor and I'm over here!' Nanovaults used to prod immune system to fight cancer
The vaults, barrel-shaped nanoscale capsules found in the cytoplasm of all mammalian cells, were engineered to slowly release a protein, the chemokine CCL21, into the tumor. Pre-clinical studies in mice with lung cancer showed that the protein stimulated the immune system to recognize and attack the cancer cells, potently inhibiting cancer growth, said Leonard Rome, a researcher at UCLA's Jonsson Comprehensive Cancer Center, associate director of the California NanoSystems Institutes and co-senior author of the study.
"Researchers have been working for many years to develop effective immune therapies to treat cancer, with limited success," said Rome, who has been studying vaults for decades. "In lung tumors, the immune system is down-regulated and what we wanted to do was wake it up, find a way to have the cancer say to the immune system, 'Hey, I'm a tumor and I'm over here. Come get me.' "
The study appears in the May 3, 2011 issue of PLoS ONE, a peer-reviewed journal of the Public Library of Science.
The new vault delivery system, which Rome characterized as "just a dream" three years ago, is based on a 10-year, on-going research effort focusing on using a patient's white blood cells to create dendritic cells, cells of the immune system that process antigen material and present it on the surface to other immune system cells. A Phase I study that is part of the effort, led by ULCA's Dr. Steven Dubinett, used a replication-deficient adenovirus to infect the dendritic cells and prompt them to over-secrete CCL21, the first time the chemokine has been administered to humans. The engineered cells -- 10 million at a time -- were then injected directly into the patient's lung cancer to stimulate an immune response.
The early phase study has shown the dendritic cell method is safe, has no side effects and seems to boost the immune response -- Dubinett and his team found T lymphocytes circulating in the blood stream with specific cytokine signatures, indicating that the lymphocytes were recognizing the cancer as a foreign invader.
However, the process to generate dendritic cells from the white blood cells and engineer them to over-secrete CCL21 is cumbersome, expensive and time-consuming. It also requires a Good Manufacturing Practice (GMP) suite, a specialized laboratory critical for the safe growth and manipulation of cells, which many research institutions do not have.
"It gets complicated," said Dubinett, director of the Lung Cancer Program at UCLA's Jonsson Comprehensive Cancer Center, a professor of pathology and laboratory medicine, member of the California NanoSystems Institute and a co-senior author of the paper. "You have to have a confluence of things happen -- the patient has to be clinically eligible for the study and healthy enough to participate, we have to be able to grow the cells and then genetically modify them and give them back."
There also was the challenge of patient-to-patient variability, said Sherven Sharma, a researcher at both the Jonsson Cancer Center and the California NanoSystems Institute, professor of pulmonary and critical care medicine and co-senior author of the study. It was easier to isolate and grow the dendritic cells in some patients than in others, so results were not consistent.
"We wanted to create a simpler way to develop an environment that would stimulate the immune system," Sharma said.
In the Phase I study, it takes more than a week to differentiate the white blood cells into dendritic cells and let them grow to the millions required for the therapy. The dendritic cells are infected with a virus engineered to carry a gene that caused the cells to secrete CCL21 and then injected into the patient's tumor using guided imaging.
"We thought if we could replace the dendritic cells with a nano-vehicle to deliver the CCL21, we would have an easier and less expensive treatment that also could be used at institutions that don't have GMP," Dubinett said.
If successful, the vault delivery method would add a desperately needed weapon to the arsenal in the fight against lung cancer, which accounts for nearly one-third of all cancer deaths in the United States and kills one million people worldwide every year.
"It's crucial that we find new and more effective therapies to fight this deadly disease," Dubinett said. "Right now we don't have adequate options for therapies for advanced lung cancer."
The vault nanoparticles containing the CCL21 have been engineered to slowly release the protein into the tumor over time, producing an enduring immune response. Although the vaults protect the packed CCL21, they act like a time-release capsule, Rome said.
Rome, Dubinett and Sharma plan to test the vault delivery method in human studies within the next three years and hope the promising results found in the pre-clinical animal tumor models will be replicated. If such a study is approved, it would be the first time a vault nanoparticle is used in humans for a cancer immunotherapy.
The vault nanoparticle would require only a single injection into the tumor because of the slow-release design, and it eventually could be designed to be patient specific by adding the individual's tumor antigens into the vault, Dubinett said. The vaults may also be targeted by adding antibodies to their surface that recognize receptors on the tumor. The injection could then be delivered into the blood stream and the vault would navigate to the tumor, a less invasive process that would be easier on the patients. The vault could also seek out and target tumors and metastases too small to be detected with imaging.
Rome cautioned that the vault work is at a much earlier stage than Dubinett's dendritic cell research, but he is encouraged by the early results. The goal is to develop an "off-the-shelf" therapy using vaults.
"In animals, the vault nanoparticles have proven to be as effective, if not more effective, than the dendritic cell approach," he said. "Now we need to get the vault therapy approved by the FDA for use in humans."
Because a vault is naturally occurring particle, it causes no harm to the body and is potentially an ideal vehicle for use in delivery of personalized therapies, Rome said.
The study was funded by a University of California Discovery Grant, a Jonsson Cancer Center fellowship grant, the National Institutes of Health, the UCLA Lung Cancer Program, the Department of Veterans Affairs Medical Research Funds and the University of California's Tobacco-related Disease Program Award.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California - Los Angeles Health Sciences.
Journal Reference:
Upendra K. Kar, Minu K. Srivastava, Åsa Andersson, Felicita Baratelli, Min Huang, Valerie A. Kickhoefer, Steven M. Dubinett, Leonard H. Rome, Sherven Sharma. Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth. PLoS ONE, 2011; 6 (5): e18758 DOI: 10.1371/journal.pone.0018758Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Thursday, 26 May 2011
'I'm a tumor and I'm over here!' Nanovaults used to prod immune system to fight cancer
The vaults, barrel-shaped nanoscale capsules found in the cytoplasm of all mammalian cells, were engineered to slowly release a protein, the chemokine CCL21, into the tumor. Pre-clinical studies in mice with lung cancer showed that the protein stimulated the immune system to recognize and attack the cancer cells, potently inhibiting cancer growth, said Leonard Rome, a researcher at UCLA's Jonsson Comprehensive Cancer Center, associate director of the California NanoSystems Institutes and co-senior author of the study.
"Researchers have been working for many years to develop effective immune therapies to treat cancer, with limited success," said Rome, who has been studying vaults for decades. "In lung tumors, the immune system is down-regulated and what we wanted to do was wake it up, find a way to have the cancer say to the immune system, 'Hey, I'm a tumor and I'm over here. Come get me.' "
The study appears in the May 3, 2011 issue of PLoS ONE, a peer-reviewed journal of the Public Library of Science.
The new vault delivery system, which Rome characterized as "just a dream" three years ago, is based on a 10-year, on-going research effort focusing on using a patient's white blood cells to create dendritic cells, cells of the immune system that process antigen material and present it on the surface to other immune system cells. A Phase I study that is part of the effort, led by ULCA's Dr. Steven Dubinett, used a replication-deficient adenovirus to infect the dendritic cells and prompt them to over-secrete CCL21, the first time the chemokine has been administered to humans. The engineered cells -- 10 million at a time -- were then injected directly into the patient's lung cancer to stimulate an immune response.
The early phase study has shown the dendritic cell method is safe, has no side effects and seems to boost the immune response -- Dubinett and his team found T lymphocytes circulating in the blood stream with specific cytokine signatures, indicating that the lymphocytes were recognizing the cancer as a foreign invader.
However, the process to generate dendritic cells from the white blood cells and engineer them to over-secrete CCL21 is cumbersome, expensive and time-consuming. It also requires a Good Manufacturing Practice (GMP) suite, a specialized laboratory critical for the safe growth and manipulation of cells, which many research institutions do not have.
"It gets complicated," said Dubinett, director of the Lung Cancer Program at UCLA's Jonsson Comprehensive Cancer Center, a professor of pathology and laboratory medicine, member of the California NanoSystems Institute and a co-senior author of the paper. "You have to have a confluence of things happen -- the patient has to be clinically eligible for the study and healthy enough to participate, we have to be able to grow the cells and then genetically modify them and give them back."
There also was the challenge of patient-to-patient variability, said Sherven Sharma, a researcher at both the Jonsson Cancer Center and the California NanoSystems Institute, professor of pulmonary and critical care medicine and co-senior author of the study. It was easier to isolate and grow the dendritic cells in some patients than in others, so results were not consistent.
"We wanted to create a simpler way to develop an environment that would stimulate the immune system," Sharma said.
In the Phase I study, it takes more than a week to differentiate the white blood cells into dendritic cells and let them grow to the millions required for the therapy. The dendritic cells are infected with a virus engineered to carry a gene that caused the cells to secrete CCL21 and then injected into the patient's tumor using guided imaging.
"We thought if we could replace the dendritic cells with a nano-vehicle to deliver the CCL21, we would have an easier and less expensive treatment that also could be used at institutions that don't have GMP," Dubinett said.
If successful, the vault delivery method would add a desperately needed weapon to the arsenal in the fight against lung cancer, which accounts for nearly one-third of all cancer deaths in the United States and kills one million people worldwide every year.
"It's crucial that we find new and more effective therapies to fight this deadly disease," Dubinett said. "Right now we don't have adequate options for therapies for advanced lung cancer."
The vault nanoparticles containing the CCL21 have been engineered to slowly release the protein into the tumor over time, producing an enduring immune response. Although the vaults protect the packed CCL21, they act like a time-release capsule, Rome said.
Rome, Dubinett and Sharma plan to test the vault delivery method in human studies within the next three years and hope the promising results found in the pre-clinical animal tumor models will be replicated. If such a study is approved, it would be the first time a vault nanoparticle is used in humans for a cancer immunotherapy.
The vault nanoparticle would require only a single injection into the tumor because of the slow-release design, and it eventually could be designed to be patient specific by adding the individual's tumor antigens into the vault, Dubinett said. The vaults may also be targeted by adding antibodies to their surface that recognize receptors on the tumor. The injection could then be delivered into the blood stream and the vault would navigate to the tumor, a less invasive process that would be easier on the patients. The vault could also seek out and target tumors and metastases too small to be detected with imaging.
Rome cautioned that the vault work is at a much earlier stage than Dubinett's dendritic cell research, but he is encouraged by the early results. The goal is to develop an "off-the-shelf" therapy using vaults.
"In animals, the vault nanoparticles have proven to be as effective, if not more effective, than the dendritic cell approach," he said. "Now we need to get the vault therapy approved by the FDA for use in humans."
Because a vault is naturally occurring particle, it causes no harm to the body and is potentially an ideal vehicle for use in delivery of personalized therapies, Rome said.
The study was funded by a University of California Discovery Grant, a Jonsson Cancer Center fellowship grant, the National Institutes of Health, the UCLA Lung Cancer Program, the Department of Veterans Affairs Medical Research Funds and the University of California's Tobacco-related Disease Program Award.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California - Los Angeles Health Sciences.
Journal Reference:
Upendra K. Kar, Minu K. Srivastava, Åsa Andersson, Felicita Baratelli, Min Huang, Valerie A. Kickhoefer, Steven M. Dubinett, Leonard H. Rome, Sherven Sharma. Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth. PLoS ONE, 2011; 6 (5): e18758 DOI: 10.1371/journal.pone.0018758Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.