Cancer ‘vaccine’ eliminates tumors in mice

February 05, 2018

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.

The approach works for many different types of cancers, including those that arisespontaneously, the study found.

The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

“When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”

One agent is currently already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma.

Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which was published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.

‘Amazing, bodywide effects’

Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anticancer treatment in humans.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides — from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.

“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”

Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

Levy’s method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.

Cancer-destroying rangers

Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.

Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span, the researchers found.

Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

The study’s other Stanford co-authors are senior research assistant and lab manager Debra Czerwinski; professor of medicine Shoshana Levy, PhD; postdoctoral scholar Israt Alam, PhD; graduate student Aaron Mayer; and professor of radiology Sanjiv Gambhir, MD, PhD.

Levy is a member of the Stanford Cancer Institute and Stanford Bio-X.

Gambhir is the founder and equity holder in CellSight Inc., which develops and translates multimodality strategies to image cell trafficking and transplantation.

The research was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation and the Phil N. Allen Foundation.

Stanford’s Department of Medicine also supported the work.

This article was originally published by:
https://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html

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What artificial intelligence will look like in 2030

November 14, 2016

ai

Artificial intelligence (AI) has already transformed our lives — from the autonomous cars on the roads to the robotic vacuums and smart thermostats in our homes. Over the next 15 years, AI technologies will continue to make inroads in nearly every area of our lives, from education to entertainment, health care to security.

The question is, are we ready? Do we have the answers to the legal and ethical quandaries that will certainly arise from the increasing integration of AI into our daily lives? Are we even asking the right questions?

Now, a panel of academics and industry thinkers has looked ahead to 2030 to forecast how advances in AI might affect life in a typical North American city and spark discussion about how to ensure the safe, fair, and beneficial development of these rapidly developing technologies.

“Artificial Intelligence and Life in 2030” is the first product of the One Hundred Year Study on Artificial Intelligence (AI100), an ongoing project hosted by Stanford University to inform debate and provide guidance on the ethical development of smart software, sensors, and machines. Every five years for the next 100 years, the AI100 project will release a report that evaluates the status of AI technologies and their potential impact on the world.

 AI Landscape: Global Quarterly Financing History

Image: CB Insights

 

“Now is the time to consider the design, ethical, and policy challenges that AI technologies raise,” said Grosz. “If we tackle these issues now and take them seriously, we will have systems that are better designed in the future and more appropriate policies to guide their use.”

“We believe specialized AI applications will become both increasingly common and more useful by 2030, improving our economy and quality of life,” said Peter Stone, a computer scientist at the University of Texas, Austin, and chair of the report. “But this technology will also create profound challenges, affecting jobs and incomes and other issues that we should begin addressing now to ensure that the benefits of AI are broadly shared.”

The report investigates eight areas of human activity in which AI technologies are already affecting urban life and will be even more pervasive by 2030: transportation, home/service robots, health care, education, entertainment, low-resource communities, public safety and security, employment, and the workplace.

Some of the biggest challenges in the next 15 years will be creating safe and reliable hardware for autonomous cars and health care robots; gaining public trust for AI systems, especially in low-resource communities; and overcoming fears that the technology will marginalize humans in the workplace.

Issues of liability and accountability also arise with questions such as: Who is responsible when a self-driven car crashes or an intelligent medical device fails? How can we prevent AI applications from being used for racial discrimination or financial cheating?

The report doesn’t offer solutions but rather is intended to start a conversation between scientists, ethicists, policymakers, industry leaders, and the general public.

Grosz said she hopes the AI 100 report “initiates a century-long conversation about ways AI-enhanced technologies might be shaped to improve life and societies.”

https://www.weforum.org/agenda/2016/09/what-artificial-intelligence-will-look-like-in-2030

Read the report: https://ai100.stanford.edu/2016-report

Telomere extension turns back aging clock in cultured human cells, study finds

January 26, 2015

A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease, according to scientists at the Stanford University School of Medicine.

Treated cells behave as if they are much younger than untreated cells, multiplying with abandon in the laboratory dish rather than stagnating or dying.

The procedure, which involves the use of a modified type of RNA, will improve the ability of researchers to generate large numbers of cells for study or drug development, the scientists say. Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells. The research may point to new ways to treat diseases caused by shortened telomeres.

Telomeres are the protective caps on the ends of the strands of DNA called chromosomes, which house our genomes. In young humans, telomeres are about 8,000-10,000 nucleotides long. They shorten with each cell division, however, and when they reach a critical length the cell stops dividing or dies. This internal “clock” makes it difficult to keep most cells growing in a laboratory for more than a few cell doublings.

‘Turning back the internal clock’

“Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life,” said Helen Blau, PhD, professor of microbiology and immunology at Stanford and director of the university’s Baxter Laboratory for Stem Cell Biology. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

A paper describing the research was published today in the FASEB Journal. Blau, who also holds the Donald E. and Delia B. Baxter Professorship, is the senior author. Postdoctoral scholar John Ramunas, PhD, of Stanford shares lead authorship with Eduard Yakubov, PhD, of the Houston Methodist Research Institute.

The researchers used modified messenger RNA to extend the telomeres. RNA carries instructions from genes in the DNA to the cell’s protein-making factories. The RNA used in this experiment contained the coding sequence for TERT, the active component of a naturally occurring enzyme called telomerase. Telomerase is expressed by stem cells, including those that give rise to sperm and egg cells, to ensure that the telomeres of these cells stay in tip-top shape for the next generation. Most other types of cells, however, express very low levels of telomerase.

Transient effect an advantage

The newly developed technique has an important advantage over other potential methods: It’s temporary. The modified RNA is designed to reduce the cell’s immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division.

The transient effect is somewhat like tapping the gas pedal in one of a fleet of cars coasting slowly to a stop. The car with the extra surge of energy will go farther than its peers, but it will still come to an eventual halt when its forward momentum is spent. On a biological level, this means the treated cells don’t go on to divide indefinitely, which would make them too dangerous to use as a potential therapy in humans because of the risk of cancer.

The researchers found that as few as three applications of the modified RNA over a period of a few days could significantly increase the length of the telomeres in cultured human muscle and skin cells. A 1,000-nucleotide addition represents a more than 10 percent increase in the length of the telomeres. These cells divided many more times in the culture dish than did untreated cells: about 28 more times for the skin cells, and about three more times for the muscle cells.

“We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase,” said Ramunas. “Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic. Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”

Potential uses for therapy

“This new approach paves the way toward preventing or treating diseases of aging,” said Blau. “There are also highly debilitating genetic diseases associated with telomere shortening that could benefit from such a potential treatment.”

Blau and her colleagues became interested in telomeres when previous work in her lab showed that the muscle stem cells of boys with Duchenne muscular dystrophy had telomeres that were much shorter than those of boys without the disease. This finding not only has implications for understanding how the cells function — or don’t function — in making new muscle, but it also helps explain the limited ability to grow affected cells in the laboratory for study.

The researchers are now testing their new technique in other types of cells.

“This study is a first step toward the development of telomere extension to improve cell therapies and to possibly treat disorders of accelerated aging in humans,” said John Cooke, MD, PhD. Cooke, a co-author of the study, formerly was a professor of cardiovascular medicine at Stanford. He is now chair of cardiovascular sciences at the Houston Methodist Research Institute.

“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally useful,” said Blau, who also is a member of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.

“One day it may be possible to target muscle stem cells in a patient with Duchenne muscular dystrophy, for example, to extend their telomeres. There are also implications for treating conditions of aging, such as diabetes and heart disease. This has really opened the doors to consider all types of potential uses of this therapy.”


Story Source:

The above story is based on materials provided by Stanford University Medical Center. The original article was written by Krista Conger. Note: Materials may be edited for content and length.


Journal Reference:

  1. J. Ramunas, E. Yakubov, J. J. Brady, S. Y. Corbel, C. Holbrook, M. Brandt, J. Stein, J. G. Santiago, J. P. Cooke, H. M. Blau. Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. The FASEB Journal, 2015; DOI: 10.1096/fj.14-25953

 

 

New targeted, noninvasive treatments for mental illness to combine TMS and ultrasound

November 30, 2014

Transcranial_magnetic_stimulation

A new interdisciplinary Stanford University initiative called NeuroCircuit aims to find the specific brain circuits that are responsible for mental-health conditions and then develop ways of noninvasively stimulate those circuits to potentially lead to improved treatments for depression, anxiety, and post-traumatic stress disorder.

“You see things activated in brain images but you can’t tell just by watching what is cause and what is effect,” said Amit Etkin, Neurocircuit co-leader and a Stanford assistant professor of psychiatry and behavioral sciences. “Right now, if a patient with a mental illness goes to see their doctor they would likely be given a medication that goes all over the brain and body. While medications can work well, they do so for only a portion of people and often only partially.”

Etkin has been working with transcranial magnetic stimulation (TMS) to map and remotely stimulate parts of the brain. A TMS device generates a strong magnetic field that stimulates brain circuits near the surface. TMS is currently used as a way of treating depression and anxiety, but Etkin said the brain regions being targeted are the ones available to TMS, not necessarily the ones most likely to treat a person’s condition. They are also not personalized for the individual.

The solution may involve combining TMS with ultrasound. In his lab, Baccus has been using ultrasound to stimulate nerve cells of the retina to develop a prosthetic retina. Other members of the team are modifying existing ultrasound technology to direct it deep within the brain at a safe frequency. If the team is successful, ultrasound could be a more targeted and focused tool than TMS for remotely stimulating circuits that underlie mental health conditions.

Baccus said that before merging with Etkin’s team they had been focusing on the technology without specific brain diseases in mind. “This merger really gives a target and a focus to the technology.”

The initiative is part of the Stanford Neurosciences Institute‘s Big Ideas, which bring together teams of researchers from across disciplines to solve major problems in neuroscience and society.


Stanford University/Kurt Hickman | Researchers hope to find the brain circuits that are responsible for mental health conditions, develop ways to remotely stimulate those circuits, and potentially treat those conditions.

http://www.kurzweilai.net/new-targeted-noninvasive-treatments-for-mental-illness-to-combine-tms-and-ultrasound?utm_source=KurzweilAI+Weekly+Newsletter&utm_campaign=8eaab9a0b6-UA-946742-1&utm_medium=email&utm_term=0_147a5a48c1-8eaab9a0b6-282129417