New therapy extends breast cancer survival rate, prevents reoccurrence

Vaccine to treat and prevent lung, bowel and pancreatic cancer shows promise in the lab

  • October 22, 2020

An experimental vaccine, designed to enlist the body’s own immune system to target cancer cells, has shown promise for treating and preventing cancer in mice.

The vaccine was created to target a gene called KRAS that is involved in the development of many types of cancer, including lung, bowel and pancreatic cancer.

Researchers from the same team have also found a new way to spot and treat aggressive forms of lung cancers that are able to evade the body’s immune system.

Both studies will be presented on Sunday at the 32nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online.

Scientists have known for decades that the KRAS gene goes wrong – or mutates – in many cancers. However, until now, researchers have struggled to find a way to turn this knowledge into an effective treatment.

The vaccine study [2] was carried out by Dr Rachel Ambler, a postdoctoral research fellow, and colleagues at The Francis Crick Institute, London, UK. She said: “We know that if KRAS goes wrong, it enables cells in our bodies to start multiplying and turning into cancer cells. Recently, we’ve learned that, with the right help, the body’s immune system might be capable of slowing this growth.

“We wanted to see if we could use this knowledge to create a cancer vaccine that could not only be used to treat cancer, but also give long-lasting protection against cancer, with minimal side-effects.”

Dr Ambler and her colleagues created a set of vaccines that are capable of stimulating an immune response towards the most common KRAS mutations.

The vaccines are made up of two elements joined together. One element is a fragment of the protein produced by cancer cells with a mutated KRAS gene. The other element is an antibody that helps to deliver the vaccine to a cell of the immune system called a dendritic cell. These cells play a key role in helping the immune system spot and destroy cancer cells, an ability that could be boosted by the vaccines.

The team tested the vaccine on mice that already had lung tumours and mice that were induced to grow tumours. Researchers studied the mice for indications that their immune systems were responding to the vaccine and for signs that tumours were shrinking or not even forming in the first place.

In mice with tumours, 65% of those treated with the vaccine were alive after 75 days, compared to 15% of mice that were not given the vaccine.

In mice treated to induce tumours, 40% of vaccinated mice remained tumour-free after 150 days, compared to only 5% of unvaccinated mice (one mouse). By vaccinating the mice, researchers found that the appearance of tumours was delayed by an average of around 40 days.

Dr Ambler said: “When we used the vaccine as a treatment, we found that it slowed the growth of cancers in the mice. And when we used it as a preventative measure, we found that no cancers grew in the mice for quite a long period of time and, in many cases, cancers never developed.

“Previous trials of cancer vaccines have failed because they have not been able to create a strong enough response from the immune system to find and destroy cancer cells. This research still has a long way to go before it could help prevent and treat cancer in people, but our results suggest that the design of this vaccine has created a strong response in mice with very few side-effects.”

Researchers from the same team have also made an important discovery about how lung cancers are able to evade the body’s immune system, making them harder to treat. Their findings will be discussed in two further presentations at the 32th EORTC-NCI-AACR Symposium. [3,4]

Dr Sophie de Carné, a postdoctoral researcher, and Dr Phil East, deputy head of bioinformatics, from The Francis Crick Institute used a collection of hundreds of human tumour samples with information on which genes are mutated and which genes are active inside the tumours. They were also interested in the KRAS gene and its role in the development of hard-to-treat cancers.

Dr de Carné said: “In patients with some of the most aggressive cancers, we discovered that the activity of the KRAS gene results in the build up of a chemical called adenosine. Higher levels of adenosine are known to dampen the body’s immune response, making it harder for immune cells to target and destroy cancer cells.”

The researchers then studied cancers with similar KRAS activity in mice to see whether it was possible to manipulate the levels of adenosine to make it easier to treat the cancer. By giving the mice a drug designed to lower adenosine, oleclumab made by AstraZeneca, alongside existing cancer drugs that help the immune system fight cancer, the researchers found that they could improve survival.

Dr East added: “Together these results suggest it could eventually be possible to identify patients who have this aggressive type of lung cancer and use a combination of drugs to support their immune system and successfully treat their tumours.”

Dr James L. Gulley is co-chair of the 32th EORTC-NCI-AACR Symposium for the NCI and Director of the Medical Oncology Service, Center for Cancer Research, NCI, USA, and was not involved in the research. He said: “These studies focus on types of cancer – such as lung and pancreatic cancer – that are difficult to treat. Survival rates for these cancers remain very poor so we urgently need new treatments for patients.

“Boosting the immune system with drugs to treat cancer or even developing a vaccine to prevent cancer are both exciting possibilities, especially if they can be achieved with minimal side effects. We hope that these promising approaches will one day be reproduced in patients.”

###

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

How to live longer: echinacea may suppress cancer and boost immune system

How to live longer: echinacea may suppress cancer and boost immune system

  • October 19, 2020

In another test-tube study, extracts from echinacea plants (Echinacea purpurea, Echinacea angustifolia and Echinacea pallida) killed human cancer cells from the pancreas and colon by stimulating a process called apoptosis or controlled cell death.

Researchers believe that this effect occurs due to echinacea’s immune-boosting properties.

There was some concern that echinacea could interact with conventional cancer treatments, such as doxorubicin, but newer studies have found no interaction.

General tips to promote longevity

Echinacea should form only one part of your overall approach to healthy living and your commitment to a healthy, balanced diet is what counts.

Olivia Newton-John shares advice to women fighting breast cancer

Olivia Newton-John shares advice to women fighting breast cancer

  • October 19, 2020

ONJ FoundationBy HAYLEY FITZPATRICK

(NEW YORK) — Olivia Newton-John continually uses her platform to advocate for cancer research and now she is taking it a step further with the launch of her new foundation.

The four-time Grammy Award-winning singer and actress, who is currently battling breast cancer for the third time, launched the Olivia Newton-John Foundation this month to fund research for treatments and therapies to cure cancer.

The star was first diagnosed with breast cancer in 1992 and again in 2013. She revealed in 2018 that the disease returned and metastasized to her spine.

In a recent interview with ABC News’ Good Morning America, the actress, 72, revealed she is “feeling really good” and spoke about what led her to launch this new charity.

“I feel really positive and very excited about bringing this foundation and a lot of knowledge to people, and funding research to find out lots of answers — to find kinder treatments for cancer,” she shared.

“The inspiration has been a long one because I’ve been on this cancer journey for 28 years,” she added. “I’m a thriver of three times going through this process.”

Having gone through surgery, chemotherapy and radiation, she said she now is interested in funding treatments that aren’t as taxing to the body.

“I’ve always thought, ‘Gosh, wouldn’t it be wonderful if we could create kinder therapies that help boost the body’s immune system instead of knocking us down?’” she said.

Newton-John is an outspoken advocate for plant medicine and says that’s largely due to the influence of her husband, John Easterling. She affectionately calls him “Amazon John” because he spent several years in the Amazon rain forest learning about this type of medicine.

“I’m very lucky that I have him in my corner, and teaching me about the plants and the herbs,” she said. “He grows cannabis for me and I take tinctures that have helped me greatly.”

Ongoing efforts are being made to research what role cannabis may play in the future.

“While some like Newton-John find relief of cancer-related pain and nausea from cannabis, it has not clinically proven to be the best choice,” according to health expert Dr. Imran Ali, a contributor to the ABC News Medical Unit.

Newton-John says she believes there is a significant lack of progress in research for these treatments.

“There are lots of ideas on how we can help people with cancer and treat cancer, but there’s been no real science behind the studies,” she explained. “So the idea is to raise money to fund the research on the other kinds of things that are kinder, including a lot of plant medicine.”

Newton-John is dedicating the foundation to all forms of cancer treatments — not just breast cancer research — because she dreams of one day “realizing a world beyond cancer.”

“That’s everything that drives me forward,” she said. “To think that we could help people to live in a world where cancer was just something that you treated like diabetes, or asthma, or the flu, or you know, something that you could live well with, which I’m doing. And I hope to continue to do that for a long time.”

She hopes to find ways to “support the body, mind and spirit of people going through cancer” through her new charity.

One of the first efforts she is doing to raise money for the ONJ Foundation is her upcoming auction with Julien’s Auctions on Nov. 30. More than 300 items, including artwork, memorabilia and more, are up for sale. The proceeds from the auction will be donated to her foundation.

Amid the COVID-19 pandemic, Newton-John has been quarantined in her California home with her husband, and she said she is mainly focused on her health and positivity in her life.

“I think being at home so much, which has been wonderful for me because it’s a novelty because I’ve been on the road most of my life it seems … and to wake up every day and to hear the birds and see the sunshine in the trees,” she shared on what she values. “I’m so grateful for every day.”

Although the pandemic has largely affected the way many treat and prioritize their health, Newton-John says this is just the way of life for cancer patients.

“Because of this pandemic people have become extremely conscious of their health and how important it is to help boost their immune systems, how to eat properly, and how to protect each other and themselves,” she said. “And people with cancer have been going through that, always, and they’ll be doing that long after the pandemic is over.”

“It’s a good time to kind of reinforce the idea that, ‘Yes, we’re all going through something, but cancer patients have been dealing with this forever, sadly, and going forward, let’s help them,’” she added.

Her message to women fighting breast cancer? Prioritize putting yourself first and remember “your mind is such an important part of your healing.”

“The first time I had breast cancer was in 1992 and I’m still here,” she said. “The treatments weren’t as good then as they are now, and there’s a lot of information you can get online on how to support yourself and how to think well.”

She urged those fighting cancer to take care of their mental health and surround themselves with good energy.

“We’re not just a body going through cancer — we’re a whole human with the mind, body, spirit and soul,” she said. “And we need to try and think positive thoughts. We need to surround ourselves with people who are going to give us positivity back. It really helps.”

The actress implored survivors to “do something for yourself every day that you love.”

She also recommended finding a person in your life to answer questions from those seeking information on your health — so you can instead put your energy into “doing something that you love doing for yourself.”

Copyright © 2020, ABC Audio. All rights reserved.

Olivia Newton-John talks new foundation and shares advice to women fighting breast cancer

Olivia Newton-John talks new foundation and shares advice to women fighting breast cancer

  • October 19, 2020

Olivia Newton-John continually uses her platform to advocate for cancer research and now she is taking it a step further with the launch of her new foundation.

The star was first diagnosed with breast cancer in 1992 and again in 2013. She revealed in 2018 that the disease returned and metastasized to her spine.

In a recent interview with “Good Morning America,” the actress, 72, revealed she is “feeling really good” and spoke about what led her to launch this new charity.

“I feel really positive and very excited about bringing this foundation and a lot of knowledge to people, and funding research to find out lots of answers — to find kinder treatments for cancer,” she shared.

“The inspiration has been a long one because I’ve been on this cancer journey for 28 years,” she added. “I’m a thriver of three times going through this process.”

Having gone through surgery, chemotherapy and radiation, she said she now is interested in funding treatments that aren’t as taxing to the body. “I’ve always thought, ‘Gosh, wouldn’t it be wonderful if we could create kinder therapies that help boost the body’s immune system instead of knocking us down?'” she said.

Newton-John is an outspoken advocate for plant medicine and says that’s largely due to the influence of her husband, John Easterling. She affectionately calls him “Amazon John” because he spent several years in the Amazon rain forest learning about this type of medicine.

“I’m very lucky that I have him in my corner, and teaching me about the plants and the herbs,” she said. “He grows cannabis for me and I take tinctures that have helped me greatly.”

Ongoing efforts are being made to research what role cannabis may play in the future. “While some like Newton-John find relief of cancer-related pain and nausea from cannabis, it has not clinically proven to be the best choice,” according to health expert Dr. Imran Ali, a contributor to the ABC News Medical Unit.

Newton-John says she believes there is a significant lack of progress in research for these treatments.

“There are lots of ideas on how we can help people with cancer and treat cancer, but there’s been no real science behind the studies,” she explained. “So the idea is to raise money to fund the research on the other kinds of things that are kinder, including a lot of plant medicine.”

Newton-John is dedicating the foundation to all forms of cancer treatments — not just breast cancer research — because she dreams of one day “realizing a world beyond cancer.”

“That’s everything that drives me forward,” she said. “To think that we could help people to live in a world where cancer was just something that you treated like diabetes, or asthma, or the flu, or you know, something that you could live well with, which I’m doing. And I hope to continue to do that for a long time.”

She hopes to find ways to “support the body, mind and spirit of people going through cancer” through her new charity.

One of the first efforts she is doing to raise money for the ONJ Foundation is her upcoming auction with Julien’s Auctions on Nov. 30. More than 300 items, including artwork, memorabilia and more, are up for sale. The proceeds from the auction will be donated to her foundation.

Amid the COVID-19 pandemic, Newton-John has been quarantined in her California home with her husband, and she said she is mainly focused on her health and positivity in her life.

“I think being at home so much, which has been wonderful for me because it’s a novelty because I’ve been on the road most of my life it seems … and to wake up every day and to hear the birds and see the sunshine in the trees,” she shared on what she values. “I’m so grateful for every day.”

Although the pandemic has largely affected the way many treat and prioritize their health, Newton-John says this is just the way of life for cancer patients.

“Because of this pandemic people have become extremely conscious of their health and how important it is to help boost their immune systems, how to eat properly, and how to protect each other and themselves,” she said. “And people with cancer have been going through that, always, and they’ll be doing that long after the pandemic is over.”

“It’s a good time to kind of reinforce the idea that, ‘Yes, we’re all going through something, but cancer patients have been dealing with this forever, sadly, and going forward, let’s help them.’”

Her message to women fighting breast cancer? Prioritize putting yourself first and remember “your mind is such an important part of your healing.”

“The first time I had breast cancer was in 1992 and I’m still here,” she said. “The treatments weren’t as good then as they are now, and there’s a lot of information you can get online on how to support yourself and how to think well.”

She urged those fighting cancer to take care of their mental health and surround themselves with good energy.

“We’re not just a body going through cancer — we’re a whole human with the mind, body, spirit and soul,” she said. “And we need to try and think positive thoughts. We need to surround ourselves with people who are going to give us positivity back. It really helps.”

The actress implored survivors to “do something for yourself every day that you love.”

She also recommended finding a person in your life to answer questions from those seeking information on your health — so you can instead put your energy into “doing something that you love doing for yourself.”

Combination therapy boosts the immune system's appetite for cancer

Cancer-killing T cells release chemicals to direct swarms towards tumors

  • October 14, 2020

When immune system T cells find and recognize a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behavior, and the chemical attractants that immune cells use to direct swarms towards tumors, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumors, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

Scientists have previously thought that cancer-killing T cells identified tumors by randomly searching for them or by following the chemical trails laid by other intermediary immune cells. We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”


Jorge Luis Galeano Niño, lead author, PhD graduate at UNSW Sydney

Using 3D tumor models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumor cells independently of intermediary immune cells. When the T cells find and recognise a tumor, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumor grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumors.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumors, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumors,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

Source:

Journal reference:

Galeano Niño, J.L., et al. (2020) Cytotoxic T Cells swarm by homotypic chemokine signalling. eLife. doi.org/10.7554/eLife.56554.

Breast cancer survivors return to work two weeks earlier

Breast cancer survivors return to work two weeks earlier

  • October 13, 2020

These trends are according to internal data from Unum (NYSE: UNM), a leading provider of disability insurance. One in eight women will be diagnosed with breast cancer over the course of their lives. A supportive employer makes a big difference in recovery, along with early detection and advances in medical treatment.

“Work often provides a sense of normalcy and support for employees with breast cancer during a time of uncertainty,” said Mandy Stogner, senior leave and disability consultant at Unum. “This is why the role of employers is so important during diagnosis, treatment, and return to work.”

Employers: 8 ways to better support employees with cancer

Aside from grappling with a diagnosis, cancer patients often face a wide range of side effects from treatment. These include a weakened immune system, fatigue and strained focus. Since employee needs may change over the course of treatment, employers should provide ongoing support.

  1. Respond fast and offer resources.
  2. Understand physical limits and how those impact their role.
  3. Clearly define work duties.
  4. Create a flexible schedule or reduced workload.
  5. Adjust workstations so they don’t have to stand or sit for too long.
  6. Build in extra breaks so they can fight fatigue.
  7. Communicate often to keep the employee engaged.
  8. Provide feedback and coaching on performance.

Cancer and COVID-19
Today’s pandemic creates even more challenges for people with cancer. Most cancer treatments suppress the immune system. This puts cancer patients at higher risk for serious illness caused by COVID-19.

Employers should consider providing adjustments that allow physical and social distancing, remote work or modified workspaces to mitigate transmission. This is especially important during stages of treatment that suppress the immune system.

Boost your benefits
Disability insurance can provide financial protection and work support for employees as they get treatment, recover and return to work. In 2019, Unum paid $3.7 billion in disability benefits and helped 275,000 people return to work after disability leave.

About Unum  
Unum Group provides a broad portfolio of financial protection benefits and services through the workplace, and is the leading provider of disability income protection worldwide. Through its Unum US, Unum UK, Unum Poland, and Colonial Life businesses, the company provides disability, life, accident, critical illness, dental and vision benefits that protect millions of working people and their families. Unum also provides leave and absence management services that streamline the leave experience for employers and employees, and stop-loss coverage to help self-insured employers protect against medical costs. Unum reported revenues of $12 billion in 2019 and paid $7.5 billion in benefits.

For more information, connect with us on Facebook, Twitter and LinkedIn.

SOURCE Unum Group

Related Links

www.unum.com

New therapy extends breast cancer survival rate, prevents reoccurrence

Cancer-killing T cells ‘swarm’ to tumors, attracting others to the fight

  • October 13, 2020

When immune system T cells find and recognise a target, they release chemicals to attract more T cells which then swarm to help subdue the threat, shows a new study published today in eLife.

The discovery of this swarming behaviour, and the chemical attractants that immune cells use to direct swarms towards tumours, could one day help scientists develop new cancer therapies that boost the immune system. This is particularly important for solid tumours, which so far have been less responsive to current immunotherapies than cancers affecting blood cells.

“Scientists have previously thought that cancer-killing T cells identified tumours by randomly searching for them or by following the chemical trails laid by other intermediary immune cells,” says lead author Jorge Luis Galeano Niño, a PhD graduate at UNSW Sydney. “We wanted to investigate this further to see if it’s true, or whether T cells locate tumours via another mechanism.”

Using 3D tumour models grown in the laboratory and in mouse models, the team showed that cancer-killing T cells can home-in on tumour cells independently of intermediary immune cells. When the T cells find and recognise a tumour, they release chemical signals, which then attract more T cells that sense the signals through a receptor called CCR5, and cause a swarm. “These cells coordinate their migration in a process reminiscent of the swarming observed in some insects and another type of immune cell called neutrophils, which help the body respond to injury and pathogens,” Galeano Niño says.

After confirming their results using computer modelling, the team genetically engineered human cells called chimeric antigen receptor (CAR)-T cells and showed they also swarm toward a 3D glioblastoma tumour grown in the laboratory.

CAR-T cells are currently being used to treat certain types of blood cancer. But the new findings suggest that it might also be possible to train these cells to attack solid tumours.

“Although this is fundamental research and at an early stage, the swarming mechanism could be exploited in the future to target CAR-T cells to solid tumours, potentially leading to enhanced immunotherapies that are more effective at infiltrating and destroying these types of tumours,” says senior author Maté Biro, EMBL Australia Group Leader at the Single Molecule Science node, UNSW.

“It will also be important to determine whether silencing the swarming mechanism could be beneficial in dampening overzealous T-cell responses following transplant surgery, in autoimmune conditions, or associated with viral infections,” he adds.

###

Reference


The paper ‘Cytotoxic T cells swarm by homotypic chemokine signalling’ can be freely accessed online at https://doi.org/10.7554/eLife.56554. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

Media contacts


Emily Packer, Media Relations Manager

eLife

e.packer@elifesciences.org

01223 855373

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UNSW Sydney

i.dubach@unsw.edu.au

+612 9385 7307, +61 432 307 244

About eLife

eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We work across three major areas: publishing, technology and research culture. We aim to publish work of the highest standards and importance in all areas of biology and medicine, including Computational and Systems Biology and Immunology and Inflammation, while exploring creative new ways to improve how research is assessed and published. We also invest in open-source technology innovation to modernise the infrastructure for science publishing and improve online tools for sharing, using and interacting with new results. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Computational and Systems Biology research published in eLife, visit https://elifesciences.org/subjects/computational-systems-biology.

And for the latest in Immunology and Inflammation, see https://elifesciences.org/subjects/immunology-inflammation.

About EMBL Australia Node in Single Molecule Science (SMS)

Researchers at SMS investigate a broad array of fundamental biological systems and medical problems including cancer biology, immunology, virology, nanotechnology and more. A common thread that runs through all our research groups is a multidisciplinary approach to providing molecular perspectives to biological processes. SMS is an interdisciplinary research department within UNSW, an EMBL Australia Partner Laboratory, and a node of the ARC Centre of Excellence in Advanced Molecular Imaging. Learn more about SMS at https://sms.unsw.edu.au.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Therapy using immune system cells preserves vision in mice implanted with rare eye cancer

Therapy using immune system cells preserves vision in mice implanted with rare eye cancer

  • October 12, 2020
Therapy using immune system cells preserves vision in mice implanted with rare eye cancer
Barbara Savoldo, MD, PhD, and colleagues at the University of North Carolina Lineberger Comprehensive Cancer Center report that a treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, preserved the vision of mice implanted with retinoblastoma tissue. The cancer, which is most commonly diagnosed in infants and young children, is treatable in early stages but can still lead to the loss of vision in about 5% of cases. Credit: UNC Lineberger

A treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, was found to preserve the vision of mice implanted with tissue from a human eye cancer known as retinoblastoma. The cancer is treatable in early stages but can still lead to the loss of vision in about 5% of cases.

The research findings from scientists at the University of North Carolina Lineberger Comprehensive Cancer Center were published is Nature Cancer on Oct. 12, 2020.

Retinoblastoma is primarily diagnosed in infants and young children. It is considered rare, with approximately 200-300 children diagnosed with the each year in the U.S. Current treatments for retinoblastoma use cold, heat, chemotherapy, lasers or radiation but vision loss still occurs, so the UNC researchers wanted to search for methods that could preserve vision.

“Based on our mouse study and the existence of an active cell immunotherapy program at UNC Lineberger, along with infrastructure for generation of CAR-Ts for clinical use, we feel confident that our efforts could be translated into a phase I in people,” said Zongchao Han, MD, Ph.D., an associate professor in the UNC School of Medicine and UNC Eshelman School of Pharmacy and a UNC Lineberger member.

The researchers used an incremental process to determine the best method for treatment of retinoblastoma. First, the researchers turned to chimeric antigen receptor-T (CAR-T) cell therapy, a type of immunotherapy where T cells that comprise the are modified in the laboratory to express chimeric antigen receptors, CARs, that target surface proteins on cancer cells. In a lab test, they found that a molecule, GD2, is expressed in retinoblastoma but the possibility to target this molecule to safely eliminate the in the eye was unknown.

Next, to test the safety and benefit of targeting GD2, the investigators injected the CAR-T that recognizes this molecule into the retina of mice implanted with retinoblastoma cancer cells and found the therapy delayed tumor development but did not eradicate the tumor. Then they combined the CAR-Ts with interleukin (IL)-15, a protein that can boost immune response, and found that 60% of mice were tumor-free for up to 70 days.

Finally, they injected a water-based gel containing the CAR-Ts and IL-15 into the retinas of the mice. The CAR-Ts and IL-15 retained an extended ability to attack the cancer , control tumor growth and prevent tumor recurrence. They corroborated the lack of tumor growth with several imaging exams of the retina.

This gel-encapsulated therapy is currently being tested in clinical trials in children with neuroblastoma, an embryonal tumor that can progress rapidly and has some of the same genetic characteristics of retinoblastoma.

“We are always looking to improve the lives of children at Lineberger,” said Barbara Savoldo, MD, PHD, professor of pediatric Hematology/Oncology at UNC School of Medicine and UNC Lineberger member. “Therefore, we hope to look at the safety of gel injection in a clinical trial of in children, and if that proves safe, we could move on to see if our methodology can reduce or eliminate these tumors.”


Genetically modified virus shown able to kill tumors in mice with retinoblastoma


More information:
GD2-specific CAR T cells encapsulated in an injectable hydrogel control retinoblastoma and preserve vision, Nature Cancer (2020). DOI: 10.1038/s43018-020-00119-y

Citation:
Therapy using immune system cells preserves vision in mice implanted with rare eye cancer (2020, October 12)
retrieved 12 October 2020
from https://medicalxpress.com/news/2020-10-therapy-immune-cells-vision-mice.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

Mitochondria

Vitamin B3 Analogue May Boost Cancer Immunotherapy

  • October 6, 2020

A widely available nutritional supplement—nicotinamide riboside (NR)—may energize tumor-infiltrating T lymphocytes (TILs) exhausted by their struggles against the tumor microenvironment. Specifically, NR may recharge TILs by improving mitochondrial fitness and stimulating mitophagy, the elimination of damaged mitochondria.

In terminally exhausted TILs, the damage typically suffered by mitochondria is depolarization. That is, the mitochondria lose the voltage they need to generate energy. They pile up like so many dead batteries.

The potential advantage of NR-stimulated mitochondria was recognized by researchers led by Ping-Chih Ho, PhD, at the Lausanne Branch of the Ludwig Institute for Cancer Research. These researchers began experimenting with NR, a vitamin B3 variant that has been shown to improve mitochondrial fitness in various cell types, after they noticed that in TILs, there is an association between T-cell exhaustion and large numbers of depolarized mitochondria.

Details of this work appeared October 5 in the journal Nature Immunology, in an article titled, “Disturbed mitochondrial dynamics in CD8+ TILs reinforce T-cell exhaustion.” The article describes a mechanism to explain how the accumulation of depolarized mitochondria is caused by decreased mitophagy activity. The mechanism is driven by stressors in the tumor microenvironment, and it not only instigates exhaustion, it also leads to terminal exhaustion, a state that reflects epigenetic reprogramming.

“Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T-cell receptor stimulation, microenvironmental stressors, and PD-1 signaling,” the article’s authors wrote. “Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T-cell exhaustion.”

By carrying out functional, transcriptomic, and epigenetic analyses, the researchers revealed that when TILs accumulate depolarized mitochondria as a result of decreased mitophagy, they exemplify terminal exhaustion.

“TILs often have a high affinity for antigens expressed by cancer cells,” said Ho. “This means that, in principle, they should attack cancer cells vigorously. But we often don’t see that.

“People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their metabolic processes to compensate—for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1—a signaling protein that suppresses T-cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and colleagues have shown that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by epigenetic modifications—chemical groups added to DNA and its protein packaging—to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling, and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprogramming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers—including co-authors in the current study, Ludwig Lausanne investigator Nicola Vannini, PhD, and Ludwig Lausanne director George Coukos, PhD—had shown that NR can boost mitophagy and improve mitochondrial fitness in a variety of other cell types. Mindful of these findings, the researchers in the current study explored whether NR might also prevent TILs from committing to terminal exhaustion.

Ho and colleagues conducted cell culture experiments showing that the supplement improved the mitochondrial fitness and function of T cells grown under stressors resembling those of the tumor microenvironment. “Supplementation with NR,” they reported, “enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment.”

Dietary supplementation with NR stimulated the antitumor activity of TILs in a mouse model of skin cancer and colon cancer. When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

Ho and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion—information that could be more generally applied to improve cancer immunotherapy.

Study finds a common nutritional supplement might boost cancer immunotherapy

Study finds a common nutritional supplement might boost cancer immunotherapy

  • October 5, 2020
mitochondria
Credit: CC0 Public Domain

A Ludwig Cancer Research study has uncovered a mechanism by which the tumor’s harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response. Reported in Nature Immunology, the study describes how a variety of stressors prevalent in the tumor microenvironment disrupt the power generators, or mitochondria, of tumor-infiltrating T lymphocytes (TILs), pushing them into a permanently sluggish state known as terminal exhaustion.

The study, led by Ludwig Lausanne Associate Member Ping-Chih Ho, also found that a widely available nutritional supplement— (NR)—helps TILs overcome the and preserves their ability to attack tumors in mouse models of melanoma and colon cancer.

“TILs often have a high affinity for antigens expressed by cancer cells,” says Ho. “This means that, in principle, they should attack vigorously. But we often don’t see that. People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their to compensate—for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1—a signaling protein that suppresses T cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and his colleagues found that exhausted TILs are packed with damaged—or ‘depolarized’—mitochondria. Like old batteries, depolarized mitochondria essentially lack the voltage the organelles require to generate energy.

“Our revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells,” said Ho.

Ho and colleagues show that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through a process known as mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by —chemical groups added to DNA and its protein packaging—to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprograming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers—including co-authors in the current study, Ludwig Lausanne Investigator Nicola Vannini and Ludwig Lausanne Branch Director George Coukos—has shown that NR, a chemical analogue of vitamin B3, can boost mitophagy and improve mitochondrial fitness in a variety of other cell types.

With this in mind, the researchers explored whether NR might also prevent TILs from committing to terminal exhaustion. Their cell culture experiments showed that the supplement improved the mitochondrial fitness and function of T grown under stressors resembling those of the .

More notably, dietary supplementation with NR stimulated the anti-tumor activity of TILs in a mouse model of skin cancer and . When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

He and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion—information that could be more generally applied to improve immunotherapy.


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More information:
Yi-Ru Yu et al, Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion, Nature Immunology (2020). DOI: 10.1038/s41590-020-0793-3

Citation:
Study finds a common nutritional supplement might boost cancer immunotherapy (2020, October 5)
retrieved 5 October 2020
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