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GSK presents positive clinical data on maternal and older adults RSV candidate vaccines | Vaccines

  • October 22, 2020

GSK presents positive clinical data on maternal and older adults RSV candidate vaccines

  • Phase I/II data presented at ID Week show that the two FDA fast-tracked candidate vaccines trigger robust immune response and are well-tolerated
  • There is currently no vaccine for respiratory syncytial virus (RSV), which causes significant morbidity and mortality in infants and older adults
  • Phase III studies are on track to start in the coming months 

LONDON, UK I October 21, 2020 I GSK today announced that its Respiratory Syncytial Virus (RSV) candidate vaccines for maternal immunisation (GSK3888550A) and older adults (GSK3844766A) were well-tolerated and highly immunogenic in Phase I/II clinical studies. The data were presented virtually at the ID Week Congress.

RSV is a leading cause of respiratory infections such as bronchiolitis (inflammation and congestion of the small airways or bronchioles of the lung) and pneumonia (an inflammatory condition of the lung small air sacs or alveoli) in infants and older adults. It is estimated to cause about 3 million hospitalisations of children under 5 year of age globally[1], and 177,000 hospitalisations of older people in the US alone[2].

Both candidate vaccines contain a recombinant subunit pre-fusion RSV antigen (RSVPreF3) which is believed to trigger the required immune response. The vaccine for older adults also includes GSK’s proprietary AS01 adjuvant system[3] to boost the immune response as this population tends to show weaker immune response to vaccination than younger adults.

The vaccine candidate for older adults was first tested in 48 healthy adults (18-40 years old) and then in 1,005 healthy older adults (60-80 years old) with different dosages of antigen and adjuvant compared with a placebo. The interim data 1-month post-immunisation show that:

  • the candidate vaccine elicited a robust humoral and cellular immunity compared with baseline
  • a close to 10 times increase of protective antibodies (RSVPreF3 IgG and RSV-A neutralising antibodies) was induced in the vaccinated group
  • importantly, the cellular immunity (RSVPreF3-specific CD4+ T-cells) of the vaccinated older adults was boosted to reach similar range to that observed in the younger adults after vaccination with the non-adjuvanted formulation, despite the initial lower baseline level observed in older adults compared with young adults.

The maternal RSV candidate vaccine was tested with 3 different doses compared with placebo in 502 healthy non-pregnant women over monthly visits (Day 8, Day 31 and Day 91 post immunisation). The data show that, compared with baseline:

  • the investigational vaccine was able to rapidly boost the pre-existing immunity at all dose levels, leading to high levels of protective neutralising antibodies
  • at Day 8, a 14-fold increase in RSV-A and RSV-B neutralising antibodies titers was observed.

These two vaccines are part of a tailored, portfolio approach GSK is pursuing with three RSV candidate vaccines – maternal, paediatric and older adults – using different novel technologies aiming to help protect the populations most impacted: infants and older adults. All three candidate vaccines have received FDA fast-track designation.

Emmanuel Hanon, Senior Vice-President and Head of Vaccines R&D, said: “RSV is an infectious disease that can have a very serious impact on families and societies. We are delighted to see these positive results confirming our approach to develop dedicated vaccines building on the strategic use of our platform technologies for the populations most at risk from RSV infections – young infants and older adults. Our portfolio strategy takes into account the unique needs of the immune system of these vulnerable populations and we look forward to progressing these assets to Phase III trials to evaluate their potential efficacy”.

Vaccines for RSV prevention could lead to significant reductions in disease, doctor’s visits, and hospitalisations in infants, toddlers, and older adults, thus having the potential for a significant benefit to individual health in the most vulnerable populations as well as a positive impact on the burden and costs of healthcare systems around the world.

Based on available data and engagement with regulators, Phase III studies for both older adults and maternal RSV candidate vaccines are in preparation and on-track to start in the coming months, while the Phase I/II (in RSV-seronegative infants) and Phase II (in RSV-seropositive infants) studies with the paediatric RSV candidate vaccine are ongoing. Phase I/II safety and immunogenicity data on the paediatric RSV candidate vaccine in RSV-seropositive infants will be presented at European Society for Paediatric Infectious Diseases (ESPID) on 26-29 October 2020.

About GSK’s RSV candidate vaccine for older adults (GSK3844766A)

The Phase I/II study investigates the safety, reactogenicity and immune response of GSK’s RSV candidate vaccine  in older adults aged 60 to 80 (NCT03814590). This candidate vaccine contains GSK’s proprietary AS01 adjuvant, which is also used in GSK’s shingles vaccine. The safety, reactogenicity and immune responses (humoral and cellular-mediated) were first assessed in 48 healthy adults aged 18–40 years who were vaccinated with either 30, 60 or 120 μg dose level of RSVPreF3 non-adjuvanted vaccine or placebo. Following favourable safety outcomes, 1005 adults aged 60–80 years were randomised in a 2-step staggered manner to receive 1 of the 9 RSV vaccine formulations containing either 30, 60 or 120 μg dose level of RSVPreF3, non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo.

Interim data presented at ID Week show that within one-month post-immunisation, the adjuvanted candidate vaccine has been well tolerated with no safety concerns identified. The most frequently reported adverse events were pain at injection site, fatigue and headache.

Moreover, data 1-month post-immunisation show that the candidate vaccine elicited a robust humoral and cellular immunity compared with baseline:

  • High levels of RSVPreF3 IgG antibodies (geometric mean antibody concentrations were 8.4–13.5 for the 18-40 year old vaccinees, and 7.2–12.8 fold-higher in the 60–80-year-old vaccinees) and RSV-A neutralising antibodies (geometric mean antibody titers were 7.5–13.7 in the 18–40 year old vaccinees, and 5.6–9.9 fold-higher in 60–80-year-old vaccinees) were induced in all vaccinated groups.
  • Before vaccination, deficiency of RSVPreF3-specific T-cells (hypothesised to help promote viral clearance) was observed in older adults compared to younger adults. After vaccination, a robust RSVPreF3 CD4+ T-cells response in older adults had been boosted to reach a similar range than the one observed in younger adults, with significantly higher immune response in the groups who received the adjuvanted formulation.

About GSK’s maternal RSV candidate vaccine (GSK3888550A)

The goal of this candidate vaccine is to prevent RSV-associated lower respiratory tract infections in infants during the first months of life by transfer of maternal antibodies – an approach based on GSK’s strong expertise in maternal immunisation acquired through pertussis and flu vaccine programmes. The polyclonal nature of the humoral response boosted by this vaccine could potentially offer broad protection across a large number of RSV strains and addressing the potential issue of virus escape mutation. Maternal immunisation could help to protect infants too young to be immunised from RSV-associated infections in their first months of life – when they are the most vulnerable – without any medical intervention required thanks to the passive transmission of neutralising antibodies from the vaccinated mother to the unborn child in the last weeks of pregnancy.

In this Phase I/II study (NCT03674177), 502 healthy non-pregnant women received 1 dose of either 30, 60 or 120 μg of recombinant protein-based RSVPreF3 or placebo. The safety, reactogenicity and immunogenicity was monitored for 6 months. The data 1-month post-immunisation show that all vaccine dose levels were well-tolerated, with no safety concerns identified: the most frequently reported solicited adverse events were minor and included pain at injection site and headache. 

Moreover, the data show that the candidate vaccine elicited a rapid and persistent immune response in all RSVPreF3 groups. The immune response peaked at Day 8 with a 14-fold increase in neutralising RSV-A and RSV-B titers from baseline. The neutralising titers declined over time but a >6-fold increase was still maintained at Day 91. Anti-RSVPreF3 IgG antibodies were boosted substantially in all groups with geometric mean concentrations of anti-RSVPreF3 IgG antibody (≥ 12-fold at Day 8 and ≥ 6-fold until Day 91 vs baseline). The 60 and 120 μg dose levels of RSVPreF3 were more immunogenic than the 30 μg formulation.

Safety and immunogenicity data from the first time in pregnant women study will be presented in the first half of 2021. The data currently available provide the confidence to advance to late stage clinical work.

About respiratory syncytial virus

Globally, there are an estimated 33 million cases of RSV annually in children less than 5 years of age, with about 3 million hospitalised and approximately 120,000 dying each year from complications associated with the infection. Nearly half of these pediatric hospitalisations and deaths occur in infants less than 6 months of age[4]. According to the Centers for Disease Control and Prevention, virtually all children in the US get an RSV infection by the time they are 2 years old and one to two out of every 100 children younger than 6 months of age with RSV infection may need to be hospitalised[5].

It also represents a significant health threat for older adults, with an estimated 177,000 hospitalisations and 14,000 deaths associated with RSV infections occurring in the US alone[6]. Without robust surveillance systems in several countries, global data on the burden of RSV in older adults is either lacking or likely to underestimate its significance. As global population ages, morbidity and mortality of respiratory infections including RSV to be steadily increasing.

About GSK

GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com.

References

[1] Shi  T. et al, Lancet. 2017;390:946–58

[2] https://www.cdc.gov/features/rsv/index.html

[3] The GSK proprietary AS01 adjuvant system contains QS-21 StimulonTM adjuvant licensed from Agenus Inc. (NASDAQ: AGEN)

[4] Shi  T. et al, Lancet. 2017;390:946–58

[5] CDC – https://www.cdc.gov/rsv/high-risk/infants-young-children.html

[6] CDC – https://www.cdc.gov/features/rsv/

SOURCE: GlaxoSmithKline

How melanoma deceives the immune system, increasing resistance to immunotherapy

How melanoma deceives the immune system, increasing resistance to immunotherapy

  • October 19, 2020
immune cell
Credit: CC0 Public Domain

The sophisticated human immune system has evolved to become an effective protection system against a great number of diseases, including cancer. The immune system recognizes and destroys cancer cells using a monitoring process called immunological surveillance. However, like Dr. Jekyll and his alter ego Mr. Hyde, the immune system sometimes takes on an alternate personality and favors tumor development instead of destroying cancerous cells. This dual behavior makes it difficult to detect prognosis indicators and targets for drug development. In fact, one of the big challenges in oncology is the development of better, more effective immunotherapy.

A research team headed by Marisol Soengas, head of the Melanoma Group at the Spanish National Cancer Research Center (CNIO), has taken an important step forward, discovering what do to remain undetected by the , which does not attack them and even transforms into an ally. The study, published in Nature Medicine, may have interesting clinical implications and its findings can be applied to other cancer types.

An inside ally for melanoma

In 2017, the researchers in the Melanoma Group at the CNIO found that the MIDKINE protein plays an essential role in metastasis, so much so that its activation determines the tumor’s potential to metastasise. Actually, melanoma has a very high potential to metastasise early. The CNIO researchers analyzed the expression of MIDKINE in a novel animal model and found that higher expression of this protein is related to higher metastasis potential, while blocking MIDKINE inhibits the spread of . Recently, the researchers have taken an important step forward, discovering a new role of the protein in the immune system, which instead of attacking melanoma cells boosts inflammation and promotes melanoma growth.

“Our results help us understand why metastatic melanoma is associated with a poor prognosis and, especially, why some patients do not respond to immunotherapy,” says Marisol Soengas. “We examined databases from six separate studies and found a group of genes associated with MIDKINE expression in patients who do not respond or develop resistance to immunotherapy.”

Dual therapeutic strategy

The observations were tested in animal models: “When we blocked MIDKINE, two important types of immune cells (macrophages and T lymphocytes) began working normally again and attacked the tumor,” says Soengas. “This means that, in treating patients with melanoma, we should take a dual therapeutic approach.” Taking the brakes off an immune response, that is, using immune checkpoint inhibitors, is not enough. “MIDKINE should be inhibited as well, so that the defense system can regain its normal functions.”

“We also studied other tumors, like glioma, lung cancer and kidney cancer,” David Olmeda, co-author of the study, says. “We believe our findings will have a considerable impact in a number of diseases,” he adds.

In recent years, researchers and clinicians have made remarkable efforts to enhance immune ‘ cancer-fighting capabilities. However, even though in some cases immunotherapies are highly successful, this approach needs to be further developed. For example, it has proven ineffective in treating pancreatic , while in the case of melanoma, around 60% of patients respond to treatment.

These differences in tumor response to immunotherapy led to the classification of tumors as hot or cold. “Some hot tumors do not fully respond to treatment, a fact we could not understand before,” says Daniela Cerezo, first author of the study. “Our results contribute to explain the reasons why this is so, and they will help increase the effectiveness of immunotherapy for these tumors.”


Study shows how interferon-gamma guides response to cancer immunotherapy


More information:
Cerezo et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine (2020). DOI: 10.1038/s41591-020-1073-3. www.nature.com/articles/s41591-020-1073-3

Citation:
How melanoma deceives the immune system, increasing resistance to immunotherapy (2020, October 19)
retrieved 19 October 2020
from https://medicalxpress.com/news/2020-10-melanoma-immune-resistance-immunotherapy.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.

New immuno-oncology combo attacks glioblastoma in mice and paves path to human trials

New immuno-oncology combo attacks glioblastoma in mice and paves path to human trials

  • October 7, 2020

The aggressive brain cancer glioblastoma is infamously “cold” when it comes to immunotherapy, meaning it typically doesn’t respond to immune-boosting therapies because of immune-suppressing molecules in its environment.

A team led by University Hospital Zurich and the University of Zurich engineered a protein-based drug that fuses immune-stimulating cytokines with antibodies that specifically target glioblastoma. The drug slowed tumor growth in mouse models of the disease and boosted the ability of immune cells to reach patients’ brain tumors in a small, ongoing clinical trial, they reported in Science Translational Medicine.

“Glioblastoma is considered an immunological ‘desert,’” the researchers wrote in the study. “Proinflammatory cytokines are ‘master regulators’ of the immune system that can turn tumors from cold to hot.” But unmodified cytokines are too toxic for patients to tolerate, necessitating new approaches to selecting and engineering them for safety and efficacy, they added.

RELATED: New insights into cancer cell escape mechanisms could boost immuno-oncology treatments

The Swiss scientists tested three different cytokines in combination with antibodies targeting glioblastoma: IL-2, IL-12 and TNF. They found that antibodies fused to IL-12 or TNF and given to mice intravenously accumulated in glioblastoma tumors, slowing their growth. Two out of five of the animals tested were cured, they reported.

To determine whether the anti-tumor response lasted, the team implanted glioblastoma tumors into the mice 180 days after the initial treatment. Without further treatment, the mice remained protected.

The researchers tested the TNF immunocytokine treatment in three glioblastoma patients. The treatment was safe and resulted in a larger infiltration of immune cells into the tumor environment. Two of the patients remained stable at six months, and the study is currently recruiting additional patients.

This is one of several new immuno-oncology approaches being tested in glioblastoma, and it’s not the first to focus on pro-inflammatory cytokines. Last year, scientists from Brigham and Women’s Hospital and the Dana-Farber Cancer Institute announced they saw early signs of efficacy in a trial of an IL-12 gene therapy in combination with Ziopharm’s oral drug veledimex in glioblastoma.

Cedars-Sinai researchers are using a polymer-based delivery vehicle to deliver drugs that block the immune checkpoints CTLA-4 and PD-1 into the brain. They showed in mice that the treatment was able to cross the blood-brain barrier and boost the infiltration of cancer-killing immune cells to tumors.

The Swiss team noted that the ongoing clinical trial of their TNF immunocytokine drug only tests one dose, and additional studies will be needed to fully understand the safety and efficacy of the treatment. They are also starting to examine combining the fused drug with other therapies, including medicines that target VEGF, a protein that promotes blood growth to tumors and has been fingered as a major factor in glioblastoma.

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.


Virus-targeting white blood cells in tumors offer intriguing insights into responsiveness to immunotherapy


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
from https://medicalxpress.com/news/2020-10-common-nutritional-supplement-boost-cancer.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.

Ludwig study finds a common nutritional supplement might boost cancer immunotherapy

Ludwig study finds a common nutritional supplement might boost cancer immunotherapy

  • October 5, 2020

IMAGE

IMAGE: Ludwig Lausanne Associate Member Ping-Chih Ho
view more 

Credit: Ludwig Cancer Research

OCTOBER 5, 2020, NEW YORK – 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–nicotinamide riboside (NR)–helps TILs overcome the mitochondrial dysfunction 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 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 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 functional analysis 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 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 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 cells grown under stressors resembling those of the tumor microenvironment.

More notably, dietary supplementation with NR stimulated the anti-tumor 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.

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 cancer immunotherapy.

###

Ho is an Associate Member of the Lausanne Branch of the Ludwig Institute for Cancer Research and an Associate Professor at the University of Lausanne.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Swiss Institute for Experimental Cancer Research, European Research Council, the Kristian Gerhard Jebsen Foundation, the Austrian Science Fund, the Austrian Academy of Sciences, the European Research Council, the Swiss Ministry of Science and Technology, the National Health Research Institute in Taiwan and the Swiss Cancer League.

About Ludwig Cancer Research


Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for nearly 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582.

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.

Ludwig Study Finds a Common Nutritional Supplement Might Boost the Effects of Cancer Immunotherapy

Ludwig Study Finds a Common Nutritional Supplement Might Boost the Effects of Cancer Immunotherapy

  • October 5, 2020

Newswise — OCTOBER 5, 2020, NEW YORK – 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—nicotinamide riboside (NR)—helps TILs overcome the mitochondrial dysfunction 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 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 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 functional analysis 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 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 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 cells grown under stressors resembling those of the tumor microenvironment.

More notably, dietary supplementation with NR stimulated the anti-tumor 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.

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 cancer immunotherapy.

Ho is an Associate Member of the Lausanne Branch of the Ludwig Institute for Cancer Research and an Associate Professor at the University of Lausanne.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Swiss Institute for Experimental Cancer Research, European Research Council, the Kristian Gerhard Jebsen Foundation, the Austrian Science Fund, the Austrian Academy of Sciences, the European Research Council, the Swiss Ministry of Science and Technology, the National Health Research Institute in Taiwan and the Swiss Cancer League.

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About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for nearly 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.

Immunotherapy Drug Boosts Survival for Lung Cancer Patients | Health News

Immunotherapy Drug Boosts Survival for Lung Cancer Patients | Health News

  • October 1, 2020

By Robert Preidt, HealthDay Reporter

(HealthDay)

THURSDAY, Oct. 1, 2020 (HealthDay News) — A newly approved drug for the leading form of the number one cancer killer, lung cancer, does improve patient survival, a new study confirms.

The immunotherapy drug Tecentriq (atezolizumab) was approved earlier this year by the U.S. Food and Drug Administration to treat patients with newly diagnosed non-small cell lung cancers (NSCLC), which comprise up to 85% of all lung tumors.

Tecentriq targets a protein known as PD-L1 that lies on the surface of tumor cells. Normally, this protein signals the body’s immune system T cells not to attack. However, by targeting PD-L1, Tecentriq unleashes the body’s natural T cells to target and destroy these cancer cells, researchers at Yale Cancer Center explained.

Tecentriq “has already shown excellent activity in patients who progress on frontline chemotherapy, but this study confirmed that the drug is active in selected patients who have not yet received any treatment for lung cancer,” said medical oncologist Dr. Nagashree Seetharamu, who treats lung cancer patients but wasn’t involved in the new study. She practices at Northwell Health Cancer Institute in Lake Success, N.Y.

The new study was funded by Tecentriq’s maker, Genentech, and the results were published Sept. 30 in the New England Journal of Medicine.

The study included 554 patients with stage 4 metastatic NSCLC tumors. All patients had tumors lacking mutations in the EGFR or ALK genes: As the researchers explained in a Yale news release, tumors with those mutations are better treated with other drugs.

Among 205 patients whose tumors had high cellular expression of PD-L1, the median overall survival was 20 months for those who received Tecentriq versus 13 months for those who received standard platinum-based chemotherapy.

Median progression-free survival — the time from treatment to the disease beginning to worsen — was eight months for patients who received Tecentriq versus five months for those on standard chemotherapy, the researchers found.

“These are exciting results that could be life-changing for many patients,” said study lead author Dr. Roy Herbst. He is chief of medical oncology at the Yale Cancer Center as well as the Smilow Cancer Hospital.

“Lung cancer is the most common cancer worldwide, with more than 1.5 million patients diagnosed each year. Half of patients are diagnosed with metastatic disease, and they could be a candidate for this drug,” Herbst said in the news release.

“Also encouraging is that [Tecentriq] was generally well tolerated,” said Herbst, who is also associate cancer center director for translational research at the Yale Cancer Center in New Haven, Conn. “Side effects for patients were similar to those seen in other trials of the drug, which has been approved for treatments of several types of cancer.”

The trial also assessed how Tecentriq performed among patients with a “high tumor mutational burden,” which means that they had high levels of genetic mutations in scraps of cancer DNA detected in blood tests. In some types of cancers, high mutational burden is tied to better responses to immunotherapy drugs like Tecentriq.

“Among these patients with NSCLC, those with high tumor mutational burden who received [Tecentriq] showed improved progression-free survival of seven months versus four months for those given chemotherapy,” Herbst said. “This finding suggests that the [blood] biomarker should be explored further.”

For her part, Seetharamu noted that “there are many commercially available and experimental drugs that target PD-L1.” And she noted that the study did have one flaw.

Tecentriq “was compared to platinum-based chemotherapy alone, which is now not the most common standard treatment,” Seetharamu pointed out. Instead, oncologists are increasingly using standard chemotherapy plus another type of immunotherapy drug, Keytruda. The new study didn’t present a head-to-head comparison of Tecentriq against chemotherapy-plus-Keytruda, however.

“That is understandable,” Seetharamu said, “since the study started before these new treatments made it into common clinical practice.”

Regardless, she said, “the overall survival of 20 months in selected patients with high PD-L1 expression treated with Tecentriq alone is impressive and may provide yet another non-chemotherapy treatment option for patients diagnosed with PD-L1-high lung cancer.”

Copyright © 2020 HealthDay. All rights reserved.

Fred Hutch Evergreen Fund awards six grants to promising projects

Fred Hutch Evergreen Fund awards six grants to promising projects

  • September 23, 2020



Drs. Kristin Anderson (left) and Lucas Sullivan

Drs. Kristin Anderson (left) and Lucas Sullivan were awarded a $200,000 Evergreen Fund grant for a project to genetically modifiy T cells to withstand the toxic microenvironment of pancreatic tumors.
Photos by Robert Hood / Fred Hutch News Service

Six Fred Hutchinson Cancer Research Center teams have been selected as this year’s recipients of grants from the Evergreen Fund, which supports early research projects thought to have enough commercial potential to attract future business partners.

Since 2017, the donor-supported Evergreen Fund has awarded over $4 million to projects proposed by scientists seeking a well-timed financial boost to translate their ideas into lifesaving advances for patients.

“Despite the disruption of COVID-19, the Evergreen Fund once again offers our researchers the opportunity to complete the critical experiments that venture capital and pharma partners expect to see when evaluating a partnership opportunity,” said Hilary Hehman, the Hutch’s associate vice president of Strategic Partnerships & Alliances.

The Hutch program also provides researchers feedback on their research, funded or not, from a group of seasoned investors who evaluated their proposals.

This year, the Evergreen Fund distributed three pilot grants of $50,000 each that are designed to give “big and bold ideas with commercial application” an infusion of funds to demonstrate the project’s potential within a six-month period. Another trio of projects were awarded $200,000 each to accelerate their research over a two-year period. The goal of these larger, so-called “Beyond Pilot” grants is to help researchers whose ideas are further along. These scientists have shown promising data and a commercial path forward, but their projects need more development to attract external financial support.

Drs. Kristin Anderson and Lucas Sullivan received a Beyond Pilot grant for their project to boost the viability of T cells engineered to destroy pancreatic tumors, malignancies stubbornly resistant to therapies. Anderson’s T cells, designed with receptors that zero in on specific molecular markers on the pancreatic tumor cell surface, have shown promise in preclinical studies.

Yet these living drugs cannot survive for long in the toxic microenvironment of pancreatic tumors. The team is experimenting with new approach they call “metabolic reprogramming,” which involves a second bit of T-cell engineering. It equips the T cells with an enzyme that allows them to make their own supply of aspartate, a critical amino acid they are starved of inside these tumors.

Both tumor and healthy cells alike need aspartate, but within these toxic tumors, T cells are outcompeted by cancer cells for the raw material both need to make it. By engineering an aspartate-making enzyme into their T cells, the researchers hope to give them the extra oomph needed to survive. If they stay alive, these T cells may have a fighting chance against a cancer known to researchers as the “beast of all beasts.”

Other recipients of Beyond Pilot project grants

Drs. Irv Bernstein and Suzanne Furuyama are studying whether they can reverse the ability of solid tumors to evade immunotherapy. Their focus is on the tumor microenvironment, where a tug-of-war is underway for control of the body’s immune response. Key to winning is to turn on an intercellular signaling system called “Notch,” which shifts the balance of immune cells from a tumor-protective to an anti-tumor state.

But simply flipping the Notch switch “on” can set inflammation loose against healthy cells as well. Bernstein’s team has engineered a  switch-flipper that recognizes both tumor cells and Notch to ramp up the inflammatory response of immune cells only in the right places. Their project will involve studies in mice to determine if the Notch-induced, anti-tumor immune cell state enhances solid tumor susceptibility to immunotherapies.

Drs. Justin Taylor and Jim Boonyaratanakornkit are developing a laboratory-designed antibody, a type of immune protein, capable of blocking four different respiratory viruses. Each of these common viruses poses a significant threat to the lives of cancer patients recovering from blood stem cell transplants. The four targeted viruses — respiratory syncytial virus, human metapneumovirus, and two common strains of human parainfluenzavirus — are among the deadliest for these patients and afflict vulnerable children and the elderly as well. Previously, the Taylor Lab has been able to isolate antibodies capable of protecting against at least two such viruses at the same time. The aim of this project is to engineer and test in animal models an antibody that can neutralize all four targeted viruses, leading to a new type of drug capable of saving thousands of lives each year.

Recipients of the three Evergreen Fund pilot awards

Drs. Jarrod Dudakov and Sinéad Kinsella study age-related decline of the thymus, the gland responsible for generating the diverse selection of T-cell receptors needed for a successful response to vaccines or pathogens. In their search for ways to stimulate regeneration of the thymus, they have identified two proteins, known as FOXN1 and DLL4, that are critical to regenerating thymus cells. The goal of their pilot project is to create a screening test for molecules that drive production of either of those proteins. Such protein-inducing molecules might serve as the basis for new clinical approaches that boost T- cell reconstitution. They could help restore immune function in transplant recipients as well as in patients whose thymus glands have been decimated by age, infection or chemotherapies.

Dr. Stephen Tapscott has joined with Dr. Robert Bradley, holder of the McIlwain Family Endowed Chair in Data Science, on a pilot project to explore the therapeutic potential of their discoveries of one way tumors may evade destruction by our immune system. Their focus is on a protein called DUX4, which may be used by a developing embryo and fetus to shield its cells from a mother’s immune system. Shut down during childhood, the DUX4 gene is reawakened by some tumor cells, which use the ensuing shower of DUX4 proteins as an invisibility cloak against assault by cancer-attacking T cells. The researchers will develop an inventory of tumor cells that ramp up production of DUX4, explore what mutations enable this reawakening and establish strategies to disrupt it.

Drs. Ming Yu and William Grady are developing a highly sensitive test for early detection of both a deadly form of esophageal cancer and a precursor condition of abnormal cell growth known as high grade dysplasia, or HGD. Their testing panel, which picks up three distinctive genetic markers in patient specimens, has been shown to detect either HGD or the cancer — esophageal adenocarcinoma — in samples from biopsies or endoscopies. However, those procedures are invasive and expensive.

The pilot project aims to validate their test panel for use in a low-cost device that probes the esophagus with a pill-sized balloon rather than an endoscope. A less-expensive early detection test is expected to reduce mortality from esophageal adenocarcinoma, which is diagnosed in nearly 20,000 Americans each year.

Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future

Boosting immuno-oncology drugs by recruiting immune messenger cells

Boosting immuno-oncology drugs by recruiting immune messenger cells

  • September 21, 2020

A popular idea for improving PD-1/L1 checkpoint inhibitors focuses on turning “cold” tumors that often evade the immune system into “hot” ones by recruiting more cancer-killing immune cells to the tumor microenvironment.

Now, scientists at University Hospital Zurich showed that immune signaling molecule IL-2 might hold the key to supporting immuno-oncology agents by engaging with dendritic cells, which function as the messengers of the immune system by presenting antigens to T cells.

Treatment with a recombinant IL-2 in mice with melanoma led to an increased number of dendritic cells, which then sensitized cold tumors to be more responsive to checkpoint blockade, according to a new study published in Science Translational Medicine. The researchers suggested that IL-2 treatment might work in synergy with immune checkpoint inhibitors to improve outcomes in patients.

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Previous studies have already linked tumor-infiltrating dendritic cells to improved effectiveness of anti-PD-1 immunotherapy. However, scientists don’t fully understand what drives these cells to accumulate in tumors.

IL-2 has been found to stimulate different types of immune cells, including T cells and natural killers, but it was not known to affect dendritic cells. So it was a surprise to the University Hospital Zurich researchers when they observed a major increase in dendritic cell counts in the spleen and lymph nodes of mice after the animals were injected with a recombinant IL-2. The team also found a similar uptick of dendritic cells in lupus patients in a clinical trial who were treated with Proleukin—a human IL-2 formerly owned by Novartis.

After further analysis, the team found that IL-2 boosted the expansion of mature dendritic cells and accelerated the differentiation of dendritic cell precursor by stimulating T cells and lymphoid cells to produce other immune molecules—such as TNF—that can activate dendritic cells.

RELATED: Could a computer-designed IL-2 be a safer cancer treatment?

Based on these findings, the team hypothesized that IL-2 might also facilitate the immune system’s anti-tumor responses. In a mouse model of melanoma, IL-2 treatment increased the number of dendritic cells traveling to cold tumors—which were unresponsive to solo anti-PD-1 antibody treatment—and slowed their growth, the scientists reported.

The researchers also analyzed data from The Cancer Genome Atlas and found that melanoma patients who displayed more IL-2 activity lived longer than those that didn’t.

Proleukin is already being used to treat kidney cancer and melanoma, but its use is limited due to toxicities. A team at the University of Washington recently designed a new protein that resembled IL-2 but spared its dangerous side effects by avoiding the binding to IL-2 receptor alpha.

Other research teams have turned to the interleukin family for help in making tumors susceptible to immunotherapy. A group at Yale University recently pinpointed a modified form of IL-18 that can avoid a decoy receptor expressed in the tumor microenvironment so that it can stimulate durable anti-tumor immune responses.

By showing that IL-2 promoted activation and expansion of tumor-infiltrating dendritic cells, which improves antigen presentation and T cell activation, the University Hospital Zurich researchers argued that IL-2 could play a role in cancer treatment.

“Our findings support the investigation of potential combinatorial approaches in which IL-2 treatment could render poorly immunogenic cancers amenable to treatment with immune checkpoint inhibitors,” the researchers wrote in the study.

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