New therapy extends breast cancer survival rate, prevents reoccurrence

New research is first to show how key gut bacterium trains infant immune system

  • June 17, 2021

DAVIS, CA, June 17, 2021 — Research published today in the journal Cell is the first to establish how a specific gut bacterium, activated Bifidobacterium infantis EVC001 (B. infantis), influences immune system development in infants, and could thereby reduce the risk of allergic and autoimmune conditions later in life.

While prior studies have shown a correlation between a lack of beneficial bacteria in the infant gut and the development of allergies and autoimmune diseases, this groundbreaking research, Bifidobacteria-mediated immune system imprinting in early life, found the presence of bifidobacteria, specifically the B. infantis EVC001 bacterial strain, early in a breastfed infant’s life, programs naïve immune cells away from responses associated with immune-related conditions while producing regulatory cells that improve the body’s ability to control inflammation.

The study also confirms the critical window of opportunity for impacting immune system development and reducing systemic inflammation is within the first 100 days of infancy.

The immune system normally guards against bacteria and viruses by marshalling specific immune T-cells to recognize and attack the foreign invaders in the body. The adaptive immune system at birth is naturally a blank slate; it has had very little exposure to viruses or dangerous bacteria, so immune cells, called naïve T-cells, have yet to be programmed accordingly. In immune disorders and allergies, these cells are misprogrammed early on, by harmful bacteria or inflammation, to attack normal healthy cells in the body. Researchers have been working to determine how this misprogramming happens, to enable clinicians with solutions to reduce the risk of childhood allergic and autoimmune conditions.

Study Details


For the study, researchers found that infants who lacked beneficial microbes able to metabolize complex sugars in breast milk, human milk oligosaccharides (HMOs), had disordered development of immune cell networks and significantly increased systemic inflammation.

Furthermore, in vitro experiments showed that gut bacterial metabolites and host factors from breastfed infants that lacked B. infantis EVC001 in their gut microbiome programmed naïve immune cells toward Th2 and Th17, two immune cell types associated with the development of autoimmune and allergic diseases.

In contrast, breastfed infants fed B. infantis EVC001 skewed those naïve immune cells toward Th1, an immune cell type that allows the body to properly react and rid itself of dangerous pathogens. Researchers also found far greater levels of interferon Beta (IFNβ) in the B. infantis EVC001 isolates, which is an important regulatory mediator that improves the body’s ability to control inflammation and viral infections.

Additionally, the research shows that the unique genetic capacity of B. infantis EVC001 to fully metabolize human milk oligosaccharides (HMOs) produced the bacterial metabolite indolelactate (ILA). ILA, in turn, amplifies a broadly immunoregulatory factor, Galactin-1, effectively silencing Th2 and Th17.

“More than 90 percent of newborns have a severe deficiency of B. infantis; this study is an exciting step forward in our understanding of the role of B. infantis EVC001 in the positive programming of immune cells and how it actually changes the trajectory of immune system development to protect against inflammation,” said Dr. Bethany Henrick, PhD, first and corresponding author of the study and Director of Immunology and Diagnostics at Evolve BioSystems. “For the first time we’ve been able to demonstrate that the unique ability of B. infantis EVC001 to fully break down HMOs and the abundance of HMO utilization genes in the microbiome is directly correlated with decreased enteric and systemic inflammation.”

The study examined the development of immune system changes in 208 infants born at the Karolinska University Hospital in Sweden between April 2014 and December 2019, evaluating bifidobacterial species and other microbes expressing HMO utilization genes. To further assess the beneficial effects of HMO utilization gene expressing microbes, a second cohort of the study involved 40 breastfed infants in California, with half receiving B. infantis EVC001, a strain of Bifidobacterium possessing all HMO utilization genes, and the other half given no supplementation.

“These are important findings because, while they point to the disturbing fact that infants lacking B. infantis – unfortunately, now the norm in developed countries – can’t properly metabolize HMOs and are missing the critical window to develop a healthy immune system, it also shows that there’s a simple fix; feeding breastfed babies B. infantis EVC001 early in infancy can shut down inflammatory processes and reduce the life-time risk of developing immune-mediated diseases,” said Dr. Petter Brodin, MD, PhD, consultant pediatrician and lead author of the study and Professor of Pediatric Immunology at the Karolinska Institute in Sweden.

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About Evolve BioSystems, Inc.

Evolve BioSystems, Inc. is a privately-held leading microbiome company dedicated to discovering and implementing solutions that improve the short and long-term health of infants worldwide. Launched at the University of California, Davis, following more than a decade of pioneering research at the Food for Health Institute, Evolve is a portfolio company of Horizons Ventures, Cargill, Manna Tree Partners, The Bill & Melinda Gates Foundation, and Johnson &Johnson Development Corporation. Since 2014, Evolve has built substantial science and technology assets, focused on the nutrition, biochemistry, physiology of the developing infant gut microbiome. The company’s breakthrough research shows that nine out of ten U.S. infants are suffering from Newborn Gut Deficiency, a dramatic shortage of key good bacteria in the infant gut microbiome. Together with clinical research partners all over the world, Evolve is on a mission to establish B. infantis EVC001 as standard-of-care for all infants – for a better life-long health trajectory.

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.

Immune system dysfunction can alter the link between cannabis use and psychosis

Immune system dysfunction can alter the link between cannabis use and psychosis

  • June 17, 2021

The presence of pro-inflammatory cytokines in the blood can boost the effects of daily cannabis use and heighten the risk of developing psychosis in adulthood. Similar results have been observed, also in the presence of cytokines, when cannabis is used during adolescence. Psychotic disorders have symptoms such as delirium, loss of a sense of reality, hallucinations, hearing voices, and cognitive and social impairments.

A study by researchers at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil, reported in an article in the journal Psychological Medicine, finds for the first time that individuals exposed to a combination of these two factors – the presence of pro-inflammatory cytokines in the blood and cannabis use (either daily or during adolescence) – are more likely to suffer from psychosis than those who are exposed to neither or to only one. According to the authors, the study provides “the first clinical evidence that immune dysregulation modifies the cannabis-psychosis association”.

The study was part of a project conducted by the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI), a consortium of research centers in 13 countries, including Brazil. An article published in The Lancet Psychiatry by the consortium in 2019 showed that daily cannabis use increased the likelihood of suffering from a psychotic disorder threefold.

In the more recent study, the researchers analyzed data for 409 people aged 16-64, including patients experiencing their first psychotic episode and community-based controls. The sample was drawn from the populations of Ribeirão Preto and 25 other cities in the region. The variables analyzed included cannabis use frequency (daily, not daily or never), duration (five years or less), and onset age (in adolescence or later).

In addition to the questionnaire on cannabis use, the researchers measured various cytokines in plasma donated by the volunteers and calculated scores representing their systemic inflammatory profiles. They also collected clinical and socio-demographic data, especially variables known as confounders, such as age, gender, schooling, ethnicity, body mass index, smoking, and use of psychoactive substances. The results obtained were independent of confounding factors.

Not everyone who uses cannabis develops psychosis. This suggests that the association may be modified by other factors, which may be biological, genetic or environmental. In a previous study conducted as part of my master’s research, we identified a correlation between plasma cytokines and the first psychotic episode. Following up on this discovery, and the consortium’s recent publication showing a higher incidence of psychosis among subjects who used cannabis on a daily basis, our next step was to see if the biological factor [inflammatory profile] affected the link between cannabis use and psychosis.”


Fabiana Corsi-Zuelli, First Author of the Article

The main conclusion was that such a link did indeed exist. “We found a statistically significant correlation between inflammatory profile and cannabis use on a daily basis or during adolescence. In sum, the results showed that immune system dysfunction can modify the association between cannabis use and psychosis and that a combination of these two factors increases the odds of suffering from a psychotic disorder,” she said.

Corsi-Zuelli is currently a PhD candidate in FMRP-USP’s graduate program in neurology and neurosciences, with support from São Paulo Research Foundation – FAPESP.

The principal investigator for the project is Cristina Marta Del-Ben, a professor at FMRP-USP’s Department of Neurosciences and Behavioral Sciences. According to Del-Ben, risk factors for psychosis may be biological, including genetic predisposition and problems during pregnancy, as well as environmental, including traumatic experiences during childhood and adolescence, and exposure to psychoactive substances, especially cannabis.

“The mechanisms of the disorder are poorly understood,” she said. “Our findings show that frequent current use of cannabis or use of the drug in adolescence is a risk factor for psychosis. We didn’t detect the same correlation with occasional or recreational use. In the multicenter study, which included European cities with varying levels and types of cannabis availability, we also found that the risk of psychosis is greater in users of stronger cannabis strains with a THC content or 10% of higher.” THC (delta-9-tetrahydrocannabinol) is the primary psychoactive constituent of cannabis or marijuana.

The medical explanation of psychosis is that it is a neuropsychiatric syndrome associated with anatomical and functional alterations in the brain, possibly linked to changes in the action of dopamine, a key neurotransmitter for communication among neurons. Excessive dopamine or direct damage to certain brain regions can lead to hallucinations, delusions, delirium and disorganized behavior.

Other neurotransmitters, such as glutamate, have also been implicated in the neurobiology of psychosis. Specialists are currently discussing what they call the neuroimmune link, and how immune system dysregulation may trigger neurochemical, morphological and behavioral alterations that heighten the risk of developing psychiatric disorders.

Psychotic symptoms may be present in several psychiatric disorders, which may or may not be affective. Recent research has taken note of cases of psychosis in patients infected by SARS-CoV-2. Treatment of psychosis involves a combination of medication, psychotherapy and family support.

Next steps

According to Corsi-Zuelli, the origin of the inflammatory alterations involved in psychosis is still obscure, but it may arise from a combination of genetic and environmental factors. “The inflammation seen in psychiatric disorders is considered low-level and isn’t as severe as in patients with autoimmune diseases or sepsis,” she said. “Nevertheless, experimental studies suggest it entails sufficient dysregulation to produce neurochemical and behavioral alterations.”

The researchers plan next to study genetic variants associated with the immune system and use neuroimaging data to explore the link with environmental risk factors. “Focusing in this way on the interactions between genetics and the environment will help us understand the neurobiology of psychosis, especially the role played by the immune system,” she said.

The association between inflammation and psychiatric disorders is highly relevant to clinical practice and has received growing attention. “It’s important to the search for alternative treatments for these disorders, and also to answering often neglected questions relating to the physical health of psychiatric patients,” Corsi-Zuelli said.

According to Del-Ben, in the pipeline for next steps is a partnership with Geraldo Busatto Filho, a professor at the Medical School (FM) in USP’s main campus, to investigate whether inflammatory markers in blood are linked to brain alterations in some of the patients studied.

The research has twice received international recognition. The Society of Biological Psychiatry selected the study for its Predoctoral Scholars Award, which was to have been formalized at SOBP’s 2020 annual meeting in New York, but the pandemic forced a postponement until April 2021, when the meeting was held online. And the study was selected by the Schizophrenia International Research Society (SIRS) for presentation at its 2020 Congress, also held online.urce:

Anti-TIGIT and ICI Combinations Supported by Early-Phase Research

Anti-TIGIT and ICI Combinations Supported by Early-Phase Research

  • June 15, 2021

Immunotherapy treatments have generated excitement by eliciting durable responses in various tumor types, making a significant contribution to the progress of oncology.1,2 However, monotherapy with anti–PD-1/PD-L1 and anti–CTLA-4 monoclonal antibodies has yielded low response rates, mainly due to insufficient immune activation.1,3 There is hope that these poor monotherapy response rates will significantly improve when these agents are combined with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) inhibitors, which are next-generation immune checkpoint antibodies (FIGURE 14).

“I do believe that PD-1 and PD-L1 inhibitors are really the first step in understanding how a cancer interacts with a patient’s immune system,” said Melissa Johnson, MD, program director of lung cancer research and of the Solid Tumor Immune Effector Cellular Therapy Program at Sarah Cannon Research Institute in Nashville, Tennessee, in an interview with Targeted Therapies in Oncology (TTO). “There’s so much more to learn, and there are many patients who aren’t benefiting from PD-1/ PD-L1 inhibitors. We owe it to them especially to keep looking and to keep evaluating strategies that would also stimulate their immune system in the same way.”

To increase response rates, immune checkpoint inhibitors have been used in combination with chemotherapy or other immune checkpoint inhibitors, although this strategy has led to more adverse events (AEs).1 Additionally, although some patients with metastatic melanoma have seen increased response rates with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) compared with either monotherapy, a substantial number of patients remained unresponsive. In an area of ongoing research, combinations of immune checkpoint inhibitors are being evaluated for their ability to further stimulate the immune system.

“It is clear that only a small subset of patients respond to PD-1 [inhibitors] alone. Understanding how to use the other immune cells, particularly the Tregs, which regulate other cells in the immune system, to jump-start immunotherapy makes good sense and is an avenue we are excited about,” Jyoti Patel, MD, said in an interview with TTO. Patel is a professor of medicine and the associate vice chair for clinical research in the Department of Medicine at Northwestern University Feinberg School of Medicine and the medical director of thoracic oncology and assistant director for clinical research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois.

Recent research has identified TIGIT as a promising emerging immune checkpoint target. TIGIT indirectly suppresses T-cell activation and is expressed on multiple types of immune cells, including regulatory T (Treg) cells, activated T cells, and natural killer (NK) cells.1,5 TIGIT is upregulated in T cells and NK cells after ligand binding, inhibiting these cells’ ability to kill tumor cells.2 Increased TIGIT expression is also associated with advanced disease and poor survival outcomes. Additionally, increased TIGIT expression after treatment is associated with disease recurrence. TIGIT and its coreceptors, including CD226 and CD96, interact with a group of ligands expressed on tumor cells: nectins and nectin-like molecules, including poliovirus receptor (PVR), the main TIGIT ligand. PVR ligands binding to TIGIT suppresses the antitumor immune response of the TIGIT-expressing cell; in contrast, ligand binding to CD226 triggers immune cell activation. Thus, TIGIT and CD226 oppose each other to regulate tumor immunity.1,2 Anti-TIGIT therapy is presumed to invigorate immune function and enhance the activity of T cells and NK cells.2

The most promising data have come from tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab (Tecentriq), an anti–PD-L1 antibody. Immunotherapy combinations featuring dual blockade of TIGIT and PD-1/PD-L1 are promising due to their synergistic enhancement of antitumor responses.1,6

“We have great comfort and a lot of options with checkpoint inhibitors targeting PD-1 and PD-L1, but it seems that [targeting the TIGIT] pathway in this combinatorial approach will be well tolerated, unlike using CTLA-4 with PD-L1,” Patel said. “Anti-TIGIT therapy is exciting because we see it as a complement with PD-1 blockade in the wide variety of tumors in which we’ve seen efficacy. It seems that by inhibiting TIGIT, we may again improve PD-1 efficacy.”

Tiragolumab was the first anti-TIGIT antibody to receive the FDA’s breakthrough therapy designation, based on findings from the CITYSCAPE trial (NCT03563716).7 CITYSCAPE (n = 135) was a prospective, randomized, double-blind, placebo-controlled, phase 2 trial in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who were chemotherapy naive with PD-L1positive status (percentage of tumor cells expressing PD-L1 or tumor proportion score [TPS], ≥ 1%) and wild-type EGFR and ALK.8 Results demonstrated that the objective response rate (ORR) was improved in patients randomized to the tiragolumab and atezolizumab (TA) group (n = 67) compared with the placebo and atezolizumab (PA) group (n = 68), at 37.3% versus 20.6%, respectively (odds ratio, 2.57; 95% CI, 1.07-6.14). Patients in the TA group also had improved median progression-free survival (mPFS) compared with PA (5.6 months vs 3.9 months; HR, 0.57; 95% CI, 0.37-0.90).

“Although there have been other checkpoint inhibitors that have been developed to try to amplify the antitumor immune response achieved by PD-1 and PD-L1 inhibitors, there are very few that actually work,” Johnson said. “The CITYSCAPE data presented at ASCO [American Society of Clinical Oncology meeting] in 2020 showed that the addition of the anti-TIGIT tiragolumab to atezolizumab improved responses and progression-free survival in patients who had PD-L1–expressing tumors. [The results of CITYSCAPE] suggest there is, in fact, a way to push those tumors that are immune sensitive a little bit further.

“Perhaps the most impressive thing about the CITYSCAPE data was the exploratory analysis in the [patients with] PD-L1–high [tumors, which] express PD-L1 at greater than 50%. The response rates were 66% in the combination group and 24% in atezolizumab alone. The [median] PFS was not reached when patients were treated with the combination, and it was 4 months for patients treated in the atezolizumab arm, suggesting that the [patients with] PD-L1–high [tumors] are the ones [who] benefit the most from [a TIGIT and PD-L1 blockade] strategy,” Johnson continued.

The safety profiles of the 2 groups in CITY-SCAPE were comparable.8 Most patients in both groups experienced treatment-related AEs (TRAEs), 80.6% in the TA group and 72% in the PA group.

“The most common [adverse] effects were what you would expect from immune-mediated therapy, like rash and thyroid issues,” Johnson said. “Most commonly, infusion reactions were seen, and that typically was with the first dose only and not with subsequent infusions. Some soft stool and diarrhea [were reported as well]. There were very few cases of more severe immune- related toxicities, like hepatitis.”

“The toxicity seems quite manageable, and we’re seeing improvements in both progression-free survival and response,” Patel added.

“My sense is that we can expect the [combination of tiragolumab and atezolizumab to be used in future practice] without toxicity rates of 30% like we’ve seen for ipilimumab and nivolumab. I think that’s certainly led to enthusiasm in larger phase 3 studies,” she said.

Ongoing Trials

Several trials are currently evaluating the use of tiragolumab in different combinations in the frontline setting to determine the efficacy of TIGIT and PD-1/PD-L1 combination therapy.

“I could envision that [tiragolumab] could be added to the armamentarium in a lot of ways,” Johnson said. “It just depends on what some of these trials show us about where the benefit is the greatest.…There are lots of things that one can do with a checkpoint inhibitor once you figure out where it’s the most useful. It’s an exciting discovery.”

One notable tiragolumab trial, SKY-SCRAPER-01 (NCT04294810), is a double-blind, randomized, placebo-controlled, phase 3 trial evaluating the frontline use of tiragolumab and atezolizumab compared with placebo and atezolizumab in advanced, PD-L1–high NSCLC. The trial is expected to enroll 560 patients, with primary outcomes of PFS and overall survival (OS).

“The SKYSCRAPER-01 trial that’s enrolling right now in frontline lung cancer is a really important trial. [The trial investigators hope] to see a significant difference between atezolizumab and tiragolumab compared with atezolizumab alone,” Johnson said.

Vibostolimab

Another anti-TIGIT antibody with encouraging results in NSCLC is vibostolimab. The ongoing, multicohort, phase 1 MK-7684-001 trial (NCT02964013) is evaluating vibostolimab in patients with advanced solid tumors, and results from the dose-confirmation/expansion phase in patients with NSCLC were recently published. One report described evaluation of vibostolimab as either monotherapy or in combination with pembrolizumab (Keytruda) in 79 heavily pretreated patients with anti–PD-1/PD-L1–refractory disease.9 The majority of patients (78%) had received at least 2 prior lines of therapy. The ORR was 7% (95% CI, 2%-20%) for vibostolimab monotherapy (n = 41) and 5% (95% CI, <1%-18%) for combination therapy (n = 38). AEs occurred in at least 97% of patients, and at least 65% experienced TRAEs. Common TRAEs included pruritus, fatigue, rash, arthralgia, and decreased appetite. Grade 3 to 4 TRAEs occurred in 10 patients, with lipase increase and hyper-tension being the most common.

Discussing the optimal sequencing of checkpoint inhibitors in therapy, Johnson said, “what we’re finding with lots of check-point inhibitors is that it’s not enough to restore an immune response to a cancer that has developed resistance to a PD-1 inhibitor alone.…We’ll have to find other therapies for patients with acquired resistance to PD-1 inhibitors, rather than trying to continue them and add other checkpoint inhibitors to them. I don’t think there’s been much success with many checkpoint inhibitors [used as therapy for PD-1– or PD-L1–refractory disease].”

In another report of results from the MK-7684-001 study, 41 anti–PD-1/PD-L1–naive patients with advanced NSCLC all received the vibostolimab-pembrolizumab combination.10 The majority of patients (73%) had received at least 1 prior treatment regimen. Results demonstrated an ORR of 29% (95% CI, 16%-46%). Patients with PD-L1–positive tumors (TPS ≥ 1%) had an ORR of 46% (95% CI, 19%-75%), whereas their PD-L1–negative counterparts (TPS < 1%) had an ORR of 25% (95% CI, 5%-57%).

The mPFS for the entire cohort was 5.4 months (95% CI, 2.1-8.2). PD-L1–positive patients had an mPFS of 8.4 months (95% CI, 3.9-10.2), double the PD-L1–negative mPFS of 4.1 months (95% CI, 1.9-not reached). TRAEs occurred in 83% of patients, with the most common being pruritus, hypoalbuminemia, and pyrexia. Serious grade 3 to 4 TRAEs occurred in 15% of patients. Investigators concluded that the combination therapy was well tolerated and had promising antitumor activity.

“Vibostolimab has certainly caught our attention…seeing [that] the drug was well tolerated and improved response rates,” Patel said.

Domvanalimab

Another noteworthy anti-TIGIT antibody is domvanalimab. This agent is currently being evaluated in patients with PD-L1–positive, locally advanced or metastatic, treatment-naive NSCLC in the ARC-7 trial (NCT04262856).

This open-label, randomized phase 2 trial includes 3 study arms: zimberelimab (anti–PD-1) monotherapy, domvanalimab with zimberelimab, and domvanalimab with zimberelimab and etrumadenant (a dual–adenosine receptor antagonist). The study is expected to enroll approximately 150 patients (FIGURE 2).

In Development

Multiple new anti-TIGIT antibodies are in the pipeline. Data presented at the American Association for Cancer Research Annual Meeting 2021 highlighted early-phase clinical and preclinical trials evaluating TIGIT- targeting antibodies.

“There are other TIGIT antibodies…and whether they work the same or not, we’re still learning,” Johnson said.

EOS884448 (EOS-448) is a potent anti-TIGIT antibody that was evaluated as monotherapy in a multicenter, open-label, phase 1/2 study in patients with previously treated advanced solid malignancies (NCT04335253). Preliminary dose-escalation results (n = 22) demonstrated no dose-limiting toxicity at any of the 5 dose levels tested and pharmacokinetic analyses indicated dose-proportional increases in plasma EOS-448.11 The patients received EOS-448 intravenously once every 2 weeks or once every 4 weeks according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg once every 2 weeks and 1400 mg every 4 weeks were evaluated. Depletion of suppressive Treg cells was observed at all dose levels. Additionally, the optimal dosing interval was found to be every 3 or 4 weeks. Patients had received a median of 3 lines of therapy prior to treatment with EOS-448.

Investigator assessment of 20 response-evaluable patients demonstrated stable disease in 9 patients and a partial response in 1 patient with melanoma previously treated with pembrolizumab. No immunogenicity was observed in any patients. Treatment-related AEs (TEAEs) occurred in 82% of patients, with pruritus, infusion- related reaction, fatigue, and pyrexia being the most common. The majority (52%) of patients with TEAEs had grade 3 or higher, with serious TEAEs occurring in 36%. Investigators concluded that these preliminary data support further exploration of EOS-448 in clinical trials.

One tumor type of interest in TIGIT research is breast cancer. Triple-negative breast cancer (TNBC) is a particular focus because immunotherapy has proven highly beneficial in that patient population. Additionally, there is increased expression of TIGIT in malignant breast tissue compared with normal tissue, further highlighting the potential for use of TIGIT-targeting therapeutics in this patient population.

Another study evaluated mRNA expression of members of the TIGIT/PVR/NECTIN family in breast tumors from 1904 patients using a publicly available data set.12

Comparison of results in different breast cancer subtypes demonstrated that most TIGIT/PVR/NECTIN genes had the highest expression levels in TNBC, followed closely by HER2-positive breast cancer. Hormone receptor–positive breast cancer had the lowest expression. No association was found between expression of most TIGIT/PVR/ NECTIN genes and OS across breast cancer subtypes. However, expression of the costimulatory receptor CD226 was associated with significantly improved OS in early TNBC (HR, 0.69; 95% CI, 0.48-0.99).

The investigators concluded that combination therapy targeting TIGIT and PD-1/ PD-L1 may provide improved efficacy in patients with TNBC.

“In triple-negative breast cancer, there’s been some question about the efficacy of immunotherapies,” Patel said. “Many of these tumors may look cold, and inhibition of TIGIT, which is suppressing the immune reaction, might make sense to make [the tumor microenvironment] more immune favorable.”

HLX53 is a novel single-domain antibody that binds TIGIT strongly, blocking binding of its ligands CD155 (NECTIN5) and CD112 (NECTIN2), thus preventing TIGIT from inhibiting the antitumor immune response. Combining HLX53 with an anti–PD-L1 antibody showed a synergistic effect on tumor inhibition.13

Another anti-TIGIT antibody with promising preclinical data is SEA-TGT.14 Its distinct, nonfucosylated antibody backbone was shown to confer enhanced antitumor activity, including Treg depletion, compared with standard-format anti-TIGIT antibodies.

A phase 1 trial (NCT04254107) has been initiated to investigate SEA-TGT alone and in combination with pembrolizumab. The study protocol was presented at the 2021 ASCO Annual Meeting.

Other anti-TIGIT therapies include etigilimab and BMS-986207. Etigilimab is currently undergoing evaluation with nivolumab in an open-label, multicenter, phase 1/2 basket study (NCT04761198) in patients with advanced solid tumors. This trial has an estimated enrollment of 125 patients.

In another phase 1/2 open-label trial (NCT04570839), BMS-986207 is being evaluated in combination with nivolumab and COM701, an inhibitor of PVRIG (a TIGIT coreceptor that binds NECTIN2). To be eligible for study, patients must have high tumor expression of NECTIN2. The investigators plan to accrue 100 patients with advanced solid tumors for the trial.

“There are a number of exciting compounds. Right now they seem to be improving response rates compared with PD-L1 inhibitors or PD-1 inhibitors alone,” Patel said.

“I think…we need to see more mature data in a larger group of patients and actually have [an] eye toward the patient selection for these compounds because [they are] clearly efficacious. We just have to understand in whom monotherapy would be more effective [compared with combination therapy].”

References

1. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol. 2018;29(1):71-83. doi:10.1093/ annonc/mdx686

2. Yeo J, Ko M, Lee DH, Park Y, Jin HS. TIGIT/CD226 axis regulates anti-tumor immunity. Pharmaceuticals (Basel). 2021;14(3):200. doi:10.3390/ph14030200

3. Ventola CL. Cancer immunotherapy, part 3: challenges and future trends. P&T. 2017;42(8):514-521.

4. Gorvel L, Olive D. Targeting the “PVR-TIGIT axis” with immune checkpoint therapies. F1000Res. 2020;9:F1000 Faculty Rev-354. doi:10.12688/f1000research.22877.1

5. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155. doi:10.1186/s12943-019-1091-2

6. Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8(2):e000957. doi:10.1136/jitc-2020-000957

7. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed April 26, 2021. https://bit.ly/3hmWDm3

8. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503

9. Ahn M, Niu J, Kim D, et al. Vibostolimab, an anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in anti-PD-1/PD-L1-refractory NSCLC. Ann Oncol. 2020;31(suppl 4):S887. doi:10.1016/j.annonc.2020.08.1714

10. Niu J, Nagrial A, Voskoboynik M, et al. Safety and efficacy of vibostolimab, an anti-TIGIT antibody, plus pembrolizumab in patients with anti-PD-1/PD-L1-naive NSCLC. Ann Oncol. 2020;31(suppl 4):S891-S892. doi:10.1016/j.annonc.2020.08.1724

11. Van den Mooter TFA, Migeotte A, Jungles C, et al. Preliminary data from phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancers. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting 2021; April 10-15, 2021; virtual.

12. DuPree K, Molinero L. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

13. Hua B, Yang M, Xue J, et al. A novel single-domain antibody targeting TIGIT for cancer use in combination therapies. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

14. Smith A, Zeng W, Lucas S, et al. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

  • June 12, 2021

A class of antidepressants known as monoamine oxidase inhibitors (MAOIs) first hit the market in the 1950s and has since been eclipsed by drugs that are less likely to cause unwanted side effects. Now, scientists at the University of California, Los Angeles (UCLA) have evidence that these drugs may be able to be repurposed in the treatment of cancer.

The UCLA researchers discovered MAOIs help the immune system fight cancer, slowing the growth of colon tumors and melanoma in mice. They reported their findings in two papers, one published Nature Communications and the other in Science Immunology, UCLA said in a statement.

By studying immune cells from melanoma tumors in mice, the UCLA team discovered that immune cells that had invaded the tumors showed high activity of the gene monoamine oxidase A. The protein that gene produces, MAO-A is the target of MAOI drugs.

Mice that didn’t produce MAO-A in tumors showed better control of melanoma and colon cancer. When the animals were treated with the MAOIs phenelzine, clorgyline or mocolobemide, tumor growth slowed. The treatment worked even better in combination with drugs that block the immune checkpoint PD-1, the researchers reported.

RELATED: Could immuno-oncology treatments get a boost from a 64-year-old antipsychotic?

So how to MAOIs fight cancer? The UCLA team discovered that by blocking MAO-A, the antidepressants boost the activity of the immune system’s T cells. The drugs also inhibit tumor-associated macrophages, which normally function to help tumors evade immune destruction.

In essence, then, MAO-A could be considered another immune checkpoint, the researchers suggested.

To back up that theory, the UCLA researchers measured MAOA gene expression in several types of tumors from patients. They discovered a link between high MAOA expression and shorter survival times.

The UCLA researchers noted the longstanding belief in the scientific community that there is cross-talk between the immune system and the nervous system. And this is not the first team to propose repurposing a brain treatment in cancer. Last year, for example, Australian researchers published a study showing that when they combined the antipsychotic prochlorperazine with a PD-L1 inhibitor in mice, it outperformed either therapy alone at shrinking tumors.

Researchers at the University of Southern California are running a phase 2 clinical trial of the MAOI phenelzine in prostate cancer patients. In interim results reported last year, they said that 11 of 20 participants saw their PSA levels drop after being treated with the antidepressant.

The UCLA researchers said they have patented the combination therapy they tested in mouse models of melanoma and colon cancer but have yet to try it in people. Still, they believe it’s an idea worth pursuing, especially because cancer patients are four times as prone to depression as the general population is.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” said senior author Lili Yang, Ph.D., associate professor of microbiology, immunology and molecular genetics, in the statement.

Research identifies potential antiviral compound for COVID-19, flu, other viral infection

Research identifies potential antiviral compound for COVID-19, flu, other viral infection

  • June 11, 2021
infection
Credit: CC0 Public Domain

UMass Medical School scientists Katherine A. Fitzgerald, Ph.D.; Fiachra Humphries, Ph.D.; and Liraz Galia, Ph.D., working with the British-based pharmaceutical company GlaxoSmithKline, have identified a novel molecule capable of stimulating the innate immune system against SARS-CoV-2 virus. A trigger for the STING (stimulator of interferon genes) pathway, the compound, diamidobenzimidazole (diABZI-4), protected animal models and human cells in the lab from SARS-CoV-2 infection. Published in Science Immunology, these results show that diABZI-4 has the potential to be an effective antiviral prophylaxis against COVID-19.

“Identifying antiviral therapies for SARS-CoV-2 is still desperately needed while vaccines continue to rollout worldwide,” said Dr. Fitzgerald, the Worcester Foundation for Biomedical Research Chair, professor of medicine, vice chair of research in the Department of Medicine and director of the Program in Innate Immunity. “An approach like this, using a STING agonist, could be deployed to protect those at highest risk in this pandemic but also in future pandemics before we have drugs that target the virus itself.” Fitzgerald and Dr. Galia, a postdoctoral associate in the Fitzgerald lab, are authors on the paper.

Dr. Humphries, instructor in medicine and first author of the study, added, “Not everybody can receive a vaccine. For those who are immuno-compromised or have allergies, this treatment, which could be delivered through an inhaler, can be a viable alternative for boosting the .”

Vaccines work by stimulating the adaptive immune system, which creates antibodies against diseases and viruses. By taking a small piece of a virus that doesn’t cause , in the case of SARS-CoV-2 a part of the spike protein that latches onto and infects epithelial cells, scientists can teach the adaptive immune system to recognize specific viral invaders. Once the adaptive immune system has been trained, it can more quickly respond to subsequent encounters by producing the antibodies that fight off the virus. This prevents serious illness, such as COVID-19, and in some cases entirely blocks infection.

The innate immune system, however, is more of a generalist, explained Humphries. The innate immune system identifies any pathogen that it may encounter—whether it be bacterial, viral or fungal. One of its chief functions is to produce cytokines that serve as a first line of defense, antiviral responder. It also alerts the immune system to the presence of the invader and triggers the adaptive immune system to wake up.

The intracellular protein STING is like an early alarm system for the immune system. Once it has been activated, it triggers production of the cytokine interferon. This activity stimulates the to fight off the infection. A STING agonist, such as diABZI-4, could potentially serve a wake-up call to the immune system, giving it a boost to fight off pathogens before they get established.

Humphries and colleagues believed that the immune stimulating properties of diABZI-4 could also serve as an antiviral drug. It is already being tested as an immunotherapy for cancer.

By administering diABZI-4 intranasally, directly to the site of infection in mice, Humphries showed that it could activate the immune system and eliminate viral infection, such as SARS-CoV-2.

“It was kind of amazing,” said Humphries. “A single dose was able to protect 100 percent of the mice from severe disease. After taking diABZI-4, the mice were completely protected from infection.”

Subsequent cell studies showed that diABZI-4 was able to stimulate the innate immune response by activating the STING pathway that produces interferon I.

In part, what makes SARS-CoV-2 so effective is its ability to circumvent the antiviral response of the , said Fitzgerald. “But what we show is we can use a STING agonist to illicit antiviral immunity and be effective.”

Use of diABZI-4, which is stable at room temperature and can be produced relatively easily, may be an important adjuvant for current vaccine treatments for COVID-19. “You could see this being important for breakthrough infections and emerging variants,” said Humphries. “You could potentially take this through an inhaler shortly after a potential exposure or even prophylactically before entering a high-risk environment such as an airplane and you’d have a short-lived antiviral boost to your immune system that would clear any virus before infection is established.”

Fitzgerald and Humphries also showed that this antiviral response extended beyond SARS-CoV-2. It protected against influenza and herpes simplex virus as well. “Ultimately, this could have very broad antiviral applications,” said Humphries.


Researchers discover drug that blocks multiple SARS-CoV-2 variants in mice


More information:
Fiachra Humphries et al, A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection, Science Immunology (2021). DOI: 10.1126/sciimmunol.abi9002

Citation:
Research identifies potential antiviral compound for COVID-19, flu, other viral infection (2021, June 11)
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from https://medicalxpress.com/news/2021-06-potential-antiviral-compound-covid-flu.html

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Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Macrophages can aid tumor growth by distracting cancer-killing CD8+ T cells

  • June 11, 2021

A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities-;which house the lungs and organs of the gastrointestinal tract, respectively-;were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

UMMS research identifies potential antiviral compound for COVID-19, flu, other viral infection

UMMS research identifies potential antiviral compound for COVID-19, flu, other viral infection

  • June 11, 2021

UMass Medical School scientists Katherine A. Fitzgerald, PhD; Fiachra Humphries, PhD; and Liraz Galia, PhD, working with the British-based pharmaceutical company GlaxoSmithKline, have identified a novel molecule capable of stimulating the innate immune system against SARS-CoV-2 virus. A trigger for the STING (stimulator of interferon genes) pathway, the compound, diamidobenzimidazole (diABZI-4), protected animal models and human cells in the lab from SARS-CoV-2 infection. Published in Science Immunology, these results show that diABZI-4 has the potential to be an effective antiviral prophylaxis against COVID-19.

fitzgerald-katherine-330.jpg
Katherine A. Fitzgerald, PhD

“Identifying antiviral therapies for SARS-CoV-2 is still desperately needed while vaccines continue to rollout worldwide,” said Dr. Fitzgerald, the Worcester Foundation for Biomedical Research Chair, professor of medicine, vice chair of research in the Department of Medicine and director of the Program in Innate Immunity. “An approach like this, using a STING agonist, could be deployed to protect those at highest risk in this pandemic but also in future pandemics before we have drugs that target the virus itself.” Fitzgerald and Dr. Galia, a postdoctoral associate in the Fitzgerald lab, are authors on the paper.

Dr. Humphries, instructor in medicine and first author of the study, added, “Not everybody can receive a vaccine. For those who are immuno-compromised or have allergies, this treatment, which could be delivered through an inhaler, can be a viable alternative for boosting the immune response.”

Vaccines work by stimulating the adaptive immune system, which creates antibodies against diseases and viruses. By taking a small piece of a virus that doesn’t cause infection, in the case of SARS-CoV-2 a part of the spike protein that latches onto and infects epithelial cells, scientists can teach the adaptive immune system to recognize specific viral invaders. Once the adaptive immune system has been trained, it can more quickly respond to subsequent encounters by producing the antibodies that fight off the virus. This prevents serious illness, such as COVID-19, and in some cases entirely blocks infection.

humphries-fiachra-330.jpg
Fiachra Humphries, PhD

The innate immune system, however, is more of a generalist, explained Humphries. The innate immune system identifies any pathogen that it may encounter—whether it be bacterial, viral or fungal. One of its chief functions is to produce cytokines that serve as a first line of defense, antiviral responder. It also alerts the immune system to the presence of the invader and triggers the adaptive immune system to wake up.

The intracellular protein STING is like an early alarm system for the immune system. Once it has been activated, it triggers production of the cytokine interferon. This activity stimulates the adaptive immune system to fight off the infection. A STING agonist, such as diABZI-4, could potentially serve a wake-up call to the immune system, giving it a boost to fight off pathogens before they get established.

Humphries and colleagues believed that the immune stimulating properties of diABZI-4 could also serve as an antiviral drug. It is already being tested as an immunotherapy for cancer.

By administering diABZI-4 intranasally, directly to the site of infection in mice, Humphries showed that it could activate the immune system and eliminate viral infection, such as SARS-CoV-2.

“It was kind of amazing,” said Humphries. “A single dose was able to protect 100 percent of the mice from severe disease. After taking diABZI-4, the mice were completely protected from infection.”

Subsequent cell studies showed that diABZI-4 was able to stimulate the innate immune response by activating the STING pathway that produces interferon I.

In part, what makes SARS-CoV-2 so effective is its ability to circumvent the antiviral response of the innate immune system, said Fitzgerald. “But what we show is we can use a STING agonist to illicit antiviral immunity and be effective.”

Use of diABZI-4, which is stable at room temperature and can be produced relatively easily, may be an important adjuvant for current vaccine treatments for COVID-19. “You could see this being important for breakthrough infections and emerging variants,” said Humphries. “You could potentially take this through an inhaler shortly after a potential exposure or even prophylactically before entering a high-risk environment such as an airplane and you’d have a short-lived antiviral boost to your immune system that would clear any virus before infection is established.”

Fitzgerald and Humphries also showed that this antiviral response extended beyond SARS-CoV-2. It protected against influenza and herpes simplex virus as well. “Ultimately, this could have very broad antiviral applications,” said Humphries.

Related story on UMassMed News:
New study of oral therapy candidate indicates positive results for patients with mild-to-moderate COVID-19

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Ludwig Cancer Research Study Shows How Certain Macrophages Dampen Anti-Tumor Immunity

  • June 10, 2021

Newswise — JUNE 10, 2021, NEW YORK – A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells. 

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells. 

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK. 

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies. 

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said. 

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy. 

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities—which house the lungs and organs of the gastrointestinal tract, respectively—were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors. 

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said. 

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal. 

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4. 

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow. 

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

Taha Merghoub is co-director of the Ludwig Collaborative & Swim Across America Laboratory at MSK and professor of immunology research in medicine at Weill Cornell Medical College.

Jedd Wolchok is associate director of the Ludwig Center and director of the Ludwig Collaborative & Swim Across America Laboratory, chief of the immuno-oncology service, the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation and director of the Parker Institute for Cancer Immunotherapy at MSK.

This study was supported by Ludwig Cancer Research, Swim Across America, Parker Institute for Cancer Immunotherapy, The Emerald Foundation, the US National Cancer Institute, MSKCC, the American Cancer Society, the International Association for the Study of Lung Cancer and the US Department of Defense.

# # #

 

About Ludwig Cancer Research

 

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 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 nearly $3 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.

 

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Common antidepressant drugs help the immune system to attack tumors in mice

  • June 10, 2021

A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain’s “happiness hormone.”

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

MAOIs had not been linked to the immune system’s response to cancer before. What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”


Lili Yang, Study Senior Author and Member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles Health Sciences

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That’s because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs — phenelzine, clorgyline or mocolobemide — either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven’t tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells’ response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

Source:

Journal reference:

Wang, Y-C., et al. (2021) Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy. Nature Communications. doi.org/10.1038/s41467-021-23164-2.

Restoring gut microbes can improve antibiotic-induced dysbiosis and prevent colitis in mice

Restoring gut microbes can improve antibiotic-induced dysbiosis and prevent colitis in mice

  • June 8, 2021

A new study at the University of Chicago has determined that restoring a single microbial species — Bacteroides sp. CL1-UC (Bc) — to the gut microbiome at a key developmental timepoint can prevent antibiotic-induced colitis in a mouse model of the condition. The results, published on June 7 in Gastroenterology, have major implications for humans dealing with inflammatory bowel disease (IBD), and underscore the impact of early childhood exposures on health throughout the lifetime.

Prior studies in human patients have found that early life exposure to antibiotics can skew the gut microbiome, causing dysbiosis, or an imbalance of the microbial populations in the gut, which is correlated with increase risk for developing pediatric IBD.

We know that the kinds of microbes that you’re exposed to early in life actually determine how your immune system develops. Our immune system learns to recognize our own selves, and the trillions of microbes in our gut — they’re ‘us’ as well, so our immune system has to learn to tolerate these organisms, just as it tolerates our own cells. Early exposure to antibiotics can eradicate some of the organisms that are essential for educating the immune system to develop immune tolerance.”


Eugene Chang, MD, Senior Author, Martin Boyer Professor of Medicine, UChicago

Due to the challenges of conducting such studies in human patients, the researchers opted to use a common model for studying colitis: mice that lack a gene known as IL-10 (IL-10-/-). “This mouse model has been established as being genetically susceptible to IBD, and we know that the gut microbiome plays a crucial role in the development of colitis in this model,” said first author Jun Miyoshi, MD, PhD, a Senior Assistant Professor in the Department of Gastroenterology and Hepatology at Kyorin University School of Medicine, and a former postdoctoral scholar at UChicago.

While only very rarely do these mice develop spontaneous colitis without any intervention in a clean environment, if their mothers are exposed to antibiotics during pregnancy and nursing, the disrupted microbiome can be transmitted to the pups at an early age. Around 30% of pups with this vertically transmitted disrupted microbiome go on to develop colitis.

The investigators used a technique known as shotgun metagenomic sequencing to screen the fecal microbiomes of IL-10-/- mice that had antibiotic-induced dysbiosis, alongside an untreated control group, and identify specific microbial species that might distinguish the two groups. This led them to members of the bacterial phylum Bacteroides.

One clue of the phylum’s importance was that Bacteroides was very abundant in the microbiomes of untreated mice, but completely lacking in the mice that had been exposed to antibiotics. What’s more, the researchers never saw Bacteroides in the treated mice that did not go on to develop colitis — but they often found Bacteroides in the guts of mice that did end up with the condition.

“These bacteria were eradicated by early exposure to antibiotics and were essential for educating the immune system in developing immune tolerance,” said Chang. “When those mice later acquired the bacteria, their immune system had never seen it. It was viewed as foreign, not as self, and their immune systems reacted to it.”

In an effort to determine whether restoring important Bacteroides back to the microbiome could correct the dysbiosis, the researchers honed in on a particularly abundant species known as Bacteroides sp. CL1-UC (Bc). They tried adding Bc back to the microbiomes of the mice with dysbiosis at two timepoints: around infancy (three weeks of age) and adulthood (11 weeks of age).

Engrafting Bc into the younger mice, during the critical immune system developmental window, corrected their dysbiosis and prevented colitis, but adding Bc back to adult mice could not correct the dysbiosis, and even worsened their colitis.

“This shows that you can’t just restore the missing bacteria at any time point, it has to be at a specific time early in life to have a beneficial effect,” said Chang. “In young animals, we know that the immune system is developing, it’s naive, it has to be taught, and it’s taught by being exposed to certain kinds of microbes. In some ways, it’s similar to a peanut allergy — early exposure to the antigen can tolerize the immune system to help avoid a peanut allergy, but it has to happen within a very finite window.”

The researchers were surprised to learn that restoring a single microbe was enough to correct lifelong dysbiosis, and said it highlighted how relatively small changes can have a dramatic impact on a system. “It’s like the tall trees of the Amazon rainforest,” said Chang. “You need the tall trees, because if you don’t have them, the ecosystem below cannot develop properly. But if you have those trees in place, the rest of the ecosystem will flourish.”

The results also go against popular theories on the origin of IBD. “There’s a misconception that colitis is caused by a classical pathogen, like salmonella, and scientists have spent years looking for a culprit,” said Chang. “But what our data are pointing to is that these diseases are caused by our own commensal microbes. They are present in the normal, healthy microbiome, but given the right circumstance and opportunity, they can transform into disease-promoting microbes.”

While this early study was proof-of-concept, if the results translate to humans, the ripple effects are likely to be far-reaching. “This shows that we probably have to rethink our approach to these kinds of complex immune disorders,” said Chang. “We can see that risk is developing early in life — even in utero — and so this has implications for practices such as C-sections and formula feeding, which can impact the microbes an infant is exposed to. What this says to me is that, as physicians, we need to shift our thinking to not what immediately preceeds these diseases but what happens early in life. That’s where we need to intervene for these patients.”

Source:

Journal reference:

Miyoshi, J., et al. (2021) Early-life microbial restitution reduces colitis risk promoted by antibiotic-induced gut dysbiosis in IL-10-/- mice. Gastroenterology. doi.org/10.1053/j.gastro.2021.05.054.

capsimmunesystem.org