For cancer patients with HIV, immunotherapy appears safe

A new category of immunotherapies called checkpoint inhibitors that has been highly effective against many different cancers appears safe to use in patients with both advanced malignancies and HIV, a population excluded from earlier trials of such therapies, according to an early-phase trial.

Study Principal Investigator, Dr. Thomas Uldrick of the HIV & AIDS Malignancy Branch at the National Cancer Institute, will present late breaking results from the first 17 patients on a phase I study of pembrolizumab in patients with HIV and advanced cancers Friday at the Society for Immunotherapy of Cancer’s annual meeting in National Harbor, Maryland. The ongoing, multi-site study is being conducted by the NCI-funded Cancer Immunotherapy Trials Network, which is headquartered at Fred Hutchinson Cancer Research Center.

Cancer has become the leading cause of death for people with HIV. But until now, they and their physicians have had little data to guide them on whether they can safely use powerful new anti-cancer drugs called immune checkpoint inhibitors.

“During the development of these drugs, people with HIV were routinely excluded from studies due to concerns that they would not tolerate these medications or perhaps not benefit from them because of their underlying HIV and associated immune dysfunction,” Uldrick said. “The most important first step was to show that this class of drug would be safe in cancer patients with HIV.”

Study participants — who were on standard antiretroviral therapy to control their HIV infections and had various cancers that had failed to respond to standard therapies — received pembrolizumab (Keytruda), known since 2015 as “the Jimmy Carter drug” after it swiftly beat back melanoma that had spread to the former president’s brain and liver.

Pembrolizumab belongs to a type of immunotherapy that blocks a braking system cancers use to tamp down the immune response. Checkpoint inhibitors have been extremely effective in some patients with advanced cancers otherwise thought untreatable. The treatments have received U.S. Food and Drug Administration approval for melanoma, lung cancer, head and neck cancer, Hodgkin’s lymphoma, and kidney and bladder cancers.

“These drugs are the backbone of cancer immunotherapy at present and have been shown to be effective in subsets of virtually every different kind of cancer,” said Fred Hutch immunotherapy researcher Dr. Martin “Mac” Cheever, who leads the Cancer Immunotherapy Trials Network and is senior author of the new study. “For patients with HIV who are using effective antiretroviral therapy and have cancers for which these drugs are approved, there’s no reason not to consider these drugs as standard therapy.”

HIV and cancer

From the earliest days of the AIDS pandemic, Kaposi sarcoma — a rarely seen cancer until then — was one of a trio of cancers known as AIDS-defining malignancies. It, non-Hodgkin lymphoma and, in women, cervical cancer, often signaled that a person’s HIV infection had progressed to full-blown AIDS. People did not die of AIDS, per se. They died of one of these cancers or of infections like pneumocystis pneumonia and toxoplasmosis that took advantage of a weakened immune system.

Since the advent of antiretroviral therapy for HIV in 1996, full-blown AIDS and AIDS deaths have dropped dramatically. But the association between HIV and cancer remains, and not just with the traditional AIDS-defining malignancies. A large study published in the journal Annals of Internal Medicine in 2015 found higher cancer incidence across the board in HIV patients, including lung cancer and Hodgkin lymphoma.

“Globally, more than 35 million people are infected with HIV, and cancer is the number one reason they are dying,” Uldrick said. “Establishing proven effective regimens to manage cancer in people with HIV is critically important.”

The ongoing study will enroll up to 36 patients, and there are plans to include more patients with Kaposi sarcoma, a cancer for which checkpoint inhibitors have not been studied. It is one of the leading causes of cancer deaths in sub-Saharan Africa — where HIV rates are high — and new treatments are sorely needed.

Further study in Kaposi sarcoma

Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus (also known as human herpesvirus 8, or HHV-8) and most commonly appears as lesions on the skin. KSHV can also cause two other B-cell tumors, primary effusion lymphoma and a form of multicentric Castleman disease. Additionally, it can infect blood cells and spread through the bloodstream to infect other cells in the body, Uldrick said.

Also to be presented Friday is the death of one patient later in the study who had Kaposi sarcoma. The death is still being evaluated but was likely due to dissemination of KSHV. Uldrick and Cheever said review of the case suggests the patient had a history of symptomatic KSHV viremia, and the study has been changed to exclude such patients in the future and provide specific guidelines for management should new symptomatic KSHV viremia be observed.

Six other study participants with Kaposi sarcoma or primary effusion lymphoma have been treated on this study. None has experienced similar problems, and some have benefitted from therapy, Uldrick said.

“We do not believe that this takes away from the safety message in patients with HIV and other, better studied cancers,” Uldrick said. “However, more experience is clearly needed in treating KSHV-associated diseases with checkpoint inhibitors.”

A passion to ‘change the culture’

Although the NCI has recommended including people with HIV in immunotherapy clinical trials for a decade, virtually every industry-sponsored study over the last five years excluded them, according to a review by Uldrick and others published in the Journal of Clinical Oncology. Uldrick believes that reluctance to include people with HIV in cancer immunotherapy studies dates back to a time when patients were still dying of opportunistic infections and antiretroviral therapies were more toxic than they are today.

As a physician-scientist who focuses on immunology, virology and cancer, Uldrick became frustrated with the lack of data.

“The culture was slow to change,” he said. “It was preventing the advance of appropriate clinical therapies.”

Dr. Holbrook Kohrt, a Stanford oncologist and researcher, shared that frustration. Kohrt instigated the current clinical trial, according to Cheever, driven by his boyhood experience being one of only two hemophiliacs in a special summer camp who did not die of AIDS. (The genetic disorder impairs the blood’s clotting ability and requires infusions of lifesaving clotting factor, which at that time was made from the pooled blood of tens of thousands of donors. Before a test was developed to detect HIV in blood, about half the hemophiliacs in the United States died of AIDS from infected clotting factor.)

“Holbrook had three patients early on with malignancies that he thought would benefit from [checkpoint inhibitors] and could not get access to the drug because they had HIV,” Cheever said. “He was passionate about this study because he was a passionate individual and physician. But he was also influenced by his experience as someone with hemophilia who lost so many peers to HIV.”

Kohrt died in 2016 from complications of hemophilia. He is named as an author of the study.

“He would have predicted these results,” Cheever said.

Getting out the message

The ongoing study is now being conducted at eight sites, each of which includes physician-researchers with expertise in both cancer and HIV. A majority of the early patients were enrolled on the trial through Uldrick’s group at the NCI Intramural Research Program in Bethesda, Maryland.

Uldrick will continue to lead the study after he leaves the NCI to become deputy head of Fred Hutch Global Oncology on Dec. 1.

He and Cheever are hoping that these early results lead to additional studies of checkpoint inhibitors in people with HIV and malignancies, especially those cancers that are more prevalent in people with HIV such as Kaposi sarcoma and cancers caused by another virus, human papillomavirus, such as cervical cancer.

In the meantime, the researchers intend to talk about their findings at multiple scientific communities so that people with HIV and their physicians become aware of the data.

“We’d recommend that patients with HIV and malignancy be considered for this therapy if it’s approved for their particular cancer,” Uldrick said.

New molecule shows promise in HIV vaccine design

Researchers at the University of Maryland and Duke University have designed a novel protein-sugar vaccine candidate that, in an animal model, stimulated an immune response against sugars that form a protective shield around HIV. The molecule could one day become part of a successful HIV vaccine.

“An obstacle to creating an effective HIV vaccine is the difficulty of getting the immune system to generate antibodies against the sugar shield of multiple HIV strains,” said Lai-Xi Wang, a professor of chemistry and biochemistry at UMD. “Our method addresses this problem by designing a vaccine component that mimics a protein-sugar part of this shield.”

Wang and collaborators designed a vaccine candidate using an HIV protein fragment linked to a sugar group. When injected into rabbits, the vaccine candidate stimulated antibody responses against the sugar shield in four different HIV strains. The results were published in the journal Cell Chemical Biology on October 26, 2017.

The protein fragment of the vaccine candidate comes from gp120, a protein that covers HIV like a protective envelope. A sugar shield covers the gp120 envelope, bolstering HIV’s defenses. The rare HIV-infected individuals who can keep the virus at bay without medication typically have antibodies that attack gp120.

Researchers have tried to create an HIV vaccine targeting gp120, but had little success for two reasons. First, the sugar shield on HIV resembles sugars found in the human body and therefore does not stimulate a strong immune response. Second, more than 60 strains of HIV exist and the virus mutates frequently. As a result, antibodies against gp120 from one HIV strain will not protect against other strains or a mutant strain.

To overcome these challenges, Wang and his collaborators focused on a small fragment of gp120 protein that is common among HIV strains. The researchers used a synthetic chemistry method they previously developed to combine the gp120 fragment with a sugar molecule, also shared among HIV strains, to mimic the sugar shield on the HIV envelope.

Next, the researchers injected the protein-sugar vaccine candidate into rabbits and found that the rabbits’ immune systems produced antibodies that physically bound to gp120 found in four dominant strains of HIV in circulation today. Injecting rabbits with a vaccine candidate that contained the protein fragment without the sugar group resulted in antibodies that primarily bound to gp120 from only one HIV strain.

“This result was significant because producing antibodies that directly target the defensive sugar shield is an important step in developing immunity against the target and therefore the first step in developing a truly effective vaccine,” Wang said.

Although the rabbits’ antibodies bound to gp120, they did not prevent live HIV from infecting cells. This result did not surprise Wang, who noted that it usually takes humans up to two years to build immunity against HIV and the animal study only lasted two months.

“We have not hit a home run yet,” Wang noted. “But the ability of the vaccine candidate to raise substantial antibodies against the sugar shield in only two months is encouraging; other studies took up to four years to achieve similar results. This means that our molecule is a relatively strong inducer of the immune response.”

The researchers’ next steps will be to conduct longer-term studies in combination with other vaccine candidates, hone in on what areas of gp120 the antibodies are binding to and determine how they can increase the antibodies’ effectiveness at neutralizing HIV.

Drug targeting technique could aid therapies for immune diseases

A new technique that targets drugs to specific cells could lead to improved therapies for diseases caused by an overactive immune response.

The approach could help people affected by conditions such as arthritis and inflammatory bowel diseases, where the body’s own immune system mistakenly attacks healthy tissues.

Researchers focused on a group of immune cells called macrophages – some of which help the body heal after injury, while others can promote harmful inflammation.

The team at the University of Edinburgh sought to devise a new therapy to remove harmful macrophages while leaving healing cells unaffected

They coupled a drug compound to a carrier molecule that only becomes active in acidic conditions, such as those found inside harmful macrophages.

A fluorescent tag attached to the molecules enabled the team to track the cells affected by the drug.

Lab tests on human macrophages showed the treatment preferentially affected inflammatory macrophages and did not affect healing cells.

Studies with zebrafish, which share features of their immune system with people, found the treatment helped to improve the recovery of tissues after injury.

The team hopes their approach could lead to more effective therapies, with fewer side effects, for the treatment of immune-related diseases.

Their research was published in the journal ACS Central Science.

Dr Marc Vendrell, of the Medical Research Council Centre for Inflammation Research at the University of Edinburgh, who led the study, said: “This is an important step forward in the design of more precise drugs with fewer side effects. In future studies, we want to exploit this technology to improve the treatment of diseases in which macrophages and immune cells are important.”

Immune Cells Produce Wound Healing Factor, Could Lead To New IBD Treatment

Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according to a new research study.

The research team, led by Georgia State University and the University of Michigan, wanted to understand how a wound heals in the intestine because in IBD, which includes Crohn’s disease and ulcerative colitis, damage to the intestinal epithelial barrier allows bacteria in the intestine to go across the barrier and stimulate the body’s immune system. This can lead to excessive inflammation and IBD. Efficient repair of the epithelial barrier is critical for suppressing inflammation and reestablishing intestinal homeostasis.

In this study, the researchers found that a specific population of immune cells called macrophages have the ability to secrete or produce a protective or healing factor known as Interleukin-10 (IL-10), which can interact with receptors on intestinal epithelial cells to promote wound healing. The findings are published in The Journal of Clinical Investigation.

“Understanding how wounds can be healed is believed to be very important and a potential therapeutic avenue for the treatment of inflammatory bowel disease,” said Dr. Tim Denning, associate professor in the Institute for Biomedical Sciences at Georgia State. “In this study, we tried to understand some of the cellular mechanisms that are required for optimal wound healing in the intestine. To do this, we used a cutting-edge system, a colonoscope with biopsy forceps, to create a wound in mice. This is analogous to colonoscopies in humans. This cutting-edge system allowed us to begin to define what cells and factors contribute to wound healing in the mouse model.”

The researchers used a small, fiber optic camera and forceps to pinch the mouse’s intestine and take a small biopsy, just as how colonoscopies are done in humans. This small pinch created a wound, which the researchers observed as it healed. The study compared intestinal wound healing in two groups of mice: 1) typical mice (wild type) found in nature and 2) mice genetically deficient in the healing factor IL-10, specifically in macrophages, which impairs their ability to have normal wound repair.

The team also analyzed the effects of IL-10 on epithelial wound closure in vitro using an intestinal epithelial cell line.

They concluded that macrophages are a main source of IL-10 in the wound bed, and IL-10 stimulates in vitro intestinal epithelial wound healing and increases in expression during in vivo intestinal epithelial wound repair. In vitro, exposure to IL-10 increased wound repair within 12 hours and the response was further enhanced after 24 hours.

“Basically, you have a wound, and you have an immune cell that comes in,” Denning said. “That’s the macrophage. The macrophage can produce a factor (IL-10), and that factor can then cause the cells that are around the wound to start closing the wound.”

In addition, the researchers defined some of the signaling pathways that IL-10 uses to orchestrate wound repair. They found IL-10 promotes intestinal epithelial wound repair through the activation of cAMP response element-binding protein (CREB) signaling at the sites of injury, followed by synthesis and secretion of the WNT1-inducible signaling protein 1 (WISP-1).

“The implications are that understanding these cells, the factors and the pathways may offer us the ability to modulate this pathway during inflammatory bowel disease, which could lead to treatment and promote healing and recovery from inflammatory bowel disease,” Denning said. “There are different ways we think about it, but perhaps we could deliver the beneficial compounds (IL-10 and the downstream signaling pathways) to those patients, orally or even intravenously, or somehow drive the natural production of those compounds.”

Modulating T-Cell Metabolism Uncovers New Technology for Enhancing Immunotherapy

T lymphocytes found in tumors and implicated in killing tumor cells cope with the shortage of oxygen and nutrients in the tumor microenvironment by using fat as the main source of energy. Promoting a switch from glucose to fatty acid to generate energy enhances T cell antitumor activity. These findings from a study conducted at The Wistar Institute were published in the journal Cancer Cell.

The presence of tumor infiltrating T lymphocytes (TILs) in solid tumors is often associated with better clinical outcomes and better patient responses to some immunotherapeutic treatments. These cells can be isolated from a cancer patient, manipulated ex vivo, and infused into the same patient to treat her/his own cancer. However, the effectiveness of TILs antitumor responses is limited by their progressive loss of functions. Metabolic stress plays a central role in the exhaustion of T cells as they compete with tumor cells for oxygen and nutrients in the tumor microenvironment. In these unfavorable conditions, the function of TILs is impaired, reducing their potency against the tumor and the efficacy of T cell-based immunotherapy.

“The mechanisms behind TILs exhaustion are poorly understood,” said lead author of the study Hildegund C.J. Ertl, M.D., Caspar Wistar Professor in Vaccine Research and member of Wistar’s Vaccine & Immunotherapy Center. “Considering the central importance of TILs for cancer immunotherapy, we believe that our findings may have critical implications to boost the efficacy of T cell-based therapies.”

This study by Ertl and colleagues shows that low oxygen levels combined with low glucose availability cause TILs to adapt their metabolism and change their source for energy production from glucose to fatty acids, the building blocks of fat. Further inducing this metabolic shift instructs the T cells to increase their use of fatty acids for energy production, thus improving TILs’ effector functions and their ability to delay tumor progression.

The Ertl lab studied the effectiveness of metabolic manipulations to improve TIL functions in two melanoma mouse models and in the context of two different immunotherapy approaches. Ertl and colleagues confirmed the clinical relevance of these observations by showing that T cells isolated from metastases of melanoma patients have increased fatty acid metabolism compared with circulating lymphocytes from healthy donors. Furthermore, using fibrates, a class of FDA approved drugs used to lower cholesterol levels, they promoted the breakdown of fatty acids and observed that this enforced metabolic switch is associated with improved T cell functions within tumors. Importantly, these drugs can also synergize with immune checkpoint blockade therapy, improving the efficacy of this melanoma immunotherapy.

“Pharmacological interventions aimed at promoting the metabolic adaptation of TILs towards fatty acid metabolism may have a broad implication for T cell-based immunotherapy for different cancer types,” added Ertl.

Cell Surface Protein May Offer Big Target in Treating High-Risk Childhood Cancers

Oncology researchers studying high-risk children’s cancers have identified a protein that offers a likely target for immunotherapy–harnessing the immune system in medical treatments. In cell cultures and animal models, a potent drug attached to an antibody selectively zeroes in on cancer cells without harming healthy cells.

“We have built a strong foundation for developing a completely new and hopefully much less toxic treatment for neuroblastoma, the most common cancer in infants,” said study supervisor John M. Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP). “Furthermore, our findings may also lend support to the development of other immune-based therapies, such as CAR T-cells, in children with multiple aggressive cancers in addition to neuroblastoma.”

Maris, along with study leader and first author Kristopher R. Bosse, MD, and colleagues published their study today in Cancer Cell, which featured their findings as the cover story.

Neuroblastoma is a cancer of the developing peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen, and is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children. Over decades, CHOP clinicians and researchers have built one of the world’s leading programs in neuroblastoma.

The study team used sophisticated sequencing tools to first discover molecules that are much more commonly found on the surface of neuroblastoma cells than on normal cells. “Our rationale was to identify a cell-surface molecule that an immune-based therapy could target without damaging healthy tissues,” said Bosse. “Using this approach, we identified a protein called glypican-2, or GPC2.” GPC2 is one of a family of glypicans—cell-surface proteins that interact with growth factors and cell surface receptors, influencing many intracellular signaling pathways important in development and cancer.

In addition to GPC2’s presence on neuroblastoma cells, the study team also found that GPC2 is necessary for a neuroblastoma tumor to proliferate. Both of those facts implied that a compound that acted against GPC2 might kill cancer cells, spare healthy cells, and limit the possibility of these tumors developing “immune escape” mechanisms, in which cancer cells resist an immunotherapy by shedding the target. “Given GPC2’s critical role in the growth of neuroblastomas, we hope that tumors will not be able to simply downregulate this protein in order to escape recognition by our immunotherapies that target GPC2,” said Bosse.

After pinpointing GPC2 as a very promising target for therapy, the researchers next worked with their colleagues at the National Cancer Institute to search for a weapon. They developed an antibody-drug conjugate (ADC) called D3-GPC2-PBD, which combined a very specific antibody that recognizes GPC2 with a potent chemotherapy drug that is internalized specifically by cancer cells. The drug payload damages DNA in tumors, while sparing healthy tissues from its toxic effects.

In cell cultures and mouse models of neuroblastoma, the ADC robustly killed neuroblastoma cells with no discernible toxicity to normal cells. “These findings establish that this type of immunotherapy could be potentially safe and effective against neuroblastoma,” said Maris. “Our next steps will be to further evaluate this ADC and also develop other immune-based therapies directed against GPC2. Because other glypicans in addition to GPC2 are overexpressed in other childhood cancers, it may also be possible to apply this approach across various types of high-risk pediatric cancers.”

Wistar scientists develop novel immunotherapy technology for prostate cancer

A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific protein. This is the first application of the new technology, called DNA-encoded monoclonal antibody (DMAb), for cancer immunotherapy. The study was published online in Cancer Immunology, Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Traditional treatments are invasive and can impair the quality of life of patients, underscoring the need for alternative therapeutic strategies, including immunotherapy. One of the immunotherapeutic approaches that has been explored thus far relies on the use of monoclonal antibodies that specifically target a protein present on the surface of prostate cancer cells called prostate specific membrane antigen (PSMA) to elicit an anti-tumor immune response and control the cancer. Although promising, this strategy is limited by the production cost required to make these therapeutic antibodies. Additionally, multiple infusions are often required to achieve efficacy.

Wistar researchers devised a novel DNA-based approach in which an engineered DNA plasmid is constructed and used to deliver the instructions to make the desired anti-PSMA antibody so that the therapy can be generated in the patient’s body in a sustained manner. This research has important implications for the use of DNA-encoded monoclonal antibody technology as a platform for delivering the next generation of immunotherapies for cancer and many human diseases.

“This is an important demonstration of the possibilities opened up for immunotherapy by DMAb technology to direct in vivo production of antibodies of major relevance to human cancer,” said David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. “There is a great need for such new approaches for prostate disease as well as many other cancers. As recent data suggest, PSMA is an important cancer antigen expressed on many human prostate, bladder, renal as well as ovarian cancers, so additional study of the possible benefits of this therapy are important.”

The new technology was tested in mice for the ability to generate antibodies in their blood stream that would target human PSMA as well as target PSMA-positive tumors. Results showed that antibodies were able to bind to the cancer cells and recruited specific immune cells called natural killer cells, resulting in shrinkage of the tumor, significantly improving survival.

“Our data provide proof of concept that DMAb engineered DNA plasmids can be successfully used to target important cancers,” said Kar Muthumani, M.Sc., Ph.D., assistant professor in the Translational Tumor Immunology Program at Wistar, member of the Vaccine & Immunotherapy Center and lead author of the study. “The unique features of our synthetic DNA-based system make it a promising novel approach for cancer therapy, alone or in combination with other treatments.”

Targeting ‘broken’ metabolism in immune cells reduces inflammatory disease

The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune diseases and sepsis.

In a study published this week in the journal Nature Communications, they explain how blocking a single enzyme enabled them to reprogram macrophages – the immune cells which are activated in inflammatory conditions – to calm their activity and reduce inflammation in rats and mice with human-like disease.

At the heart of the research is the Krebs cycle, a complex loop of reactions which cells use to feed on sugar and generate molecules of ATP, the universal energy currency for cells.

In recent years, research has shown that the usual pathway is interrupted in immune cells such as macrophages, leading to a broken Krebs cycle.

“In immune cells that have to fight invaders, the metabolism is diverted from its usual cycle to make compounds that fight microbes,” explained Dr Jacques Behmoaras, from the Department of Medicine at Imperial, who led the research.

Dr Behmoaras added: “What we have found is that there’s an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds. If you block that enzyme, you block that specific branch of their metabolism, and make the cells cause less damage during inflammation.”

Using human macrophages, the researchers found that an enzyme called BCAT1 was pivotal in reprogramming macrophages. When the cells were activated – by exposing them to molecules found on the surface of bacteria – BCAT1 interfered with their usual metabolic pathways, and regulated another enzyme, responsible for producing bacteria-killing chemicals.

They used an experimental compound called ERG240, developed by Ergon Pharmaceuticals, a small biotech company based in the US. ERG240 resembles the amino acid leucine, one of the building blocks of proteins, which is linked together by BCAT1. By flooding the cells with ERG240 they were able to jam up BCAT1 and block its action, so stopping the metabolism being diverted and ‘fixing’ the broken Krebs cycle. What’s more, the compound was shown to work in animal models of inflammation, without toxic side effects.

The team found that when ERG240 was given to mice with symptoms of rheumatoid arthritis, it reduced the inflammation in their joints by more than half while protecting the integrity of their joints. Similarly, in a rat model of severe kidney inflammation, they found that ERG240 improved kidney function by reducing the number of macrophages flooding into the affected tissue to cause inflammation.

Dr Behmoaras states that although the research is still at an early stage, there is potential for treating inflammatory conditions in patients by targeting the metabolic activity in immune cells. The team believes that BCAT1 works together with other key enzymes of the Krebs cycle, which could themselves provide targets for therapy.

However, one of the key challenges in developing a therapy would be in finding the balancing point: calming the immune cells enough such that they reduce inflammation, but enabling them to react to microbial invaders.

“I think this ability to regulate metabolism in cells could have an effect on many human diseases,” said Dr Behmoaras. “Manipulating cell activity in inflammatory diseases where macrophages have a role, could have important therapeutic benefits.

“Our next step is to understand how other enzymes in the cycle are involved, to see if there is any possibility to block them and have similar effects. Understanding the complex metabolic circuits of these immune cells is a huge task. We will need to tackle this before we can manipulate cell activity and influence disease.

“This is a growing field of research with exciting discoveries ahead.”

Trials show unique stem cells a potential asthma treatment

A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

The Monash Biomedicine Discovery Institute (BDI) scientists provided the experimental expertise to test Cynata Therapeutics’ induced pluripotent stem cell-derived mesenchymal stem cells (MSCs) in a model of experimental asthma. Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from adult cells; they have the ability to be differentiated into a variety of tissue types and, in this case, MSCs that can regenerate damaged lung tissue.

Lead researchers Associate Professor Chrishan Samuel and Dr Simon Royce tested the efficacy of the MSCs on three key components of asthma in a preclinical model of chronic allergic airways disease: inflammation; airway remodeling (structural changes that occur in lungs as a result of prolonged inflammation); and airway hyperresponsiveness (the clinical symptom of asthma).

The study, published in the FASEB Journal, found that the MSCs could effectively reduce inflammation, reversed signs of airway remodelling and completely normalised airway/lung fibrosis and airway hyperresponsiveness, particularly when delivered intranasally.

It concluded that they may provide a novel stand-alone therapy or an adjunct therapy for groups of asthma sufferers who do not respond to current (corticosteroid) therapy.

“Most importantly, what we found was you can treat fibrosis (hardening or scarring of the lung) very effectively,” said Associate Professor Samuel, who heads the Monash BDI’s Fibrosis Laboratory.

“When we’ve tested other types of stem cells they haven’t been able to fully reverse scarring and lung dysfunction associated with asthma – we’ve had to combine them with anti-scarring drugs to achieve that. These cells were remarkable on their own as they were able to effectively reverse the scarring that contributes to lung dysfunction and difficulty in breathing,” he said.

One in nine – or around 2.5 million- Australians have asthma.

Further research will be conducted to test the MSCs in combination with, or compared to a clinically-used corticosteroid. Clinical trials using the cells as a novel target for asthma are then envisaged.

Cynata Therapeutics Limited is an Australian clinical-stage stem cell and regenerative medicine company developing therapies based on its proprietary Cymerus™ stem cell technology platform.

Immunotherapy with DNA vaccine shows promise for HPV-related head and neck cancer

A novel vaccine therapy can generate immune responses in patients with head and neck squamous cell carcinoma (HNSCCa), according to researchers at the Abramson Cancer Center of the University of Pennsylvania. The treatment specifically targets human papillomavirus (HPV), which is frequently associated with HNSCCa, to trigger the immune response. Researchers will present the results of their pilot study during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago (Abstract #6073).

HNSCCa is a cancer that develops in the mucous membranes of the mouth, and throat. While smoking and tobacco use are known causes, the number of cases related to HPV infection – a sexually transmitted infection that is so common, the Centers for Disease Control says almost all sexually active adults will contract it at some point in their lifetimes – is on the rise. The CDC now estimates 70 percent of all throat cancers in the United States are HPV-related. Sixty percent are caused by the subtype known as HPV 16/18.

“This is the subtype we target with this new therapy, and we’re the only site in the country to demonstrate immune activation with this DNA based immunotherapeutic vaccine for HPV 16/18 associated head and neck cancer,” said the study’s lead author Charu Aggarwal, MD, MPH, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The vaccine is delivered as an injection of antigens – which leads the immune system to start producing antibodies and activate immune cells. At the time of injection, physicians use a special device to deliver a pulse of electricity to the area, which stimulates the muscles and speeds the intake of the antigens. Aggarwal noted that this study represents a multidisciplinary approach involving the lab and the clinic.

“This is truly bench-to-bedside and shows the value of translational medicine within an academic medical center,” Aggarwal said.

Penn researchers treated 22 patients with the vaccine. All of the patients had already received therapy that was intended to be curative – either surgery or chemotherapy and radiation. When doctors followed up an average of 16 months later, 18 of those patients showed elevated T cell activity that was specific to HPV 16/18. All of the patients in the study are still alive, and none reported any serious side effects.

“The data show the therapy is targeted and specific, but also safe and well-tolerated,” Aggarwal said.

Because of the positive activity, Aggarwal says the next step is to try this therapy in patients with metastatic disease. A multi-site trial will open soon that combines the vaccine with PD-L1 inhibitors, which target a protein that weakens the body’s immune response by suppressing T-cell production.

Researchers Develop Mouse That Could Provide Advance Warning of Next Flu Pandemic

Researchers in Germany have developed a transgenic mouse that could help scientists identify new influenza virus strains with the potential to cause a global pandemic. The mouse is described in a study, “In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein,” that will be published April 10 in The Journal of Experimental Medicine.

Influenza A viruses can cause devastating pandemics when they are transmitted to humans from pigs, birds, or other animal species. To cross the species barrier and establish themselves in the human population, influenza strains must acquire mutations that allow them to evade components of the human immune system, including, perhaps, the innate immune protein MxA. This protein can protect cultured human cells from avian influenza viruses but is ineffective against strains that have acquired the ability to infect humans.

To investigate whether MxA provides a similar barrier to cross-species infection in vivo, Peter Staeheli and colleagues at the Institute of Virology, Medical Center University of Freiburg, created transgenic mice that express human, rather than mouse, MxA. Similar to the results obtained with cultured human cells, the transgenic mice were resistant to avian influenza viruses but susceptible to flu viruses of human origin.

MxA is thought to target influenza A by binding to the nucleoprotein that encapsulates the virus’ genome, and mutations in this nucleoprotein have been linked to the virus’ ability to infect human cells. Staeheli and colleagues found that an avian influenza virus engineered to contain these mutations was able to infect and cause disease in the transgenic mice expressing human MxA.

MxA is therefore a barrier against cross-species influenza A infection, but one that the virus can evade through a few mutations in its nucleoprotein. Staeheli and colleagues think that their transgenic mice could help monitor the potential dangers of emerging viral strains. “Our MxA-transgenic mouse can readily distinguish between MxA-sensitive influenza virus strains and virus strains that can evade MxA restriction and, consequently, possess a high pandemic potential in humans,” Staeheli says. “Such analyses could complement current risk assessment strategies of emerging influenza viruses, including viral genome sequencing and screening for alterations in known viral virulence genes.”

Progesterone Promotes Healing In The Lung After A Bout Of Flu

Over 100 million women are on hormonal contraceptives. All of them contain some form of progesterone, either alone or in combination with estrogen. A study published on Sept. 15th in PLOS Pathogens reports that treatment with progesterone protects female mice against the consequences of influenza infection by reducing inflammation and improving pulmonary function, primarily through upregulation of amphiregulin in lung cells.

Progesterone signals through progesterone receptors present on many immune cells (e.g., NK cells, macrophages, dendritic cells, and T cells) and other cells throughout the body. In general, progesterone appears to dampen immune responses and reduce inflammation. Although the immunomodulatory effects of progesterone-based contraception have been studied in the context of sexually transmitted diseases such as HIV and herpes simplex virus, the potential impact of progesterone on viral infections outside of the reproductive tract has not received much attention.

In the present study, Sabra Klein, from Johns Hopkins University in Baltimore, USA, and colleagues examined whether levels of progesterone that mimic physiological concentrations present after ovulation (and equivalent to levels used in contraceptives) influence the host response to influenza infection. The researchers studied female mice whose ovaries had been removed and whose progesterone was supplied by implanted pellets that kept hormone levels constant.

When female mice were challenged with influenza virus, the researchers found that the exogenous progesterone was able to protect females from the consequences of influenza infection to some extent. Progesterone did not reduce the level of virus present in the mice, but decreased the amount of inflammation and tissue damage in the lungs and promoted faster recovery from the infection.

Consistent with this, the researchers found that progesterone treatment was associated with elevated levels of immune cells called T helper 17 (Th17) cells, which are known to be involved in maintaining mucosal barriers and pathogen clearance at mucosal cell surfaces. Progesterone also increased the levels of a protein called amphiregulin (AREG).

When the researchers supplied AREG to progesterone-depleted influenza-infected females, their disease and recovery characteristics resembled those of females on progesterone treatment. This suggests that progesterone exerts its effects through boosting of AREG levels in the lungs. The researchers were able to support this further with data from mice lacking AREG–in these females, progesterone failed to protect against the serious consequences of influenza infection.

To assess the contribution of progesterone treatment to the repair of damaged lung tissue, the researchers studied mouse respiratory cell cultures that had been mechanically injured. Progesterone increased the levels of AREG following injury in these cultures, as well as the speed of the subsequent wound repair.

“Progesterone”, the researchers conclude, “causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells”. Their study illustrates, they say, “that sex hormone exposure, including through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract”.

Molecular Switch Controlling Immune Suppression May Help Turn Up Immunotherapies

Researchers at University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to maximize the effectiveness of anti-cancer immune therapy. The researchers identified a molecular switch that controls immune suppression, opening the possibility to further improving and refining emerging immunotherapies that boost the body’s own abilities to fight diseases ranging from cancer to Alzheimer’s and Crohn’s disease.

The findings are published in the September 19 online issue of Nature.

“Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,” said Judith A. Varner, PhD, professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine. “We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”

When confronted by pathogens, injury or disease, the initial response of the body’s immune system comes in the form of macrophages, a type of white blood cell that express pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat. The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair.

In chronic inflammatory diseases such as Alzheimer’s and Crohn’s, however, macrophages associated with the malignancy continue to produce pro-inflammatory cytokines and other substances that kill or transform normal cells. In cancer, highly abundant microphages express anti-inflammatory cytokines that induce immune suppression, effectively stopping the healing process.

In the Nature paper, Varner and colleagues pinpoint a key, suspected player: an enzyme in macrophages called PI-3 kinase gamma (PI3Ky). In mouse studies, they found that macrophage PI3Ky signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3Ky activated the immune response and significantly suppressed growth of implanted tumors in animal models. It also boosted sensitivity of some tumors to existing anti-cancer drugs and synergized with existing immune therapy to eradicate tumors. Varner and her colleagues at the Moores Cancer Center also identified a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immunotherapy.

“Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body’s own adaptive immune response,” said co-author Ezra Cohen, MD, who heads the cancer immunotherapy program at Moores Cancer Center. “But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors. ”

The Nature paper builds upon other work by Varner and colleagues. In a paper first published online in May in Cancer Discovery, Varner’s team reported that blocking PI3Ky in tumor-associated macrophages stimulated the immune response and inhibited tumor cell invasion, metastasis and fibrotic scarring caused by pancreatic ductal adenocarcinoma (PDAC) in animal models.

In humans, PDAC is the most common malignancy of the pancreas It’s aggressive and difficult to treat. Though only the 12th most common type of cancer in the United States, pancreatic cancer is the fourth most common cause of cancer-related death.

“PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed,” said Megan M. Kaneda, PhD, an assistant project scientist in Varner’s lab and collaborator on all of the papers.

In a December 2015 paper published online in Cancer Discovery, Varner and colleagues described animal studies that revealed how disrupting cross-talk between B cells (another type of immune cell) and tumor-associated macrophages inhibited PDAC growth and improved responsiveness to standard-of-care chemotherapy.

Specifically, that research team, which included scientists in San Francisco, Oregon and Switzerland, reported that inhibiting Bruton tyrosine kinase, an enzyme that plays a crucial role in B cell and macrophage functions, restored T cell-dependent anti-tumor immune response. In other words, it reactivated the natural, adaptive immune response in tested mice.

Flesh-Eating Infections In Rheumatoid Arthritis Patients Spur New Discovery

Rheumatoid arthritis patients taking medications that inhibit interleukin-1beta (IL-1beta), a molecule that stimulates the immune system, are 300 times more likely to experience invasive Group A Streptococcal infections than patients not on the drug, according to University of California San Diego School of Medicine researchers. Their study, published August 19 in Science Immunology, also uncovers a critical new role for IL-1beta as the body’s independent early warning system for bacterial infections.

“The more we know about each step in the body’s immune response to bacterial infections, the better equipped we are to design more personalized, targeted therapies for autoimmune diseases — therapies that are effective, but minimize risk of infection,” said senior author Victor Nizet, MD, professor of pediatrics and pharmacy at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

IL-1beta is a molecule that stimulates an immune response, calling white blood cells to the site of an infection so they can engulf and clear away invading pathogens. The body first produces the molecule in a longer, inactive form that must be cleaved to be activated. The scientific community long believed that only the body itself could cleave and activate IL-1beta, by employing a cellular structure known as the inflammasome. But in experiments using cell cultures and mouse models of infection, Nizet and team found that SpeB, an enzyme secreted by strep bacteria, also cleaves and activates IL-1beta, triggering a protective immune response.

“This finding may explain why some of the more invasive, flesh-eating strep strains have a genetic mutation that blocks SpeB production — it helps them avoid tripping the alarm and setting off an immune response,” said first author Christopher LaRock, PhD, a postdoctoral researcher in Nizet’s lab.

The researchers hypothesize that for less invasive strains, like those that cause strep throat, producing SpeB and activating IL-1beta might be advantageous — the resulting immune response may wipe out competing bacteria and help strep establish a foothold in the body.

While the human immune system can quickly recognize and respond to bacterial infections, sometimes this reaction can go overboard, leading to autoimmune diseases such as rheumatoid arthritis. In this case, a person’s own immune system attacks “self” proteins instead of just foreign invaders.

In their efforts to investigate IL-1beta function, Nizet, LaRock and team analyzed a U.S. Food and Drug Administration (FDA) database on adverse events in rheumatoid patients who took anakinra, a drug that dampens autoimmunity by inhibiting IL-1beta. They found that patients receiving anakinra were more than 300 times more likely to experience invasive, flesh-eating strep infections than patients not taking the drug.

“A likely explanation for this increased risk is that with IL-1beta out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system,” LaRock said.

This finding underscores IL-1beta’s importance as an early warning system that’s triggered not only by the host, but also directly by bacterial enzymes, essentially “taking out the middle man,” Nizet said. The UC San Diego researchers believe this capacity for direct pathogen detection represents IL-1beta’s original role in immunity, going all the way back in evolution to simpler animals, such as fish.

“Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection,” Nizet said, “but just the fact that we now know that this patient population is at higher risk and why means we can take simple steps — such as close monitoring and prophylactic antibiotics — to prevent it from happening. ”

Cancer Research Institute to Honor Three Scientists for Outstanding Contributions to Cancer Immunotherapy Research

The Cancer Research Institute (CRI), a nonprofit organization established in 1953 to advance biomedical research with the goal of developing lifesaving immunotherapies for all forms of cancer, will bestow its highest honors on three scientists who have made fundamental contributions to the fields of immunology and cancer immunology.

CRI will present the 2016 William B. Coley Award for Distinguished Research in Tumor Immunology to Ton N. Schumacher, Ph.D., for his contributions to our understanding of how immune cells identify and target tumor-specific neoantigens, and how this capability can provide anti-tumor immunity. Neoantigens—called so because they are newly formed during cancer development—may represent ideal immunotherapy targets as they are solely expressed on tumor cells. Schumacher was the first to develop a technology for high-throughput analysis of immune cell reactivity to cancer neoantigens, which has allowed researchers to better observe the effects of immunotherapy in patients and has made it possible to develop personalized, patient-specific immunotherapies. With nearly 200 peer-reviewed publications, Schumacher has won numerous awards for his research, including the Meyenburg Cancer Research Award in 2015, Queen Wilhelmina Cancer Research Award in 2014, and the Amsterdam Inventor Award in 2010. He is a senior member of the Department of Immunology of The Netherlands Cancer Institute in Amsterdam, The Netherlands, is a member of the CRI Scientific Advisory Council, and is a CRI-SU2C Cancer Immunology Dream Team grantee.

Receiving the 2016 William B. Coley Award for Distinguished Research in Basic Immunology is Dan R. Littman, M.D., Ph.D., for his definitive work on immune cell differentiation and his contributions to the identification and biology of unique immune cell subsets and their underlying interaction with the microbiome. He discovered the key regulator of Th17 immune cell differentiation, and was the first to identify a bacterial species that induces differentiation of these Th17 cells. A greater understanding of this regulator will allow for the development of novel treatments for cancer as well as inflammatory diseases. Littman is the Helen L. and Martin S. Kimmel Professor of Molecular Immunology, a professor of pathology and microbiology, and a faculty member in the Molecular Pathogenesis program in the Skirball Institute for Biomedical Research at the New York University School of Medicine in New York, NY. He is the recipient of many awards and honors, including the Vilcek Prize in Biomedical Science in 2016 and the New York City Mayor’s Award for Excellence in Science and Technology. Littman is a member of the CRI Scientific Advisory Council and has sponsored 19 CRI postdoctoral fellows since 1990.

CRI will also present the 2016 Frederick W. Alt Award for New Discoveries in Immunology to E. John Wherry, Ph.D. The award honors a former CRI Irvington postdoctoral fellow whose research in academia or industry has had a major impact in the field of immunology. Wherry, who was a CRI Irvington postdoctoral fellow from 2000 to 2003 at Emory University, is currently the professor of microbiology, director of the Institute for Immunology at Perelman School of Medicine, and co-director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania, Philadelphia, PA. His discoveries include insights into how changes in gene expression affect T cell exhaustion, a waning of immune function that occurs in response to chronic viral infection and cancer. Current immunotherapies, such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®), work in part by reversing T cell exhaustion. Wherry is on the Thomson/Reuters Highly Cited Researchers list, and was selected as one of America’s Young Innovators by Smithsonian Magazine in 2007.

The Coley Award winners receive a stipend of $5,000 and a gold medallion bearing the likeness of Dr. William B. Coley. In addition, Littman will present the 2016 William B. Coley Lecture on Monday, September 26, 2016, as part of the CRI-CIMT-EATI-AACR Cancer Immunotherapy Conference, which will be held September 25-28, 2016, at the Sheraton Times Square Hotel and New York Hilton Midtown in New York City.

The award ceremony honoring Drs. Littman, Schumacher, and Wherry will take place at the Cancer Research Institute’s 30th Annual Awards Dinner on Tuesday, September 27, 2016, at The Plaza in New York City.

New Research Studies Identify Potential Cause of and New Treatment for Autoimmune Diseases

The American Autoimmune Related Diseases Association, Inc. (AARDA) is spotlighting two new research studies originally reported in ScienceDaily. The first study advances understanding of a potential cause of autoimmune disease, while the second examines a new treatment approach that could have wide-ranging implications for many autoimmune diseases.

In both cases, AARDA believes the research is promising and additional studies are needed to confirm the findings.

Potential Genetic Trigger of ADs Identified

Researchers at the Hospital for Special Surgery (HSS) in New York City, reporting in the June issue of Arthritis and Rheumatism, have found virus-like elements within the human genome that may be a potential genetic trigger of systemic autoimmune disease.

According to ScienceDaily (June 27, 2016):
“For their study, the HSS researchers hypothesized that the abnormal expression of genetic elements known as LINE-1 ( L1) retroelements might trigger an innate immune response similar to that produced by outside viruses and contribute to an overproduction of interferons.

Interferons are molecules our body produces in the presence of viruses and other pathogens to mobilize the immune system. They’re part of the complex immune response to combat danger. However, if levels of interferon are too high, instead of playing a protective role it can contribute to the development of autoimmune disease.”
The researchers sought to understand why a class of interferon known as type 1 interferon, is excessively produced in patients with SLE and Sjogren’s syndrome.

“Our genomes are packed with sequences derived from viruses that were inserted many thousands of years ago, and these virus-like sequences can move around, causing genetic mutations and contributing to the evolution of our genomes. We hypothesized that they sometimes generate virus-like RNA sequences that can be detected by the immune system,” said Mary K. Crow, MD, physician-in-chief at Hospital for Special Surgery and senior study author.

“Our findings support the hypothesis that L1 retroelements, perhaps along with other virus-derived genomic elements, may contribute to the development of autoimmune disorders characterized by high levels of type 1 interferon,” said Dr. Crow, chair, Department of Medicine, and Benjamin M. Rosen Chair in Immunology and Inflammation Research at HSS. “Although it may not be the only cause, it’s intriguing to think that virus-derived elements in our own genome are either quiet and don’t cause any trouble, or they get stirred up and contribute to disease.”

Commenting on the study, Noel R. Rose, MD, Ph.D., chairman emeritus of AARDA’s Scientific Advisory Board, said the findings, “Iook very much like what I have always called the “adjuvant effect”. All of us are prone to develop some autoimmunity (self-reactive lymphocytes) depending upon our genetics. But we need an extra push — the adjuvant to move from benign autoimmunity to autoimmune disease. Often the adjuvant is supplied by infection or the body’s response to infection. This study suggests that an interferon-like molecule is the adjuvant.”

Promising New AD Treatment in PreClinical Study Reported
A new treatment approach used in a preclinical study may hold promise for a wide array of autoimmune disease. Scientists at the University of Pennsylvania School of Medicine (Penn) have developed “a method for removing the subset of antibody-making cells that produce autoimmune disease without harming the immune system,”

ScienceDaily (June 30, 2016) reports:
“The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients’ T cells. In human trials, researchers remove some of patients’ T cells through a process similar to dialysis and then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells — so that they swiftly destroy their targets.

Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers demonstrated their new technique by successfully treating pemphigus vulgaris, an otherwise fatal autoimmune disease, in a mouse model, without apparent off-target effects which could harm healthy tissue. The results are published in an online First Release paper in Science.

“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology.
Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas.

“Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

AARDA’s Rose said of the study, “What a great example of the ‘Ying-Yang’ synergy between cancer research and research on the autoimmune diseases. Many of the key ideas behind CAR T cells arose from years of fundamental research on autoimmunity. Now a new method of cancer immunotherapy is being applied to treating autoimmune disease.
“You never know where basic research will take you.”

New anti-cancer strategy mobilizes both innate and adaptive immune response

Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount a response to cancer cells. Now, scientists from the RIKEN Center for Integrative Medical Sciences have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form. In the study published in Cancer Research, they found that the vaccine made it possible for killer CD8+T-cells–important players in the immune response against cancer–to enter the tumor microenvironment and target cancerous cells.

According to Shin-ichiro Fujii, leader of the Laboratory for Immunotherapy, who led the study, “Cancer cells have different sensitivities to the innate or adaptive response, so it important to target both in order to eradicate it. We have developed a special type of modified cell, called aAVC, which we found can do this.”

The aAVC cells are not taken from the subject’s own body but are foreign cells. The cells are modified by adding a natural killer t-cell ligand, which permits them to stimulate natural killer T-cells, along with an antigen associated with a cancer. The group found that when these cells are activated, they in turn promote the maturation of dendritic cells, which act as coordinators of the innate and acquired response. Dendritic cells are key because they allow the activation of immune memory, where the body remembers and responds to a threat even years later.

To find whether it worked in actual bodies, they conducted experiments in mice with a virulent form of melanoma that also expresses a model antigen called OVA. Tests in mice showed, moreover, that aggressive tumors could be shrunken by vaccinating the animals with aAVC cells that were programmed to display OVA antigen. Following the treatment, the tumors in the treated animals were smaller and necrotic in the interior–a sign that the tumor was being attacked by the killer CD8+T-cells.

Fujii continues, “We were interesting in finding a mechanism, and were able to understand that the aAVC treatment led to the development of blood vessels in the tumors that expressed a pair of important adhesion molecules, ICAM-1 and VCAM-1, that are not normally expressed in tumors. This allowed the killer CD8+T cells to penetrate into the tumor.”

They also found that in animals that had undergone the treatment, cancer cells injected even a year later were eliminated. “This indicates,” says Fujii, “that we have successfully created an immune memory that remembers the tumor and attacks it even later.”

Looking to the future, Fujii says, “Our therapy with aAVC is promising because typical immunotherapies have to be tailor-made with the patient’s own cells. In our case we use foreign cells, so they can be made with a stable quality. Because we found that our treatment can lead to the maturation of dendritic cells, immunotherapy can move to local treatment to more systemic treatment based on immune memory.”

New International Initiative Will Focus on Immunology Research and Treatments

Immunology – and the idea that many diseases can best be addressed by boosting the body’s own immune response – is one of the hottest areas in medical research and clinical treatment. University of California San Diego School of Medicine and Chiba University School of Medicine in Japan have announced a new collaborative research center to investigate the most promising aspects of immunology, especially the area of mucosal immunology, and to speed development of clinical applications.

The Chiba University-UC San Diego Immunology Initiative and associated research center, to be based at UC San Diego School of Medicine, will be established with a $2 million contribution from Chiba University, the funding allocated over five years together with support from UC San Diego.

“This agreement reflects our shared interest in furthering scientific understanding of the human immune system, what happens when things go wrong and how best to remedy them,” said David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of the School of Medicine.

“The microbiome has a major impact upon human health, particularly mucosal immune responses that affect virtually every type of disease, from acute and chronic conditions like infection, allergy, asthma, inflammatory bowel disease and arthritis to type 1 diabetes, multiple sclerosis and cancer. Hundreds of millions of people worldwide are affected by immune system dysfunction so the need to find new, effective treatments is incredibly powerful and compelling.”

The effort, which will be co-directed by Peter Ernst, DVM, PhD, professor of pathology at UC San Diego School of Medicine, and Hiroshi Kiyono, DDS, PhD, professor, University of Tokyo and Chiba University, will involve exchanges of faculty, researchers, staff and students. Initial joint projects will focus on medical and veterinary science, vaccine development, allergy, inflammation, infectious diseases, mucosal immunology and the interactions between mucosal immunity and commensal microbiota that promote health.

“This is a collaboration of partners, both with a deep interest in advancing immunology research across disciplines,” said Ernst, who also directs the Center for Veterinary Sciences and Comparative Medicine. “The topics we are grappling with are global in scale. We want to be leaders in both understanding mucosal immunology and in how to use that knowledge to prevent and treat a vast array of diseases such as infectious, allergic and inflammatory diseases. We want to cultivate the next generation of scientists, here, in Japan and around the world.”

Specifically, the agreement outlines creation of multiple affiliated laboratories with principal investigators at Chiba University, UC San Diego and the La Jolla Institute for Allergy and Immunology, which last year formed a multi-year partnership with UC San Diego to boost collaborative basic research of immune system diseases. The Chiba-UC San Diego initiative would also contribute to a new graduate program in immunology.

“Through collaboration and combined resources, we hope to develop new concepts and technologies that ultimately lead to development a preventive vaccine against infectious diseases, allergies and cancers, boosting the body’s ability to block the transmission of agents entering through mucous membranes,” said Takeshi Tokuhisa, MD, PhD, president of Chiba University. “It would be a new approach to next-generation vaccines.”

Temple Scientists Eliminate HIV-1 From Genome of Human T-Cells

a team of researchers in the Lewis Katz School of Medicine at Temple University became the first to successfully eliminate the HIV-1 virus from cultured human cells. Fewer than two years later, the team has made further strides in its research by eliminating the virus from the genome of human T-cells using the specialized gene editing system they designed.

In a new study published in Scientific Reports, the researchers show that the method can both effectively and safely eliminate the virus from the DNA of human cells grown in culture.

How this research differs
In previous work, the team—led by Kamel Khalili, professor and chair of the Department of Neuroscience at Temple—had demonstrated the ability of their technology to snip out HIV-1 DNA from normal human cells. The newest findings used that same technology to snip out the virus from latently and productively infected CD4+ T-cells, which host the virus in persons infected with HIV.

In this round of research, the scientists used blood drawn from actual patients living with HIV. These ex vivo experiments allowed T-cells from patients infected with HIV to be grown in cell culture and treated with the gene editing system. Results showed that the treatment system can eliminate the virus and protect cells against reinfection.

Another major component of the study addressed questions about potential side effects and toxicity. The researchers used the gold standard in genomic assessment known as ultra-deep whole-genome sequencing to analyze the genomes of HIV-1-eradicated cells for mutations in genes outside the region targeted by the process. Their analyses ruled out off-target effects on genes and showed that HIV-1-eradicated cells were growing and functioning normally.

St. Jude Researchers Reveal How Two Types of Immune Cells Can Arise From One

The fates of immune cells can be decided at the initial division of a cell. Researchers at St. Jude Children’s Research Hospital have discovered that the production of daughter cells with different roles in the immune system is driven by the lopsided distribution of the signaling protein c-Myc. Nudging c-Myc in one direction or the other could make vaccines more effective or advance immunotherapies for cancer treatment. The research appears online today in the scientific journal Nature.

Asymmetric cell division generates two types of cells with distinct properties. This type of cell division is essential for producing various cell types and plays an important role in development. Rather than producing two identical daughter cells, the cells undergoing asymmetric division produce daughter cells that are fated for vastly different roles. In the case of activated T cells, researchers knew that one daughter cell became the rapidly dividing effector T cells that launch the immediate attack on infectious agents and other threats. The other daughter cell became the slowly dividing memory T cells that function like sentries to provide long-term protection against recurring threats. Until now, the mechanism underlying the process was unknown.

“Our study shows that the way in which the regulatory protein c-Myc distributes during asymmetric cell division directly influences the fate and roles of activated T cells,” said corresponding author Douglas Green, Ph.D., St. Jude Department of Immunology chair. “We also show how this asymmetry is established and sustained.”

The researchers worked with cells growing in the laboratory and in mice. Scientists showed that during asymmetric cell division of activated T cells, high levels of c-Myc accumulated in one daughter cell. There, c-Myc functioned like a shot of caffeine to launch and sustain the rapid proliferation of effector T cells, including those in mice infected with the influenza virus. In contrast, the daughter cells with low levels of c-Myc functioned like memory T cells, proliferating to mount an immune response a month later when mice were again exposed to the virus.

Researchers also identified the metabolic and signaling pathways that serve as a positive feedback loop to sustain the high levels of c-Myc that effector T-cells require to maintain their identities and function. The scientists showed that disrupting certain components of the system disturbed c-Myc production, which altered the fate of T cells and caused effector T cells to operate like memory T cells.

“Our work suggests that it may be possible to manipulate the immune response by nudging production of c-Myc in one direction or the other,” Green said. “Potentially that could mean more effective vaccines or help to advance T-cell immune therapy for cancer treatment.”

c-Myc is an important transcription factor that regulates expression of a variety of genes and plays a pivotal role in cell growth, differentiation and death via apoptosis (programmed cell death). Excessive or inappropriate production of c-Myc is a hallmark of a wide variety of cancers. Previous research from Green and his colleagues showed that c-Myc also drives metabolic changes following T cell activation. The metabolic reprogramming fuels proliferation of effector T cells. “Activated T cells divide every four to six hours. There is no other cell in adults that can divide that fast, not even cancer cells,” Green explained.

In this study, the researchers observed several metabolic changes that arose from the way c-Myc partitioned in the cell. These metabolic changes help regulate the way the cells divide, proliferate and differentiate. In a series of experiments, researchers showed how manipulating that system could affect T cell fate following asymmetric cell division by modifying production of c-Myc. “While daughter cells of activated T cells seem to have very different fates, we showed their behavior could be altered by manipulating these metabolic and regulatory pathways to increase or decrease c-Myc levels.” Green said.

Asymmetric cell division is an important driver of other fundamental processes in cells, including early embryonic development and the self-renewal of stem cells.

“Similar control mechanisms exist in other cells that divide asymmetrically, including stem cells in the digestive and nervous systems,” he added.