Nanoparticles Reprogram Immune Cells to Fight Cancer

Researchers at Fred Hutchinson Cancer Research Center have developed biodegradable nanoparticles that can be used to genetically program immune cells to recognize and destroy cancer cells — while the immune cells are still inside the body.

In a proof-of-principle study to be published April 17 in Nature Nanotechnology, the team showed that nanoparticle-programmed immune cells, known as T cells, can rapidly clear or slow the progression of leukemia in a mouse model.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Fred Hutch’s Dr. Matthias Stephan, the study’s senior author. “The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Cellular immunotherapies have shown promise in clinical trials, but challenges remain to making them more widely available and to being able to deploy them quickly. At present, it typically takes a couple of weeks to prepare these treatments: the T cells must be removed from the patient and  genetically engineered and grown in special cell processing facilities before they are infused back into the patient. These new nanoparticles could eliminate the need for such expensive and time consuming steps.

Although his T-cell programming method is still several steps away from the clinic, Stephan imagines a future in which nanoparticles transform cell-based immunotherapies — whether for cancer or infectious disease — into an easily administered, off-the-shelf treatment that’s available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis I would want to start treatment right away,” Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

The body as a genetic engineering lab

Stephan created his T-cell homing nanoparticles as a way to bring the power of cellular cancer immunotherapy to more people.

In his method, the laborious, time-consuming T-cell programming steps all take place within the body, creating a potential army of “serial killers” within days.

As reported in the new study, Stephan and his team developed biodegradable nanoparticles that turned T cells into CAR T cells, a particular type of cellular immunotherapy that has delivered promising results against leukemia in clinical trials.

The researchers designed the nanoparticles to carry genes that encode for chimeric antigen receptors, or CARs, that target and eliminate cancer. They also tagged the nanoparticles with molecules that make them stick like burrs to T cells, which engulf the nanoparticles. The cell’s internal traffic system then directs the nanoparticle to the nucleus, and it dissolves.

The study provides proof-of-principle that the nanoparticles can educate the immune system to target cancer cells. Stephan and his team designed the new CAR genes to integrate into chromosomes housed in the nucleus, making it possible for T cells to begin decoding the new genes and producing CARs within just one or two days.

Once the team determined that their CAR-carrying nanoparticles reprogrammed a noticeable percent of T cells, they tested their efficacy. Using a preclinical mouse model of leukemia, Stephan and his colleagues compared their nanoparticle-programming strategy against chemotherapy followed by an infusion of T cells programmed in the lab to express CARs, which mimics current CAR-T-cell therapy.

The nanoparticle-programmed CAR-T cells held their own against the infused CAR-T cells. Treatment with nanoparticles or infused CAR-T cells improved survival 58 days on average, up from a median survival of about two weeks.

The study was funded by Fred Hutch’s Immunotherapy Initiative, the Leukemia & Lymphoma Society, the Phi Beta Psi Sorority, the National Science Foundation and the National Cancer Institute.

Next steps and other applications

Stephan’s nanoparticles still have to clear several hurdles before they get close to human trials. He’s pursuing new strategies to make the gene-delivery-and-expression system safe in people and working with companies that have the capacity to produce clinical-grade nanoparticles. Additionally, Stephan has turned his sights to treating solid tumors and is collaborating to this end with several research groups at Fred Hutch.

And, he said, immunotherapy may be just the beginning. In theory, nanoparticles could be modified to serve the needs of patients whose immune systems need a boost, but who cannot wait for several months for a conventional vaccine to kick in.

“We hope that this can be used for infectious diseases like hepatitis or HIV,” Stephan said.  This method may be a way to “provide patients with receptors they don’t have in their own body,” he explained.  “You just need a tiny number of programmed T cells to protect against a virus.”

Patients with Lung Cancers Responsive to Immunotherapy Drug Beat Standard Odds of Survival

More than seven years after the start of one of the first clinical trials of the immunotherapy drug nivolumab, researchers at the Johns Hopkins Kimmel Cancer Center report that the five-year survival estimate for a limited subset of people with advanced nonsmall cell lung cancer taking the drug is 16 percent, compared with a historical survival rate for that group of 1 to 4 percent.

A summary of the trial data, gleaned from follow-up information gathered on a total of 129 patients since it began in 2010, is scheduled for presentation April 3 at the American Association for Cancer Research Annual Meeting 2017 (abstract #CT077).

According to results of the data analysis of the 129 patients with advanced nonsmall cell lung cancer treated at more than 11 hospitals nationwide, including The Johns Hopkins Hospital, 16 survived at least 58 months (nearly five years). Twelve of the 16 received no further therapy and showed no evidence of worsening disease at the time the data were analyzed in November 2016. The other four received further chemotherapy or joined other clinical trials. Nine of the 16 are male.

“A small subset of nonsmall cell lung cancer patients appear to respond to nivolumab and have beaten the odds that most patients with this cancer face,” says Julie Brahmer, M.D., program leader at the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and director of the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview Medical Center campus. “Now, we need to figure out how to make more patients responsive to immunotherapy by exploring combinations of immunotherapy drugs and other treatment agents.”

“It’s clear that the patients who beat the survival odds are in some ways truly unique biologically, and the goal now is to discover exactly how immunotherapy is keeping their disease in check,” says Brahmer.

Applying their analysis more broadly, Brahmer and her colleagues estimate that 16 percent of patients with nonsmall cell lung cancer who receive nivolumab will survive beyond five years.

Thus far, Brahmer and the team of physicians who conducted the trial have not been able to identify specific genes or proteins shared by the 16 patients that could be linked to long-term survival.

Typically, says Brahmer, only 1 to 4 percent of patients with advanced nonsmall cell lung cancer survive five years, a form of lung cancer that strikes an estimated 222,500 Americans each year and accounts for 85 percent of all lung cancers in the United States.

Apart from nivolumab, which was approved by the U.S. Food and Drug Administration for lung cancer therapy in 2015 based on research led by Brahmer, standard treatments include various types of chemotherapy.

b Patients in the study received nivolumab once every two weeks for up to two “years. Brahmer says that defining which patients need continued therapy and which don’t not only would get the best treatments to each patient more quickly, but also present an opportunity for cost savings for patients who won’t benefit from the expensive drug, which can cost more than $100,000 per year.

Brahmer cautions that the study’s value is limited by the fact that patients who received nivolumab were not directly compared with patients who did not receive the drug.

Cytotoxins Contribute to Virulence of Deadly Epidemic Bacterial Infections

Beginning in the mid-1980s, an epidemic of severe invasive infections caused by Streptococcus pyogenes (S. pyogenes), also known as group A streptococcus (GAS), occurred in the United States, Europe, and elsewhere. The general public became much more aware of these serious and sometimes fatal infections, commonly known as the “flesh-eating disease.” Potent cytotoxins produced by this human pathogen contribute to the infection. A new study in The American Journal of Pathology reports that the bacteria’s full virulence is dependent on the presence of two specific cytotoxins, NADase (SPN) and streptolysin O (SLO).

Bacteria produce cytotoxins that can cause cell death and result in infections of the deep fascia and other tissues, including necrotizing fasciitis. “Our research revealed that the most severe form of the disease requires two cytotoxins. If either one or both are missing, the infection is much less dangerous,” explained lead investigator James M. Musser, MD, PhD, chairman of the Department of Pathology and Genomic Medicine at Houston Methodist Research Institute (Houston, TX).

To evaluate how the toxins SPN and SLO act together, investigators used mice infected with genetically altered S. pyogenes strains that produced either, both, or neither of the toxins. They found that mutant strains lacking either SPN or SLO or both do not cause the most severe forms of necrotizing fasciitis, necrotizing myositis, bacteremia, and other soft tissue infections. Production of both toxins was required for full infection virulence.

Resistance to bacterial infections depends in part on innate immunity conferred by white blood cells, including polymorphonuclear leukocytes (primarily neutrophils). The researchers found evidence that infections with SPN- and SLO-deficient S. pyogenes could be controlled better because they were less likely to resist the bactericidal effects of human polymorphonuclear leukocytes.

According to the Centers for Disease Control and Prevention, approximately 700 to 1,100 cases of necrotizing fasciitis caused by group A streptococcus have occurred yearly since 2010. Although the disease primarily affects the young and old and those with underlying chronic conditions, it may also develop in healthy individuals. Transmission occurs person-to-person, many times through a break in the skin.

“We do not have a Group A strep vaccine that works right now,” commented Dr. Musser. “The information we gained from this research may help to develop more effective therapeutics, such as inhibitors of these two toxins, or even a vaccine.”

Immune Responses Against a Virus-Related Skin Cancer Suggest Ways to Improve Immunotherapy

Researchers at Seattle’s Fred Hutchinson Cancer Research Center and the University of Washington say a new study suggests ways to improve immune therapy for certain cancers including a virus-associated form of Merkel cell carcinoma, a rare, aggressive skin cancer.

Merkel cell carcinoma, or MCC, is 35 times less common than melanoma, but on average, it is about three times more likely to be deadly. There are currently no therapies approved by the Food and Drug Administration for this cancer. About 80 percent of the 2,000 new cases diagnosed in the U.S. each year are caused in part by a virus – Merkel cell polyomavirus – that is often present on normal skin without consequence.

Previous studies have linked a weaker immune system with poorer survival in patients with the disease. In this study, researchers at UW and Fred Hutch, a leading center developing experimental, genetically engineered T-cell therapies, conducted an unprecedented in-depth analysis of the immune system’s “killer” (CD8) T cells that respond to a specific part of the Merkel cell polyomavirus.

The immune system’s effectiveness is determined by many factors, including how well T cells can infiltrate a tumor and bind to the “foreign” proteins, or antigens. More specifically, T cells seek out and attach to antigens using their highly diverse T-cell receptors. In this multicenter study, the researchers focused on T cells that target a piece of the virus referred to as “KLL”.

“We found that a surprisingly low number of patients – only about 20 percent – had T cells specific for the ‘KLL’ region of the virus. This suggests that about 80 percent of patients aren’t making T cells that recognize this very prominent target,” said Dr. Paul Nghiem, affiliate investigator of the Clinical Research Division at Fred Hutch, and professor of medicine, Division of Dermatology at the University of Washington School of Medicine.

Nghiem, senior author of an article published online Jan. 16 in Cancer Immunology Research, said the study is important because an increase in the KLL-specific T cells infiltrating the tumor is associated with a striking improvement in patient survival.

First author Natalie Miller, an MD/PhD student in Nghiem’s research lab, performed in-depth analysis on blood and tumors from 12 patients who had T cells that could recognize KLL.

“T cells that recognize this part of the virus are incredibly diverse. In fact, among these 12 patients, there were 397 unique ways for the T cells to recognize this single short piece of the virus; only one T-cell receptor was shared between two patients,” Miller said. “In addition, T cells from patients with better outcomes tended to stick to the viral target more tightly. This suggests that while nature has created many ways for the immune system to fight this cancer, some ways are better than others. Our hope is that these ‘better’ T-cell receptors can be turned into a therapy for patients who do not have them.”

At diagnosis, virus-associated MCC is typically treated with surgery and radiation, and although 95 percent of patients appear to be cancer-free, the disease returns in about half of cases, Nghiem said. The cancer often responds to chemotherapy, but the response is short-lived, with most tumors progressing about three months after treatment begins.

In April, Nghiem’s group published findings of a phase 2 clinical trial of the immunotherapy drug pembrolizumab, reporting that the “checkpoint inhibitor” helped to revive “exhausted” T cells, providing significant and lasting responses in more than half of patients.

With their new findings, the research team expects to propose the launch of a clinical trial in which T cells engineered with the most effective tumor tracking and attacking receptors would be transferred to patients who are unable to mount an effective immune response of their own.

“Like Merkel cell carcinoma, cancers that have a viral component provide a variety of potential targets for immunotherapy. We’re eager to find out if transgenic T cell therapy can ‘reprogram’ lymphocytes to eliminate tumors in combination with checkpoint inhibition,” Nghiem said.

The study was supported by grants from the National Institutes of Health and other sources including the Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award, ARCS Fellowship, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund, and the Deutsche Forschungsgemeinschaft (SFB TR36).

Nghiem, corresponding author, is a leading expert on MCC and a pioneer of immunotherapy for the disease. His research has shed light on the importance of the immune response to Merkel cell polyomavirus. A practicing physician, he treats patients with MCC and other skin cancers at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. He is a consultant for EMD Serono Inc. and receives funding from Bristol-Myers Squibb to perform biomarker studies in MCC clinical trials.

New Study Highlights Role for Immune Cells in Cancer’s Ability to Evade Immunotherapy

One of the main reasons cancer remains difficult to treat is that cancer cells have developed a multitude of mechanisms that allow them to evade destruction by the immune system. One of these escape mechanisms involves a type of immune cell called myeloid-derived suppressor cells (MDSCs). A recent study led by Sharon Evans, PhD, Professor of Oncology and Immunology at Roswell Park Cancer Institute, provides new insight into how MDSCs enable tumor cells to circumvent immune attack and offer the potential for improving cancer immunotherapy. The research has been published today in the journal eLife.

Tumor cells cause extensive expansion of MDSCs, which are associated with poor prognosis in patients with various types of cancer. Dr. Evans and colleagues used a state-of-the-art microscopy system to visualize T lymphocytes, the professional killers of cancer cells within the arsenal of the immune system. They discovered that MDSCs can blunt the immune reaction to cancer by preventing the ability of T lymphocytes to enter lymph nodes, important sites where the immune response to invading cancers becomes ramped up. MDSCs accomplish this by removing a molecule known as L-selectin from the surface of T lymphocytes that is essential for cellular trafficking into lymph nodes. As a result, the protective immune response to cancer is severely compromised.

Given the rapid movement of cells within the circulation, one of the most surprising findings of this investigation was that MDSCs can act directly on T cells within fast-flowing blood to limit their widespread trafficking to lymph nodes. This subversive activity of MDSCs was not restricted only to T lymphocytes but included B lymphocytes, which are responsible for generating protective antibodies against tumor cells. The team’s research established for the first time that B lymphocytes are also a target of MDSCs in cancer.

“This investigation could lead to the identification of novel therapeutic targets that bolster the body’s protective mechanisms against the development of metastatic disease,” says Dr. Evans, senior author of the new study. “These new insights may allow us to address a pressing challenge faced by physicians: how to determine which cancer patients are most likely to benefit from T lymphocyte-based immune-therapeutics.”

“Because these immune-suppressive myeloid cells were found to act at long distances to prevent the activation of the T lymphocyte response to tumors, this research reinforces the important message that routine profiling of the cellular constituents within tissues does not always provide the whole picture in cancer,” adds the paper’s first author, Amy Ku, MD/PhD student in the Department of Immunology at Roswell Park.

UH Seidman Cancer Center Expert Presents Novel Triple-Negative Breast Cancer Immunotherapy Trial at 2016 San Antonio Breast Cancer Symposium

Meeting focuses on state-of-the-art breast cancer research, including immunotherapeutic approaches

A researcher from University Hospitals Seidman Cancer Center discussed his upcoming immunotherapy clinical trial for triple-negative breast cancer at the 2016 San Antonio Breast Cancer Symposium. The annual symposium is the premier meeting for more than 7,500 physicians and scientists dedicated to breast cancer treatment, featuring state-of-the-art breast cancer research such as experimental biology, etiology, prevention, diagnosis, and therapy of both breast cancer and premalignant breast disease.

Joseph Baar, MD, PhD, Director of Breast Cancer Research at UH Seidman Cancer Center and Associate Professor at Case Western Reserve University School of Medicine, shared details about a phase II clinical trial testing the effectiveness of combining the chemotherapy drugs carboplatin and nab-paclitaxel with an immunotherapeutic agent called pembrolizumab (Keytruda) for use in patients with metastatic triple-negative breast cancer. Dr. Baar’s poster presentation was part of the Ongoing Trials-Targeted Therapy session on Dec. 8, 2016.

“Up until now, women with triple-negative breast cancer have only had one treatment option, which is chemotherapy. However, more recently, we’ve seen that the immune modulator pembrolizumab improves outcomes in patients with metastatic triple-negative breast cancer,” said Dr. Baar. “As a result, it is now critical to explore how the addition of pembrolizumab to chemotherapy might improve survival in patients with this type of breast cancer.”

Triple-negative breast cancer is a highly aggressive form which comprises 10-15 percent of newly diagnosed early-stage breast cancer. Most triple-negative tumors are high grade and have a high incidence of recurrence and metastases (spreading to other organs). Unlike other types of breast cancer, there is no standard follow-up treatment for triple-negative breast cancer to prevent recurrence.

As triple-negative breast cancer progresses, tumor cells express a protein ligand called PD-L1, which interacts with the PD-1 receptor on T-cells. T-cells are the immune system’s primary mechanism for fighting back against harmful foreign invaders. The PD-L1 to PD-1 interaction prevents the T-cell from responding to the tumor as a threat. Pembrolizumab binds to the T-cell’s PD-1 receptors and therefore blocks the PD-1 to PD-L1 interaction, allowing the T-cells to be activated against the tumor cells. The research team hypothesizes that the addition of such an immunotherapeutic agent to chemotherapy will allow the body’s natural immune response to reduce disease recurrence to a greater extent than either modality alone.

This is the first phase II trial to study the effectiveness of combining these two chemotherapeutic agents with the immunotherapeutic agent pembrolizumab for this type of cancer.

The trial will enroll approximately 30 patients beginning in early 2017. Eligible patients must have radiologically measurable and documented metastatic triple negative breast cancer, be mostly functional day to day as measured by an ECOG performance status of between zero and one, must not have received more than two prior therapies for this disease, and must be willing to undergo a preliminary biopsy for research purposes. The trial is sponsored by Merck, which produces pembrolizumab as Keytruda.

“Trials our faculty members present at SABCS and other research meetings around the world illustrate the remarkable advances in oncology taking place today,” says Neal J. Meropol, MD, Chief, Division of Hematology and Oncology, University Hospitals Seidman Cancer Center and Associate Director for Clinical Research, Case Comprehensive Cancer Center at Case Western Reserve.

The symposium, which began Dec. 6 and continues until Dec. 10, 2016, is hosted by The Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and Baylor College of Medicine.

Combination Immune Therapy Shows Promise Against Hodgkin Lymphoma

The combination of two new drugs that harness the body’s immune system is safe and effective, destroying most cancer cells in 64 percent of patients with recurrent Hodgkin lymphoma, according to the results of an early-phase study.

Presented Dec. 5 at the annual meeting of the American Society of Hematology in San Diego, the study in 19 patients found that the combination of brentuximab vedotin (marketed as Adcentris) and nivolumab (Opdivo) decreased tumor size or spread (achieved remission) to some degree in all patients after three months of treatment.

Researchers say the dual therapy was “generally well tolerated,” with “manageable” side effects, such as itchiness and rash, and that only two patients who experienced inflammation in the lungs were withdrawn from treatment.

The multicenter clinical trial, led by a researcher at the Perlmutter Cancer Center at NYU Langone Medical Center, was conducted in patients for whom initial chemotherapy or stem cell transplantation had failed to stop cancer cell growth. The research team says its latest results extend work presented at the same meeting in 2015, which found that a similar combination, with brentuximab vedotin and ipilimumab (Yervoy), also was safe and highly active against lymphoma.

“Although our study offers reason for optimism, the results of larger, longer-term studies already underway are needed before combination immunotherapy could become the new standard of care for people whose Hodgkin lymphoma returns after initial treatment,” says study lead investigator and hematologist-oncologist Catherine Diefenbach, MD. The disease, she notes, affects mostly those under age 40, with one in 10 experiencing relapse, leading to some 1,300 deaths per year. Most cases of Hodgkin lymphoma are considered curable if diagnosed and treated early.

“If further testing proves successful, such dual therapies could potentially become an alternative curative regimen for relapsed Hodgkin lymphoma,” says Diefenbach, an assistant professor at NYU Langone and clinical director of lymphoma program services at the Perlmutter Cancer Center.

Diefenbach says the team’s experiments were inspired by her laboratory’s research in 2012, which had found that in patients with Hodgkin lymphoma, the workhorses of the immune system, or circulating T cells, showed signs of immune dysfunction that could make them less likely to be activated.

This led her and her colleagues to test whether drugs that spur the immune system to attack cancer cells, such as “checkpoint inhibitors” like nivolumab and ipilimumab, would work well with targeted chemotherapy with brentuximab vedotin, a drug known as an antibody-drug conjugate.

Like a Trojan horse, researchers say, brentuximab vedotin homes in on CD30, a protein on the surface of some Hodgkin lymphoma cells, and then delivers an attached dose of chemotherapy to destroy the cell. Nivolumab turns off an inhibitory switch, or “checkpoint,” called PD1on T cell surfaces, which is known to prevent the immune system from identifying and attacking tumor cells. (Ipilimumab targets a different checkpoint, called CTLA4.)

Moving forward, Diefenbach says she hopes to apply the concepts from this treatment strategy to other types of non-Hodgkin lymphoma.

New Ovarian Cancer Immunotherapy Study Poses Question: Can Microbiome Influence Treatment Response?

Roswell Park Study with pembrolizumab in untried combination is first ovarian cancer clinical trial to incorporate gut flora analysis

A new clinical study underway at Roswell Park Cancer Institute is the first to test the combination of the immunotherapy pembrolizumab with two other drugs as treatment for recurrent epithelial ovarian cancer, and is also the first ovarian cancer clinical trial to incorporate analysis of patients’ microbiomes — the bacteria present in the human gut and other organs.

This new study, led by Principal Investigator Emese Zsiros, MD, PhD, FACOG, Assistant Professor of Oncology in Roswell Park’s Department of Gynecologic Oncology and Center for Immunotherapy, is a phase II clinical trial that will enroll approximately 40 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and will evaluate the impact of the combination of the PD1-targeting antibody pembrolizumab (Keytruda) with intravenous bevacizumab (Avastin) and oral cyclophosphamide (Cytoxan) on antitumor immune responses and on progression-free survival.

Pembrolizumab has been approved by the U.S. Food and Drug Administration for treatment of advanced melanoma, some metastatic non-small cell lung cancers and recurrent squamous cell head/neck carcinoma, but has only been tested in a small number of ovarian cancer patients, as a single drug and showing modest response. The investigators say a strong scientific rationale supports their hypothesis that the combination of pembrolizumab with two other drugs that have already been approved to treat ovarian cancer — bevacizumab and low-dose oral cyclophosphamide — may have much broader benefit for patients.

“Our biggest hope is that by trying these three drugs in combination, we can significantly extend the lives of patients with recurrent ovarian cancer. We also hope to minimize the side effects associated with chemotherapy drugs, and to markedly improve the quality of our patients’ lives,” says Dr. Zsiros. “We will be looking at potential biomarkers that will tell us who can most benefit from this therapy combination and to better understand how cancer cells and immune cells communicate with one another so that we can design better medications to kill cancer efficiently.“

As part of this study, the clinical team will analyze blood, tumor, stool, vaginal and skin microbiome samples, looking to identify possible associations between these markers with clinical outcomes and tumor response. The study, which is supported by a grant from Merck & Co. Inc., maker of pembrolizumab, will be one of the first to analyze these bacteria to determine possible associations with response to immunotherapeutic agents in patients with cancer.

“We’re looking at how to improve our immune defenses to cancer, but we’re looking at it from a variety of angles,” says Dr. Zsiros. “There’s a whole new area of research suggesting that what’s going on in our gut, our gut flora, has a huge influence on your overall health and happiness, and this study will extend that work into some new directions.”

According to the National Cancer Institute, epithelial ovarian cancer is one of the most common gynecologic malignancies, and is the fifth most frequent cause of cancer death in women.

 

Successfully Treating Genetically Determined Autoimmune Enteritis

Using targeted immunotherapy, doctors have succeeded in curing a type of autoimmune enteritis caused by a recently discovered genetic mutation. This report comes from researchers at the Department of Biomedicine of the University of Basel and University Hospital Basel. Their results raise new possibilities for the management of diarrhea, which is often a side effect of melanoma treatment.

Immunodeficiencies can arise due to gene mutations in immune system proteins. As such mutations rarely occur, these immunodeficiencies often go unrecognized or are detected too late for effective treatment. Currently, there are more than 300 different known genetically determined immunodeficiencies, with new examples being described almost every week.

Prof. Mike Recher’s research group at the Department of Biomedicine of the University of Basel and University Hospital Basel recently discovered a genetic immunodeficiency associated with serious, chronic autoimmune enteritis in an adult patient. Happily, according to the researchers’ report in the Journal of Allergy and Clinical Immunology, they were able not only to describe the new mutation, but also to successfully treat the patient with targeted therapy.

Autoimmune reaction caused by mutation

The patient had a rare mutation in the CTLA-4 protein found on the surface of T-cells. Normally, this protein prevents immune cells from attacking an patient’s own body. However, as it was not functioning adequately due to the mutation, T-cells attacked the patient’s own intestinal cells, causing chronic inflammation. This resulted in the patient suffering from severe diarrhea and weight loss.

These unusual symptoms led the cantonal hospital of Graubünden to refer the patient to the special clinic for immunodeficiency at the University Hospital Basel. Initial immunological investigations suggested a genetically determined dysregulation of the immune system. The new CTLA-4 gene mutation was discovered following subsequent analysis of the entire genome at the University Hospital Zurich. Further investigations showed that the mutation causes reduced CTLA-4 function, which led to increased infiltration of the intestinal mucosa by T-cells and therefore to chronic diarrhea.

Treatment with therapeutic antibodies

Working in close cooperation with University Hospital Basel’s gastroenterology department, the doctors opted for a therapy that uses a new drug from the monoclonal antibody group to prevent the T-cells from penetrating the intestinal mucosa. This drug (vedolizumab) blocks a specific adhesion molecule on the surface of the T-cell and thereby inhibits immune cells from binding themselves to receptors present in the intestine, preventing the T-cells from penetrating the blood vessels in the intestinal tissue. This treatment produced the desired outcome: after three months, the patient’s chronic diarrhea had stopped completely.

Preventing diarrhea in melanoma patients

In some diseases, however, CTLA-4 inhibition can be used therapeutically, as in the treatment of skin cancer (melanoma). The drug Ipilimumab works similarly to the CTLA-4 mutation, meaning that immune system T-cells are no longer properly inhibited and can more efficiently attack the malignant skin cancer cells. One of the side-effects of this therapy is autoimmune intestinal inflammation – analogous to the inflammation that occurs in patients with the CTLA-4 gene mutation. It is possible that melanoma patients, who suffer severe diarrhea due to the inhibition of their CTLA-4 function, will benefit from this new insight, which opens up new therapeutic possibilities for Vedolizumab.

Cooperation between regional hospitals, basic research and university medical departments

This case demonstrates the importance of precise diagnosis of the molecular causes of an illness in enabling targeted, personalized treatment. “In order to expand our knowledge in these areas, doctors in clinics and regional hospitals must be on the alert for unusual disease phenotypes and refer such patients to specialized university hospital clinics for further evaluation,” says study author Mike Recher. “We also need clinical university centers that are closely linked to research laboratories.”

Experimental CAR-T Treatment Halted as Two More Patients Die During Clinical Trials

Juno Therapeutics said Wednesday it has suspended a Phase II clinical trial of a cancer drug after two patients suffered cerebral edema earlier this week, leaving one dead and the other not expected to recover. The company’s ‘Rocket’ trial for B cell acute lymphoblastic leukemia is testing a drug it calls JCAR015.

These drugs work by extracting T cells from patients and then equipping them with chimeric antigen receptors, which then zero in on cancer cells. This first generation of CAR-Ts, which is likely to be eclipsed by early-stage efforts, has been known to trigger harsh side effects.

The cause of death in these patients was cerebral edema, or swelling in the brain. Cerebral edema was the same condition that killed three patients earlier this year and forced the company to stop the trial in this summer. Juno, at that time, had blamed the deadly reaction on one of the chemotherapy drugs that it was using to “precondition,” or prepare the patients for JCAR015. The FDA allowed Juno to restart the trial in short order, however, without the chemo drug, called fludarabine.

Juno said it has notified the Food and Drug Administration of the voluntary hold and is working with the agency and the Data and Safety Monitoring Board to determine next steps. Juno’s trials and plans for its other product candidates are not affected, the company said in a prepared statement.

 

Photo-Bombing Cancer

When Kerstin Stenson, MD, describes the innovative technique she is helping develop to fight cancer, it seems like she’s describing a Tom Clancy military espionage novel.

Stenson is treating patients with photoimmunotherapy, PIT for short, an experimental technique that combines the immune system’s ability to target cancer cells precisely with laser energy’s ability to destroy those cells. Like a high-tech weapon in a Clancy thriller, PIT delivers extremely precise, lethal payloads with minimum collateral damage.

“This treatment is so unique and promising because its cancer cell-killing power is so selective and immediate,” says Stenson, director of Rush University Medical Center’s Head and Neck Cancer Program. “It really is just like a guided missile.”

Cold war spy novels like Clancy’s that celebrate military technology aren’t Stenson’s first fiction choice, but she appreciates their parallels to her work when it comes to developing new weapons to fight an old enemy. Just as a hero needs to defeat the bad guys while also saving the hostages, PIT meets the fundamental challenge in defeating cancer: balancing the ability to destroy cancer cells while limiting the damage to surrounding tissue.

Delivering a payload, aiming a laser, and setting off an explosion

Photoimmunotherapy expands upon an existing therapy called photodynamic therapy, a two-step process that starts with a patient being injected with a specialized drug, called a photosensitizer, that’s designed to accumulate in and near a cancerous tumor. Then doctors beam specific wavelengths of light at the tumor, causing the absorbed photosensitizer to produce a form of oxygen which kills nearby cells.

But in photoimmunotherapy, the photosensitizer is combined with a laboratory-produced antibody — called a monoclonal antibody — that specifically targets and binds with receptors found only on the surface of head and neck cancer cells. Administered intravenously, the photosensitizer/antibody combination — referred to as a “payload drug” — circulates throughout the patient’s body, but only latches onto head and neck cancer cells.

The next day, Stenson affixes tiny, laser-optic fibers near the surface of the tumor. If the tumor is difficult to reach, she threads the fibers through small catheters directly into the tumor. Then the laser light energy is beamed through the fibers, hitting the photosensitizer target. The laser sets off molecular-level explosions that weaken the cancer cell walls, allowing water molecules contained in the surrounding tissue to rush in until cancer cells burst.

“Almost immediately, you can see the tumor start dying. It turns white and melts away,” Stenson says. Because the payload drug remains inert unless activated by a specific wavelength of light that doesn’t damage human tissue, destroying the cancer cells causes almost no damage to surrounding cells. “The drug/dye combination (the monoclonal antibody combined with the photosensitizer) is not toxic until activated by near infrared light, thus is very safe from a systemic perspective,” Stenson explains.

By comparison, patients treated with conventional photodynamic therapy, PIT’s predecessor, must avoid strong sunlight for several months because tiny amounts of photosensitizer that remain in their systems could be activated by the sunlight, causing a severe sunburn.

PIT provides option after other treatments have failed

Stenson is leading a clinical trial that is testing the safety and effectiveness of PIT for patients whose head and neck cancer is not responding to radiation or chemotherapy, or when surgery is not feasible due to a tumor’s hard to access location. “Getting inside the cancer cell means we can get systemic treatment locally more than any other treatment,” she says, adding that PIT is the most exciting and promising therapy she has ever been involved with.

The study is sponsored and funded by Aspyrian Therapeutics, the biotechnology firm that created the monoclonal antibody conjugate, RM-1929, and secured the exclusive license for the technology from the National Cancer Institute, which developed the original photoimmuno therapy technology.

“Photoimmunotherapy is a first-in-class treatment platform designed to provide an option for patients whose head and neck cancer has failed standard of care treatments,” says Merrill Biel, MD PhD, who developed the PIT clinical trial program and recruited Stenson and Rush to be one of the five participant sites in the safety and effectiveness study. “Chemo has not worked, radiation has not worked. Surgery can’t help them.” Rush is the only center in Illinois offering this treatment.

He asked Stenson to participate because of her national reputation in the field of head and neck cancer care. “She is known across the country for developing cutting-edge, innovative and life-saving treatments that advance our field and offer hope to patients who’ve run out of options,” he says. “Her expertise and insight have been a great addition.”

PIT could be treatment for other types of cancers.

Beyond the exciting potential of PIT as a very effective therapy for head and neck cancer, it has great potential for treating other forms of cancer and as a combination therapy with immune-modulation chemotherapy. “We hope that once we prove the safety and effectiveness of this treatment specifically for head and neck cancer, the photosensitizer could be combined with immune stimulating drugs that target other forms of cancer,” Stenson says.

Because PIT therapy seems to work so precisely and quickly, there also may be great potential in combining the approach with surgery. Even when a cancer surgeon successfully removes a cancerous tumor, some cancer cells invariably remain in the surrounding tissue and are a danger to spread, which is why cancer surgery often is followed by chemotherapy. Since surgery makes those areas temporarily accessible, PIT’s one-two punch of light energy-activated targeted therapy might greatly reduce the chance that the cancer redevelops.

LJI Scientists Flip Molecular Switches To Distinguish Closely Related Immune Cell Populations

The cornerstone of genetics is the loss-of-function experiment. In short, this means that to figure out what exactly gene X is doing in a tissue of interest—be it developing brain cells or a pancreatic tumor—you somehow cut out, switch off or otherwise destroy gene X in that tissue and then watch what happens. That genetic litmus test has been applied since before people even knew the chemical DNA is what makes up genes. What has changed radically are the tools used by biologists to inactivate a gene.

Until now, scientists wishing to delete a gene in a model organism like a mouse did it by clipping out stretches of DNA encoding entire genes or very big chunks of them from the animal’s genome. This type of gene “knockout” is what La Jolla Institute for Allergy and Immunology (LJI) investigator Catherine C. Hedrick, Ph.D., used in 2011, when her lab discovered that mice without the gene Nr4a1 lack an anti-inflammatory subtype of white blood cells, nicknamed ‘patrolling monocytes’.

Now, the Hedrick group’s latest study reports a next-generation molecular manipulation aimed at inactivating Nr4a1 in a more precise manner. That study, published in the November 15, 2016, edition of Immunity, reports the loss of the same patrolling monocyte population following inactivation of a molecular switch that turns on Nr4a1. “This new work is exciting, because it shows that we can directly target genes within a specific cell type, which is important for targeted therapies,” says Hedrick, a Professor in the Division of Inflammation Biology.

The Hedrick laboratory’s previous demonstration that patrolling monocytes disappear following global Nr4a1 loss proved that the gene is necessary for development of that cell type. Later, her group reported that cancer cells injected into mice lacking Nr4a1 (therefore lacking patrolling monocytes) underwent unchecked metastasis, supporting the idea that patrolling monocytes play anti-cancer roles. But an important experimental question lingered: could the cancer metastasis seen in Nr4a1 knockout mice have anything to do with potential loss of Nr4a1 in a closely related group of cells called macrophages, which use Nr4a1 to control inflammation?

The new paper answers this question by silencing Nr4a1 only in patrolling monocytes. The Hedrick group accomplished this by applying good old-fashioned biochemistry to isolate stretches of DNA that flank the gene and define the on-switch for monocytes. Scientists call tissue-specific gene regulatory elements like this “enhancers.” They then showed that when activated, that DNA region, which they called “enhancer #2” (E2), was capable of switching on Nr4a1 expression only in patrolling monocytes, and not in related cells like macrophages.

The group proved the specificity of the enhancer by engineering mice whose genomes lacked only the E2 enhancer—not the gene itself—and indeed observed a lack of patrolling monocytes. “Until now, we did not have a way to delete a gene only in monocytes without also deleting it in macrophages,” says Graham Thomas, Ph.D., a postdoc in the Hedrick lab and the study’s first author. “Targeting the enhancer allows us to study particular cell types in a highly specific way,” says Thomas. “Also, eliminating enhancers teaches us what turns these genes on in the first place. That knowledge is essential if we are going to design rational targets to go after these cells.”

To confirm that macrophages throw an entirely different molecular switch to turn on Nr4a1, the group exposed mice missing the monocyte E2 switch to a noxious toxin found in bacterial membranes, as a way of seeing whether macrophages can still mount normal inflammatory responses. Indeed, the macrophage response was entirely normal in E2 mutants, unlike the global Nr4a1 “knockout”, showing that macrophages do not use the genetic E2 switch.

Finally, to make sure that E2 enhancer loss mimicked deletion of the entire gene in monocytes the group revisited a tumor model previously used to test Nr4a1’s anti-cancer effect. To do so, they injected melanoma cells into the bloodstream of normal or E2 mutant mice and monitored lung metastasis. Remarkably, outcomes following loss of the switch mirrored what the group had previously observed when they physically removed the gene itself: the lungs of mutant mice contained many more melanoma cells than did lungs of normal mice. This confirmed that the gene regulatory switch is highly specific to one cell type, monocytes and that tumor cell invasion in the absence of this population had nothing to do with deregulated macrophage activity.

Hedrick also thinks the new findings provide new understanding of just how important DNA enhancer regions can be. “Being able to selectively target specific cell types opens up a new world for understanding how to design therapies to treat disease,” she says.

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.

JCAR014 Clinical Data Published In Science Translational Medicine: Patients With Advanced Lymphoma In Remission After T-Cell Therapy

In a paper published today in Science Translational Medicine, researchers from Fred Hutchinson Cancer Research Center shared data from an early-phase study of patients with advanced non-Hodgkin lymphoma (NHL) who received JCAR014, a Chimeric Antigen Receptor (CAR) T cell treatment, and chemotherapy. CAR T cells are made from a patient’s own immune cells that are then genetically engineered to better identify and kill cancer cells.

The paper reported the results of the first 32 patients in a dose-finding trial of JCAR014 following a round of chemotherapy, called lymphodepletion, designed to create a more favorable environment for the CAR T cells to grow in the patient’s body. Key findings of the study demonstrated the importance of the choice of lymphodepletion regimen and the effects of different doses of CAR T cells. 50 percent of the 18 patients who were evaluable for efficacy after receiving CAR T cells and chemotherapy agents fludarabine and cyclophosphamide (Cy/Flu) had a complete response, which compares favorably to the 8 percent complete response rate in patients who received JCAR014 plus cyclophosphamide-based chemotherapy without fludarabine. As previously reported, dose-limiting toxicities were observed in some patients in this dose-finding study who received the highest CAR T-cell dose. The study continues with the intermediate CAR T-cell dose.

In patients that received Cy/Flu lymphodepletion and the intermediate dose of JCAR014, the data showed a promising early efficacy and side effect profile. Specifically:

• Overall Response rate: 82 percent (9/11)
• Complete Response rate: 64 percent (7/11)
• Severe Cytokine Release Syndrome: 9 percent (1/11)
• Severe neurotoxicity: 18 percent (2/11)

JCAR014’s hallmark is its use of a one-to-one ratio of helper (CD4+) and killer (CD8+) CAR T cells, which join forces to kill tumor cells that produce CD19, a molecule found on the surface of many blood cancer cells, including lymphoma and leukemia. By controlling the mixture of T cells that patients receive, the researchers can see relationships between cell doses and patient outcomes that were previously elusive. The data also suggest that with a defined one-to-one composition of cells, efficacy of treatment is increased, while toxic side effects are minimized.

“With the defined composition treatment, we are able to get more reproducible data about the effects of the cells – both the beneficial impact against the cancer and any side effects to the patient,” said Fred Hutch clinical researcher Dr. Stan Riddell, one of the senior authors of the paper, along with Dr. David Maloney. “We are then able to adjust the dose to improve what we call the therapeutic index – impact against the tumor, with lower toxicity to the patient.”

“This study shows that at the right dose of CAR T cells and lymphodepletion, we can achieve very good response rates for NHL patients who have no other treatment options,” said Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutch and one of the study leaders.

For Juno Therapeutics (NASDAQ: JUNO), these insights from the JCAR014 study are key to its development of JCAR017, a similar product candidate for the treatment of CD19 positive blood cancers. Like JCAR014, JCAR017 uses a one-to-one ratio of helper and killer CAR T cells, and the company believes it has the potential to be a “best-in-class” treatment for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and adult and pediatric acute lymphoblastic leukemia. JCAR017 is currently in a phase I, multi-center study.

“We are encouraged by the efficacy and duration of response that we are seeing with defined composition CAR T treatment in patients with lymphoma and other B-cell malignancies,” said Mark J. Gilbert, Juno’s Chief Medical Officer. “We hope that the insights from JCAR014 will make it possible to bring more life-saving treatments to more patients with blood cancers.”

In addition to Fred Hutch researchers, the study team also included scientists from Juno and the University of Washington. Juno provided one of the trial’s sources of funding, along with the National Institutes of Health, Washington state’s Life Science Discovery Fund and the Bezos Family Foundation.

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.