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NEWS
EMORY UNIVERSITY
15 Sep 2015

The National Institutes of Health has awarded an Emory-led research consortium $15 million over five years for renewal of a grant aimed at better understanding and improving human immune responses to vaccination. The grant builds on the pioneering accomplishments of the research team over the past several years in developing “systems biology” methods to accurately […]

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The National Institutes of Health has awarded an Emory-led research consortium $15 million over five years for renewal of a grant aimed at better understanding and improving human immune responses to vaccination. The grant builds on the pioneering accomplishments of the research team over the past several years in developing “systems biology” methods to accurately predict the efficacy of vaccination in humans, and providing new insights into the molecular mechanisms that drive effective immunity to vaccination.

The grant’s principal investigator is Bali Pulendran, PhD, whose laboratory is widely credited with launching the field of “systems vaccinology.” Pulendran is Charles Howard Candler Professor in the Department of Pathology and Laboratory Medicine, the Emory Vaccine Center and Yerkes National Primate Research Center

Systems vaccinology combines immunology, genomics and bioinformatics to predict the effectiveness of a vaccine without exposing individuals to infection, and offers a means to probe the molecular mechanisms underlying immunity to vaccination. Researchers already have provided proof of concept of this approach through studies of innate and adaptive human immune responses to vaccines including yellow fever, smallpox, seasonal influenza, meningococcal disease and dengue fever.

Co-principal investigator is Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar. The National Institute of Allergy and Infectious Diseases will administer the grant as part of its Human Immunology Project Consortium (HIPC) program. The research team also includes scientists at the Broad Institute; Dana Farber Cancer Institute; Georgia Institute of Technology; University of California, Berkeley; University of Chicago; University of Colorado; University of Sao Paolo, Brazil; and several pharmaceutical firms.

“Although most of our team’s studies thus far have focused on healthy young adults, the renewal grant will allow us to expand the reach of our study to include vaccine responses in populations that are particularly vulnerable to infections: infants, the elderly, and transplant patients,” says Pulendran. “This is a critical need because we know elderly individuals have weaker immune responses overall, and transplant patients have compromised immune responses due to immunosuppressive drug therapy. We want to be able to offer more effective vaccines across the lifespan as well as address myriad health-care concerns,” he continues.

The team will focus on two primary projects: (1) immune response to vaccination against varicella zoster virus (VZV), which causes chicken pox in young children and shingles in adults, and (2) immune response to pneumococcal vaccines in transplant patients.

In the first major project, researchers will study immune responses to vaccination against VZV in children and the elderly with the aim of developing new insights into the immune response at the two extremes of age. VZV vaccination is the standard of care for both infants and the elderly, but Zostavax, the licensed Merck vaccine against VZV, has limited efficacy against shingles, especially in people older than 70.

Recently, the results of a randomized phase 3 trial of Glaxo Smith-Kline’s new investigational recombinant Herpes zoster subunit (HZ/su) vaccine has shown an overall vaccine efficacy of 97.2 percent across age groups, including people over 70 years old. These results represent somewhat of a paradigm shift in vaccinology because the usual barrier of immune senescence to vaccination in the elderly (the gradual deterioration of the immune response) appears to have been overcome. However the mechanisms by which this vaccine induces protective immunity in the elderly remain unexplored, and a major focus of the program by Pulendran and colleagues will be to use systems approaches to delineate such mechanisms.

In addition, the researchers will study immune responses to vaccination against varicella infection (chickenpox) in children. Although the Varivax vaccine (identical to Zostavax but at a lower dose) is highly effective in preventing chickenpox in young children, there is little known about the nature of innate and adaptive immunity to vaccination in children. The new systems approach will include a detailed analysis of the immune response to Varivax in children.

A second major focus will evaluate immune response to pneumococcal vaccines in kidney transplant patients who are on T cell immunosuppression therapy. Pneumococcal diseases are responsible for 1.6 million deaths per year globally, and the rate of invasive pneumococcal disease is 60 times greater in kidney transplant patients than in the general population. Researchers believe their new systems analysis of vaccination against pneumococcal disease in transplant patients on immunosuppressive therapy will yield important new insights that could provide new vaccination guidelines and a broader understanding of the dynamic changes following vaccination in this special population.

“The field of immunology has made tremendous progress over the years, and through this systems biology approach we have been able to dissect responses to vaccination in a much more efficient and insightful way,” says Rafi Ahmed. “We believe that by understanding the details of the response to VZV and pneumococcal vaccines in these vulnerable populations we can have an important impact on health in the United States and globally.”

“Systems biological approaches offer a unique way of probing the molecular mechanisms driving immunity to vaccination in humans, and offer exciting new insights about the workings of our immune system,” notes Pulendran. “This approach has already resulted in new insights into the fundamental mechanisms of immunity, and we are excited about the opportunity to dissect the reasons for differing responses to vaccines in individuals and special populations at the extremes of age. This will help guide clinical trials to evaluate new vaccines and future vaccine recommendations.”

Additional investigators for the consortium include Mark Mulligan, Nadine Rouphael, Evan Anderson and Aneesh Mehta, Emory University, and Myron Levin and Adriana Weinberg, University of Colorado (clinical core); Nick Haining, Dana Farber Cancer Institute and Broad Institute, Shankar Subramaniam, UCSD, Jill Mesirov, UCSD and Broad Institute, Nir Yosef, University of California, Berkeley, and Eva Lee, Georgia Institute of Technology (computational and single cell core); Tianwei Yu, Emory University (data management and statistical core); and Helder Nakaya (University of Sao Paolo) and Shuzhao Li and Dmitri Kazmin, Emory University.

NEWS
CANCER RESEARCH INSTITUTE
06 Apr 2016

Ludwig Cancer Research and the Cancer Research Institute (CRI) have launched a Phase 1/2 clinical trial of combination immunotherapy for advanced ovarian cancer. The international, multicenter trial is led by George Coukos, director of the Ludwig Institute for Cancer Research, Lausanne and Brad Monk, director of Gynecologic Oncology at St. Joseph’s Hospital and Medical Center. […]

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Ludwig Cancer Research and the Cancer Research Institute (CRI) have launched a Phase 1/2 clinical trial of combination immunotherapy for advanced ovarian cancer. The international, multicenter trial is led by George Coukos, director of the Ludwig Institute for Cancer Research, Lausanne and Brad Monk, director of Gynecologic Oncology at St. Joseph’s Hospital and Medical Center. The study is being conducted through the CVC Trials Network, which is jointly managed by Ludwig and CRI, in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca, and the biopharmaceutical company VentiRx Pharmaceuticals Inc.

“Ludwig has long supported the design and evaluation of new therapeutic strategies to improve the treatment options available to cancer patients,” said Jonathan Skipper, Ludwig’s executive vice president of Technology Development. “Employing immunotherapies in combination holds great promise in that endeavor. We are proud to be a part of this effort to bring investigational drugs being developed by different commercial partners to a single clinical trial and improve the standard of care for recurrent ovarian cancer, a disease for which patients today have few treatment options.”

The open-label trial is evaluating the combination of MedImmune’s investigational antibody cancer drug durvalumab, a PD-L1 inhibitor, and VentiRx’s investigational TLR8 agonist motolimod added to chemotherapy in locally advanced or recurrent ovarian cancers that have become resistant to platinum chemotherapy. Both of the investigational drugs have been found in other studies to have acceptable safety profiles when used alone.

The researchers expect that motolimod’s activation of TLR8 will create conditions within tumors that are optimal to enhancing the effects of durvalumab. Further, when given with chemotherapy, motolimod could boost immune responses against cancer cells that are not engaged by durvalumab by helping the immune system “see” cancer antigens. Since the two immunotherapies work in distinct ways, they could have additive effects, inducing more potent and durable anti-tumor immune responses.

“This study is a good example of what’s possible when researchers have access to new therapies and are permitted to test hypotheses supported by the most recent science,” said Ludwig Lausanne director George Coukos. “We are hopeful that the combined therapies we are testing in this trial will be of great benefit to ovarian cancer and other cancer patients.”

Patients enrolled in the trial will be treated with the chemotherapeutic drug pegylated liposomal doxorubicin (PLD), which is the current standard of care for ovarian cancer after the failure of platinum therapy. They will also receive durvalumab and motolimod, with the Phase 1 and 2 portions of the trial running successively. The primary objective of the Phase 1 cohort of the study is to evaluate the safety and optimal dosage of the combination. The Phase 2 cohort of the trial will measure the efficacy of the treatment by evaluating the number of patients whose tumors have not progressed at six months.

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 expression enables tumours to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumour’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers.

Motolimod binds and activates Toll-like receptor 8 (TLR8), which is found in a variety of immune cells and serves as a key initiator of the innate immune response. Notably, it is expressed by myeloid dendritic cells, which help direct and boost T cell responses against infectious agents and cancers. Motolimod has been shown to be safe when combined with PLD in a previous study on ovarian cancer, with evidence of clinical benefit. The motolimod-PLD combination is currently under evaluation in a large, randomized, placebo-controlled phase 2 clinical study in patients with ovarian cancer.

“This clinical trial is part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs,” said Adam Kolom, managing director of CRI’s Clinical Accelerator, which funds the trials. “All of the studies have, as additional objectives, the collection of genetic and immunologic data derived from clinical samples that are obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.”