Oncolytic virus immunotherapy is currently experiencing a renaissance, with several types of viruses having progressed to advanced efficacy trials. Recent FDA approval of Amgen’s IMLYGIC shows significant potential of this therapeutic approach for treating malignancies that would otherwise be considered untreatable. The mechanism of virotherapy is based on the fact that certain viruses have the ability to enter cancer cells and selectively replicate there. At the same time, the immune response to oncolytic viruses becomes an important component of the antitumor effect. The virotherapy field is rapidly developing and would benefit from the knowledge and opinion exchange of the stakeholders involved. Cambridge Healthtech Institute’s Inaugural Oncolytic Viruses in Cancer Therapy symposium is designed to facilitate the discussion around discovery and development of oncolytic viruses as anticancer drugs, as well as around specific issues in the clinical development of this type of biotherapeutic.
Tuesday, June 14
8:00 am Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
Pedro J. Beltran, Ph.D., Research Director, Oncology Research, Amgen, Inc.
8:30 Synergies of Oncolytic Herpes Virus with Antiangiogenic Agents and Immune Modulators
Robert L. Martuza, M.D., William and Elizabeth Sweet Professor of Neuroscience, Department of Surgery (Neurosurgery), Harvard Medical School, Chief, Neurosurgical Service, Attending Neurosurgeon, Massachusetts General Hospital
In 1991, we described the first genetically-engineered oncolytic herpes simplex virus (oHSV) for the treatment of glioblastoma. In the late 1990s, we demonstrated that viral oncolysis can also elicit an anti-cancer immune response enhanced by viral expression of a cytokine. We will describe out recent studies using armed oHSV, G47∆-IL12, to treat glioblastoma in cancer stem cell-like models and its combination with immune modulators.
9:00 Oncolytic Viral Therapy for Cancer: The Present and the Future
E. Antonio Chiocca, M.D., Harvey W. Cushing Professor of Neurosurgery, Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery, Co-Director, Institute for the Neurosciences, Brigham and Women’s/ Faulkner Hospital, Surgical Director, Center for Neuro-oncology, Dana-Farber Cancer Institute
Targeted therapies for cancers that are highly genetically diverse even within a single neoplasm are unlikely to address all of the pro-oncogenic signaling aberrancies, leading to therapy evasion. Partial initial tumor destruction with an oncolytic virus (OV) is thought to potentially lead to an immune response directed against most if not all of the tumor antigens present within the mass. As this new class of anticancer agents is being used in the clinic, future advances include the engineering of more potent OVs, the combination with other immunotherapies, and modulating the tumor microenvironment to promote more effective dissemination of the OV and of the antitumor immune response.
9:30 Mechanisms of Action of Talimogene Laherparepvec: From Bench to Bedside
Pedro J. Beltran, Ph.D., Research Director, Oncology Research, Amgen, Inc.
Talimogene laherparepvec (T-VEC) is an injectable modified oncolytic herpes simplex virus type-1 (HSV-1) approved for the treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with recurrent melanoma. T-VEC is hypothesized to be efficacious by at least two complimentary mechanisms of action: a) direct oncolysis of the injected tumor that induces local type I interferon and engages innate immunity, and b) elicitation of a systemic anti-tumor immune response that results in T cell infiltration of non-injected lesions and metastases.
10:00 Q&A with Speakers
10:15 Coffee Break
10:45 A Novel Immunostimulatory Oncolytic Virus Targeting Both the Tumor and Its Microenvironment
Angelica Loskog, Professor, IGP, Uppsala University, CEO, Lokon Pharma AB
LOAd703 is a double armed virus that focuses on enhancing immunogenicity and inducing anti-tumor immune responses. Immunotherapy is the new cornerstone of cancer therapy and the merge of immunostimulatory gene therapy with the oncolytic virus field is at focus.
11:15 Oncolytic Immunotherapy in the Age of Immune Checkpoint Blockade
Robert Coffin, Ph.D., CEO & Founder, Replimune
Oncolytic immunotherapy is a new, clinically validated, modality for the treatment of cancer which has substantial anti-tumor efficacy in its own right. This clinical activity, at least in part, likely relies on the induction of a systemic immune response to tumor neo-antigens and an inflamed tumor micro-environment, both of which are also required for the activity of immune checkpoint blockade. Combination of oncolytic immunotherapy with immune checkpoint blockade is therefore particularly attractive for cancer therapy and prior, current and future developments in these areas will be discussed.
11:45 Seprehvir, an Oncolytic Herpes Viroimmunotherapeutic, Enhances Therapeutic Efficacy of T Cell Checkpoint Inhibition in Solid Tumors By Increasing T Cell Recruitment and Remodeling the Immunosuppressive Microenvironment
Chun-Yu Chen, Ph.D., Research Scientist, Center for Childhood Cancer and Blood Diseases in The Research Institute, Nationwide Children’s Hospital
Seprehvir, a clinically active oncolytic immunotherapeutic HSV, has been tested in 98 patients, including 5 completed and 3 ongoing clinical studies. We evaluated the therapeutic benefit by combining PD-1 blockade with Seprehvir in a murine rhabdomyosarcoma model and found that the combination therapy is effective and favors a more immunogenic tumor microenvironment. Our analysis suggests the combination works by increasing CD4+ and CD8+ T cells in tumors without increasing regulatory T cell numbers.
12:15 pm Enjoy Lunch on Your Own
2:00 Chairperson’s Remarks
Khalid Shah, Ph.D., Associate Professor, Harvard Medical School, Director, Molecular Neurotherapy and Imaging Laboratory, Director, Stem
2:10 Enhancing Oncolytic Virus Activity by Engineering of Artificial MicroRNAs
John Bell, Ph.D., Senior Scientist, Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Professor, Departments of Medicine and Biochemistry, Microbiology & Immunology, University of Ottawa
We are carrying out a detailed analysis of the behavior of tumour microenvironment cells during oncolytic virus therapy. In particular, we have shown in both mouse models and samples taken from patients undergoing OV therapy that our viruses can infect and disrupt tumour vasculature.
2:40 Driving Large T Cell Responses with an Oncolytic Virus
Brian D. Lichty, Ph.D., Associate Professor, Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University
Oncolytic viruses are gaining recognition as a form of immunotherapeutic having demonstrated the ability to induce anti-tumoral immunity through an in situ vaccine effect. However, this appears to be an infrequent event, and often of low magnitude. We have devised a strategy to generate very large and potent anti-tumoral immune responses using an oncolytic virus.
3:10 Stem Cell-Based Oncolytic Viruses in Preclinical Models of Cancer: Road to Clinical Translation
Khalid Shah, Ph.D., Associate Professor, Harvard Medical School, Director, Molecular Neurotherapy and Imaging Laboratory, Director, Stem Cell Therapeutics and Imaging Program, Department of Radiology and Neurology, Massachusetts General Hospital
Stem cell-based therapies are emerging as a promising strategy to tackle cancer. In an effort to develop clinically translatable stem cell based therapeutics for cancer, we have recently established primary and metastatic tumor models in the brain and show that engineered human mesenchymal stem cells loaded with oncolytic viruses target both the primary and the metastatic tumor deposits and have profound anti-tumor effects. These studies demonstrate the strength of employing clinically relevant tumor models and engineered stem cells and form the basis for developing novel cell based therapies for cancer.
3:40 Refreshment Break
4:00 Targeting Cancer Stem Cells by Oncolytic Viruses
Faris Farassati, Ph.D, PharmD, Cancer Scientist, Marion and Henry Bloch Foundation Neuro-oncology Researcher, Midwest Biomedical Research Foundation, Kansas City Veteran Affairs Medical Center
According to the recent models for tumor development, a fraction of cells within each tumor play the role of stem cells (i.e. cancer stem cells or CSCs) and are in charge of giving rise to all other kinds of cells needed to maintain tumor integrity. An effective therapy must be able to destroy CSCs. Lack of such feature in our current chemotherapy agents leads to the eventual tumor relapse. There are no pharmacological agents currently available for specific targeting of CSCs. One of the focus areas of Dr. Farassati's team is to develop oncolytic viruses that can target and destroy CSCs, which will be reviewed in this presentation.
4:30 Targeting the Vasculature and Extracellular Matrix Improve the Distribution and Effectiveness of Oncolytic Virus in Tumors
Yves Boucher, Ph.D., Associate Professor, Radiation Oncology, Harvard Medical School
Although nanotherapeutics and oncolytic virus have offered new hope for cancer treatment, their clinical efficacy is modest. This is partly due to intratumoral barriers – like the vasculature, extracellular matrix (e.g. collagen fibers) and cancer cells – which hinder the penetration / distribution of large therapeutics in cancer lesions. Here, I will focus on how the targeting of extracellular matrix – angiotensin II signaling – and vasculature enhance the anti-tumor effectiveness of oncolytic virus.
5:00 Close of Symposium