Gregory K. Friedman, MD Associate Professor Director, Developmental Therapeutics Associate Scientist, O'Neal Comprehensive Cancer Center at UAB Neuro-Oncology Program Division of Pediatric Hematology-Oncology University of Alabama at Birmingham

Modified Cold Sore Virus Tested for Resistant Brain Cancer in Children

MedicalResearch.com Interview with:

Gregory K. Friedman, MD Associate Professor Director, Developmental Therapeutics Associate Scientist, O'Neal Comprehensive Cancer Center at UAB Neuro-Oncology Program Division of Pediatric Hematology-Oncology University of Alabama at Birmingham

Dr. Friedman

Gregory K. Friedman, MD
Associate Professor
Director, Developmental Therapeutics
Associate Scientist, O’Neal Comprehensive Cancer Center at UAB
Neuro-Oncology Program
Division of Pediatric Hematology-Oncology
University of Alabama at Birmingham

MedicalResearch.com: What is the background for this study?

Response: This was a first-in-children trial to test the safety of an immunotherapy using an altered cold-sore virus (herpes virus or HSV-1), G207, infused directly via catheters into progressive or recurrent malignant brain tumors. Due to modifications in G207, the virus does not harm normal cells but can infect and directly kill tumor cells while also stimulating the patient’s own immune system to attack the tumor. We tested G207 at two dose levels alone and when combined with a single low dose of radiation, which was used to increase virus replication and spread throughout the tumor. The research is important because outcomes are very poor for children with progressive malignant brain tumors, and the toxicities caused by current standard therapies are unacceptably high. Therefore, we greatly need effective and less-toxic targeted therapies for children.

MedicalResearch.com: What are the main findings?

Response: There were 3 main findings.

First, the virus was safe at a very high concentration (100 million virus particles) when directly infused into tumors in the brain. Side effects attributable to G207 were mild and infrequent, and there were no serious adverse events related to G207. In addition, the single dose of radiation was also well-tolerated without producing any additional toxicities over virus alone. This is important because children did not experience the degree of toxicities that occur with almost all other types of therapy; and therefore, their quality of life after treatment was not adversely impacted by the therapy.

Secondly, while not the primary objective of the study, we assessed efficacy of the therapy and found evidence of radiographic, neuropathologic and clinical responses to the therapy. The overall survival of patients that received G207 was seemingly longer than what we expect for children with progressive high-grade glioma. Historically, the median overall survival at initial progression for children treated with a variety of other therapies is only 5.6 months. The median overall survival for children that received a single dose of G207 was 12.2 months, which represents a 120% increase. While the results are promising, they will need to be confirmed in a Phase 2 trial.

The third significant finding was a striking infiltration of immune-related cells into the tumors. Classically, pediatric high-grade gliomas are immunologically ‘cold’ or silent, which means they have very few infiltrating immune cells or lymphocytes. Cold tumors are unresponsive to immunotherapies because tumor-infiltrating lymphocytes are necessary for an immune attack on the tumor. When we examined matched pre- and post-G207 tumor tissue from four patients, we discovered that the tumors had changed from immunologically ‘cold’ to ‘hot’. There was a dramatic increase in tumor-infiltrating lymphocytes between 2-9 months after G207 infusion. This change from ‘cold’ to ‘hot’ represents a critical step in the development of an effective immunotherapy for pediatric high-grade glioma.

MedicalResearch.com: What should readers take away from your report?

Response: Our findings suggest that oncolytic immunovirotherapy using a modified cold-sore virus is a safe and potentially efficacious approach to target pediatric high-grade glioma. Furthermore, our findings indicate that we can turn immunologically ‘cold’ pediatric brain tumors to ‘hot’, which is a critical step in the development of an effective immunotherapy for children with brain tumors.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Our next step is to confirm the safety and efficacy of the findings in a larger Phase 2 trial, which we are currently designing with input from the FDA and Pediatric Brain Tumor Consortium. We anticipate that the study will open later this year. We also have an ongoing first-in-human trial to assess the safety and effectiveness of G207 in recurrent pediatric malignant tumors, like medulloblastoma, that arise in the back of the brain or cerebellum. Our preclinical data suggests that these tumors may be even more sensitive to oncolytic G207 than the cerebral tumors treated in this trial.

Furthermore, the company that supplies the virus for the trials is currently working to produce more virus for future trials. We plan to test the therapy in children with newly diagnosed high-grade glioma because we believe that patients will be even more likely to respond to the therapy prior to receiving chemotherapy, which can suppress their ability to mount an immune response. Also, we intend to determine if we can improve outcomes for these children by giving multiple injections of G207 every 4-8 weeks. Lastly, we are developing and testing combination therapies with G207 in the lab with the goal of maximizing the immune response against the tumor, and we will advance the most promising combinations to clinical trials in children with brain tumors and other solid tumors outside the brain.

MedicalResearch.com: Is there anything else you would like to add?

Response: This was a Phase I trial in a limited number of children. Therefore, the findings of safety and efficacy must be confirmed in a Phase 2 trial. Also, the trial was primarily conducted at one pediatric hospital. Even though we were able to add a second site and demonstrate the feasibility of treating a patient at a different hospital, we need to ensure that the findings are reproducible at hospitals across the country. Consequently, the Phase 2 trial will be conducted through a multi-institutional pediatric consortium.

I am supported, in part, by contracts between UAB and Eli Lilly and Co. and Pfizer.

Citation:

Phase I immunovirotherapytrial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma
Gregory K. Friedman, James M. Johnston Jr., Asim K. Bag, Joshua D. Bernstock, Rong Li, Inmaculada Aban, Kara Kachurak, Li Nan, Kyung-Don Kang, Stacie Totsch, Charles Schlappi, Allison M. Martin, Devang Pastakia, Sameer Farouk Sait, Yasmin Khakoo, Matthias A. Karajannis, Karina Woodling, Joshua D. Palmer, Diana S. Osorio, Jeffrey Leonard, Mohamed S. Abdelbaki, Avi Madan-Swain, T. Prescott Atkinson, Richard J. Whitley, John B. Fiveash, James M. Markert, G. Yancey Gillespie. University of Alabama at Birmingham / Children’s of Alabama, Birmingham, AL, University of Alabama at Birmingham, Birmingham, AL, St. Jude Children’s Research Hospital, Memphis, TN, Brigham and Women’s Hospital / Boston Children’s Hospital, Boston, MA, Albert Einstein College of Medicine, Bronx, NY, Vanderbilt University Medical Center, Nashville, TN, Memorial Sloan Kettering Cancer Center / Weill Cornell Medical College, New York, NY, Nationwide Children’s Hospital, Columbus, OH, The Ohio State University Comprehensive Cancer Center, Columbus, OH, Washington University School of Medicine, St Louis, MO

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