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Minnesota Scientists Develop Small Peptide to Block Checkpoint Inhibition System in Brain, Possibly Enabling Immunotherapy Treatment of Glioblastoma; Success Seen in Dog Models; Stage 1 Human Clinical Trial Anticipated for Mid-Summer 2019

As sometimes happens in science, a seeming failure can occasionally lead to great success. That is the hope of University of Minnesota scientists Michael Olin (left in photo), PhD, and his colleague Chris Moertel (right in photo), MD, who have co-founded a new company, OX2 Therapeutics, together with Californian biotech entrepreneur Sumant Dhawan, in order to advance a promising peptide molecule into phase 1 human clinical trials for the treatment of glioblastoma, one of the deadliest brain tumors in humans. The peptide interferes with the dual paired receptor (CD200R1/CD200AR) immune checkpoint system to counter glioblastoma’s overproduction of soluble CD200 (originally named OX2) that acts to suppress the body’s immune response against the cancer. Drs. Olin and Moertel say that their team has developed a small peptide inhibitor (15 amino acids) to interfere specifically with this CD200 checkpoint inhibition system to empower the body’s own immune system to attack and defeat glioblastoma multiforme (GBM). In fact, based in part on the success of the addition of this peptide to tumor lysate vaccines in extending the lifespan of brachycephalic (short-nosed) dogs that naturally develop glioblastoma, CMO Dr. Moertel said that he “anticipates” that a phase 1 clinical trial of this peptide will begin in mid-summer 2019. This trial will be led by neuro-oncologist Elizabeth Neil, MD, Assistant Professor of Neurology at the University of Minnesota, and will include 14-18 adult glioblastoma patients who have experienced recurrent glioblastoma. Following successful treatment of 3 adult patients, the researchers plan to enroll 14-18 pediatric patients with recurrent glioblastoma, medulloblastoma, and/or ependymoma in a second arm of the trial, to be led by Assistant Professor Emily Greengard, MD, Department of Pediatrics at the University of Minnesota. Dr. Olin recently presented his group’s latest work in a featured presentation in the Immunotherapy Track of the Precision Medicine World Conference (PMWC 2019) January 20-23 in Silicon Valley, California (https://www.pmwcintl.com/2019sv/) (https://www.pmwcintl.com/michael-olin-2019sv/). In addition to reporting that the company’s peptide disrupts the CD200 checkpoint inhibition, he also noted that glioblastoma upregulates the suppressive CD200 molecules on tumor vascular endothelial cells to form an “immunological blockade” against the influx of immune cells into the tumor microenvironment from the blood stream. With the peptide-induced downregulation of the inhibitory CD200 receptor on immune cells, these immune cells can pass easily into the tumor microenvironment.

GLIOBLASTOMA & CANCER IMMUNOTHERAPY

Glioblastoma is rapidly and uniformly fatal, and there is a desperate need for new therapeutic approaches. The new approach of the Minnesota scientists is based on recent advances in cancer immunotherapy that have demonstrated ways in which the immune system can be activated to overcome the immune suppression that is often induced by cancer cells, and to then launch a vigorous and successful attack against the cancer.

Cancer immunotherapy based on overcoming checkpoint inhibition is an extremely hot topic and work in this area was recently recognized with awarding of the 2018 Nobel Prize in Physiology or Medicine to Dr. James Allison for his work on the checkpoint “brake” CTLA-4 (leading to the successful anti-cancer drug ipilimumab, which became the first checkpoint immunotherapy drug approved by the FDA in 2011) and to Dr. Tasuko Honjo for his work on the PD-1/PD-L1 immune checkpoint system (leading to the development of successful anti-cancer drugs directed against the PD-1/PD-L1 checkpoint). The first anti-PD-1/PD-L1 checkpoint immunotherapy drugs were Merck’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab), which were both approved by the FDA in 2014 for the treatment of melanoma. However, these treatments have not demonstrated efficacy against brain tumors.

FAILED CLINICAL TRIALS OF IMMUNIZATION WITH TUMOR LYSATE SPUR PRODUCTIVE INQUIRY

The Minnesota group’s focus on the CD200 checkpoint system developed in the aftermath of two phase 1 human clinical trials, led by Dr. Moertel and begun in 2012, which sought to examine the safety/effectiveness of a tumor lysate vaccine, GBM6-AD, made from an allogeneic brain tumor stem cell line (1). In the trials, a significant number of patients (~50%) initially showed a good response. Eventually, however, all patients relapsed and died, including those with an initial good response.

Dr. Olin sought to understand the fatal relapse after the initial good response. He rigorously analyzed the protein content in the serial blood samples that had been taken from the patients in the course of the trial. What he found, after extensive analysis, was the apparent key involvement of the protein, CD200. Patients who responded well initially had a low concentration of CD200 in their early blood samples, while those who responded poorly from the outset had a high concentration of CD200 in their early samples. Finally, patients who eventually relapsed showed a much-increased concentration of CD200 in blood samples taken around the time of their relapse.

PROGRESS IN UNDERSTANDING THE CD200 IMMUNE CHECKPOINT SYSTEM

Initially, in his pursuit of examining CD200 effects, Dr. Olin found that blocking CD200 in mice with CD200-based peptide ligands made their induced brain tumors disappear, and that blocking CD200 in a brain tumor cell culture system permitted the induction of an antigen-specific immune response.

Dr. Olin and colleagues went on to show that glioblastoma produces a significant quantity of soluble CD200. The CD200 modulates the immune system through the CD200 inhibitory receptor (CD200R1) and an activation receptor (CD200AR) (2, 3). The scientists demonstrated that: i) targeting CD200AR with a specific peptide ligand (CD200AR-L) induces the activation PI3K-Akt and Ras-MEK-ERK signaling molecules within the DAP10 pathway, ii) knocking out CD200R1 inhibits CD200AR activation, demonstrating that CD200R1 and CD200AR are interconnected, as previously reported (4); iii) targeting CD200AR with CD200AR-L activates antigen-presenting cells (APCs) (2, 3) and downregulates expression of the inhibitory CD200R1 on APCs and T cells; and iv) CD200AR activation of APCs induces cytokine production and the upregulation of CD80/86 and MHC-II (2, 3).

In addition, as noted earlier, Dr. Olin found that, with the increased release of soluble CD200 from the glioblastoma tumor, the CD200 checkpoint inhibition system upregulates the expression of CD200 in the membranes of tumor-associated vascular endothelial cells, creating an immunological barricade around the tumor microenvironment. Immune cell activation by the CD200AR-L peptide downregulates the inhibitory CD200 receptor on immune cells allowing these immune cells to flow into the tumor microenvironment from the circulation.

In a further development, Dr. Olin and colleagues have shown that activation by the CD200AR-L peptide may have application beyond glioblastoma as this treatment has shown success as high as 80% survival in mouse breast carcinoma.

EVOLUTION OF THERAPY IN PET DOGS

As noted previously, glioblastoma is a deadly form of brain cancer that affects both people and their pet dogs. Currently, the standard of care in people is to remove as much of the tumor as possible surgically and to then try to delay tumor regrowth using chemotherapy and radiation. Virtually universally, this treatment fails with the average lifespan being just 14 months, post-surgery/diagnosis.

At the University of Minnesota, Dr. Olin has collaborated for a number of years with G. Elizabeth Pluhar (photo at end of this article), DVM, PhD, to treat pet dogs with naturally occurring high-grade glioma. Most dogs diagnosed with a brain tumor with magnetic resonance imaging were treated by radiation therapy without a biopsy of the brain mass. Dogs given palliative care or surgery alone lived an average of 2 months after diagnosis. Dr. Pluhar was able to increase the median survival time to 7-8 months in dogs with definitively diagnosed high-grade glioma by vaccinating with autologous (made from the dog’s own tumor) lysate after surgery. However, the results were similar to those in humans, with all the dogs succumbing to tumor recurrence.

More recently, Drs. Olin and Pluhar have combined a canine-specific CD200AR-L peptide with autologous tumor lysate vaccines after surgery with great success. The results demonstrate that the addition of the peptide increased the median survival time to 12.7 months and gave a 2-year survival rate of about 35%. However, in contrast to any other treatment, approximately half of the dogs died of other than tumor-related issues.

This study is continuing in an NIH-funded clinical trial using combination immunotherapy approaches in pet dogs with high-grade glioma as a model for translation to human clinical trials. It should be noted that, for a variety of reasons, dogs are believed to be a much better animal model for cancer studies than are mice (6).
It is, in large part, this success with dogs that has spurred OX2 Therapeutics to pursue a phase 1 clinical trial of the CD200AR-L peptide in humans, anticipated to begin in mid-summer 2019.

ADMINISTRATION OF CD200AR-L PEPTIDE PLAN FOR HUMAN CLINICAL TRIAL

In the anticipated human clinical trial, the CD200AR-L peptide will be administered to patients in two intradermal injections in the region of the tumor’s draining lymph nodes, after application of topical imiquimod for local recruitment of antigen-presenting cells (APCs) following the protocol developed for the canine glioma patients. The first injection will contain the peptide. The second injection, to follow the first by 24 hours, will be of the peptide and GBM6-AD vaccine at the same site.

COMMENT FROM HEAD OF NEUROSURGERY DEPARTMENT

The renowned neurosurgeon and neuroscientist Clark Chen (https://www.neurosurgery.umn.edu/bio/neurosurgery-faculty/clark-chen), MD, PhD, who has recently been appointed head of the Neurosurgery Department at the University of Minnesota after a distinguished career at UC San Diego, said that he is intrigued by the approach of Drs. Olin and Moertel. He sees this therapeutic effort as a refreshingly new way of attacking brain cancers and has already identified opportunities for synergy between this approach and his own work (7).

BACKGROUNDS OF MAJOR PLAYERS

Michael Olin, PhD, Co-Founder

Dr. Olin is Assistant Professor in the University of Minnesota Medical School’s Department of Pediatrics, Division of Pediatric Hematology & Oncology, within the University’s Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute (NCI).He is also a Faculty Member of the Medical School’s Brain Tumor Program. He earned a BA in chemistry and BS in biochemistry from the University of Minnesota-Duluth, then spent five years working in industry, before returning to academics, earning his PhD in Veterinary Medicine (Infectious Diseases) at the University of Minnesota-Minneapolis. He did his first post-doctoral fellowship with Dr. Philip Petersen investigating the effects of opioids on tuberculosis meningitis. He then he switched to the study of brain tumors, after his mother died from brain cancer that had metastasized from her kidney.

Dr. Olin did his second post-doctoral fellowship with Minnesota’s Dr. John Ohlfest working on brain tumor immunotherapy. Dr. Olin joined the University of Minnesota Pediatrics Department Faculty as an Assistant Professor in 2011. He had earned the PharmacoNeuroImmunology Research Society’s Young Investigator’s Award in 2002 and the Society of NeuroImmune Interaction and Pharmacology’s Young Investigator’s Award in 2001.

Dr. Olin’s current scientific interest is in defining the mechanism(s) of suppression inhibiting the ability to mount a tumoricidal response evident in the tumor draining lymph nodes and tumor environment and developed potential ways to modulate the immunosuppressive activity. Immunosuppressive tumor environment is a major hurdle for the immune system to overcome. Dr. Olin is focused on the development of inhibitors derived to overcome the suppressive tumor microenvironment.

Chris Moertel, MD, Co-Founder

Dr. Moertel is the Kenneth and Betty Jayne Dahlberg Professor in the Pediatrics Department’s Division of Pediatric Hematology and Oncology of the University of Minnesota Medical School, within the University’s Masonic Cancer Center; Medical Director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs; and Clinical Neuro-Oncology Leader of the Medical School’s Brain Tumor Program. Dr. Moertel earned his MD at the University of Minnesota Medical School and did his residency in Pediatrics at the Baylor School of Medicine. He followed that with a fellowship in hematology/oncology at the Mayo Clinic/Mayo Graduate Program in Rochester, Minnesota. Among his honors, Dr. Moertel has been named one of the “Best Doctors in America” (2007-2013) and one of the “Top Doctors” in Minnesota (2009-2018). In 2012, he was the leader of two phase 1 clinical trials of a glioblastoma tumor lysate vaccine.

Sumant Dhawan, Co-Founder

Sumant Dhawan, biotech entrepreneur, is the Founder and Chief Scientific Officer of Cell Technology, Inc., in Mountain View, California. Mr. Dhawan received his bachelor’s degree from the University of Minnesota.

G. Elizabeth Pluhar, DVM, PhD, Scientific Advisory Board Member

Dr. Pluhar is a member of the OX2 Therapeutics Scientific Advisory Board. She is a veterinary neurosurgeon and Professor in the Department of Veterinary Clinical Services at the University of Minnesota, within the University’s Masonic Cancer Center. Dr. Pluhar, a specialist in canine neurosurgery, has collaborated with Dr. Olin for more than six years in the development of novel immunotherapies for canine brain tumors and conditions affecting the brain, spinal cord, peripheral nerves, and supporting structures. Together, Drs. Olin and Pluhar are successfully testing the safety and efficacy of the CD200AR-L peptide in a canine high-grade brain tumor clinical trial. Dr. Pluhar earned her DVM at Oregon State University and her PhD from the University of Wisconsin-Madison. Among her honors is receipt of the Mark of Excellence Award from the University of Minnesota’s College of Veterinary Medicine in 2009 and she is one of the founding members of the National Cancer Institute’s Comparative Brain Tumor Consortium.

KEY DONORS TO THE OX2 THERAPEUTICS EFFORTS

Key donors to the OX2 Therapeutics efforts to develop their peptide to treat and possibly cure glioblastoma include the Dahlberg Foundation, Bob and Connie Ferris, the Children’s Cancer Research Fund (CCRF), the Daniel G. Carey Brain Tumor Research Fund, the American Brain Tumor Association, the Randy Shaver Cancer Research and Community Fund, Humor to Fight the Tumor, and Love Your Melon.

by Michael D. O’Neill, MA, Editor & Publisher, BioQuick News
(http://www.bioquicknews.com/node/34)
logophile2000@yaho.com

REFERENCES

1. Olin, MR, Low, W, McKenna, DH, et al., “Vaccination with Dendritic Cells Loaded with Allogeneic Brain Tumor Cells for Recurrent Malignant Brain Tumors Induces a CD4+IL17+ Response.” Journal for ImmunoTherapy of Cancer, 2: 4 (Published Online on February 18, 2014). (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019901/).

2. Moertel CL, Xia J, LaRue R, et al. “CD200 in CNS Tumor-Induced Immunosuppression: The Role for CD200 Pathway Blockade in Targeted Immunotherapy.” Journal for ImmunoTherapy of Cancer, 2(1): 46 (December 2014). (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296547/).

3. Xiong Z, Ampudia-Mesias E, Shaver R, Horbindki CM, Moertel CL, & Olin MR, “Tumor-Derived Vaccines Containing CD200 Inhibit Immune Activation: Implications for Immunotherapy.” Immunotherapy, 8(9): 1059-1071 (September 2016). (https://www.ncbi.nlm.nih.gov/pubmed/27485078).

4. Zhang S, Cherwinski H, Sedgwick JD, & Phillips JH. “Molecular Mechanisms of CD200 Inhibition of Mast Cell Activation.” Journal of Immunology 173(11): 6786-6793.(December 1, 2004). (https://www.ncbi.nlm.nih.gov/pubmed/15557172).

5. Olin MR, Ampudia-Mesias E, Pennell CA, Sarver A, Chen CC, Moertel C, Hunt MA, and Pluhar GE. “Treatment Combining CD200 Immune Checkpoint Inhibitor and Tumor-Lysate Vaccination After Surgery for Pet Dogs with High-Grade Glioma.” Cancers 11(2): 137 (Published Online on January 24, 2019). (https://www.mdpi.com/2072-6694/11/2/137).

6. Fromer, Margot T, “Translational Research: Dogs and Humans Nearly Interchangeable in the Laboratory,” The ASCO Post (August 15, 2015). (http://www.ascopost.com/issues/august-10-2015/translational-research-dog...)

7. Frisch, Suzy, “A Cunning Opponent,” Medical School-University of Minnesota (October 18, 2017).
(https://www.med.umn.edu/news-events/medical-bulletin/cunning-opponent).

[OX2 Therapeutics] [Dr. Michael Olin’s Page on PMWC 2019 Site]

Photo at left shows Dr. Olin (l) with Dr. Moertel. Photo at right shows Dr. Pluhar with friend.