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THE RANDY SHAVER CANCER RESEARCH AND COMMUNITY FUNDGRANT APPLICATION COVER PAGE

GENERAL INFORMATION:

Name of Organization (Legal Name) Minnesota Medical Foundation at the University of Minnesota

Address: 200 Oak Street SE, Ste. 300, Minneapolis, MN 55455 Street/P.O. Box City State Zip

Contact Person Kathy Beenen Title Development Officer - Cancer

Telephone #: 612-625-6495 Fax #: 612-625-5673

Tax Status: (check one) X 501(c)3 _______Public Agency (Gov’t. created)

________Unit of Gov’t. _____Other:________________

PROJECT DESCRIPTION:

Name of Project An Advanced Vaccine for Treating Bladder Cancer

Name of Physician Christopher Weight, MD

Statement of project purpose To advance the standard of care for treating bladder cancer through the design and application of an autologous tumor cell vaccine that is individualized to the patient.

Geographic area to be served by project Minnesota, USA, and world-wide.

Check type of project: X Cancer Research ____Technology or screening tools that would enhance early

detection of cancer ____ Aid or Assistance to the Minnesota Cancer Community

____Program expansion or Special Projects____Other_______________________

Project Beginning Date 1/1/14 Project Ending Date 12/31/14

Total Project Budget $100,000 Amount Requested $30,000

(please attach Narrative Guidelines) and send to:The Randy Shaver Cancer Research and Community Fund

C/O Roseann Giovanatto-Shaver (Executive Director)1660 South Highway 100 Suite 335

CANCER RESEARCH & COMMUNITY FUND

St. Louis Park, MN 55416

An Advanced Vaccine for Treating Bladder Cancer

Executive Summary:It is estimated that more than 73,000 patients will be diagnosed with bladder cancer in the coming year. In addition to the morbidity and mortality, bladder cancer is now the most expensive malignancy in terms of cost per patient from diagnosis to death. Currently, intravesical therapy with the bacillus Calmette-Guerin (BCG) vaccine is the gold standard for decreasing the rates of recurrence and/or progression in bladder cancer. It is thought that BCG (a TB vaccine) simply functions by activating the immune system to kill tumor cells. Unfortunately, approximately 50% of patients will recur within 5 years and the only approved option for patients who fail BCG is valrubicin, which exhibits a modest response rate of 21% at 6 months. We plan to exploit the known susceptibility of bladder cancer to immunotherapy by employing a much more robust and tumor targeted vaccine strategy that is rapidly translated to the clinical setting. We will utilize our collective expertise (Dr. Weight – bladder cancer and translational medicine, Dr. Ferguson –vaccine adjuvant design and discovery and Dr. Panyam – nanoparticle-based delivery systems) to advance the current vaccination strategy by creating an autologous tumor cell vaccine that is individualized to each patient and is antigen specific and tumor targeted. The project involves the collection of tumor cells from patient donors, the evaluation and optimization of vaccine using realistic animal models and an aggressive plan for translation to human trials using local resources.

1. Description of the organization(s) or facility submitting the request and the primary populations served.

Advancing knowledge, enhancing care is the mission of the Masonic Cancer Center at the University of Minnesota. Founded in 1991, the Masonic Cancer Center fosters this mission by creating a collaborative research environment focused on the causes, prevention, detection, and treatment of cancer; applying that knowledge to improve quality of life for patients and survivors; and sharing its discoveries with other scientists, students, professionals, and the community.

The Masonic Cancer Center is part of the University's Academic Health Center, which also includes the Medical School, Dental School, Colleges of Pharmacy and Veterinary Medicine, and School of Public Health. The Masonic Cancer Center's research partners include the University's Stem Cell Institute, Center for Immunology, Center for Magnetic Resonance Research, and the Institute of Human Genetics; and its clinical research and treatment partners include the University of Minnesota Physicians; University of Minnesota Medical Center; and University of Minnesota Amplatz Children's Hospital.

The National Cancer Institute (NCI) designated the Masonic Cancer Center, University of Minnesota a comprehensive cancer center in 1998, and in 2003 and 2009, NCI renewed this designation. The Masonic Cancer Center is one of only 40 institutions in the United States to hold this designation. It is awarded only to institutions that make ongoing, significant advances in cancer research, treatment, and education. Due to the nature of the institution, we go beyond treating patients to also serving our faculty, staff and community.

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The Minnesota Medical Foundation is a 501(c)(3) public charity, founded in 1939, charged by the University of Minnesota Board of Regents with raising private support for the University of Minnesota Medical School, School of Public Health, and selected Academic Health Center programs. The Minnesota Medical Foundation, in collaboration with Masonic Cancer Center, University of Minnesota will be responsible for financial management and stewardship of any funds provided by the Randy Shaver Cancer Research and Community Fund.

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2. Description of the applicant’s, organization’s, or individual researcher’s experience in working with cancer related issues.

Christopher Weight, MD, MS, Co-Investigator: Assistant Professor, Department of Urology. Dr. Weight completed a Master’s in clinical and translation research as well as a fellowship in urologic oncology. His clinical focus is urologic cancer with one primary focus on bladder cancer. He has published multiple manuscripts devoted to the optimal management of patients with this potentially aggressive disease.

Jayanth Panyam, PhD, Co-Investigator: Associate Professor, Department of Pharmaceutics, College of Pharmacy at the University of Minnesota. Dr. Panyam is an expert in the area of nanotechnology-based biomedical applications including the use of nanoparticles as vaccine adjuvants.

David Ferguson, PhD, Co-Investigator: Professor and Director of Graduate Studies, Medicinal Chemistry, College of Pharmacy at the University of Minnesota. Dr. Ferguson is a team member on the canine brain tumor trials group and, together, with John Ohlfest, discovered new adjuvants for use in autologous cancer cell vaccines.

3. If this is a collaborative request, names and affiliation of planning and implementation partners and a description of the role of each partner in completing this project.

This project has developed as the result of internal collaboration between Drs. Weight, Panyam and Ferguson from the departments of Urology, Pharmaceutics, and Medicinal Chemistry. The University of Minnesota Medical School is a leader in the areas of translational cancer research, physician education, and patient care. The Department of Urology is an integral part of the Medical School and is comprised of physicians, PhD-trained scientists, nurses, graduate students, and residents (urologic surgeons in training). The Department of Urology is nationally recognized as being a leader in the diagnosis, treatment and prevention of urologic diseases. Drs. Ferguson and Panyam are faculty of the College of Pharmacy and have extensive experience in the formulation and manufacture of drugs and drug delivery systems. The College of Pharmacy is national leader (ranked 3rd overall) in research and training and is highly committed to innovating patient care through the design of improved therapeutics.

4. Description of how this project will serve the lives of Minnesota’s cancer patients. i.e. (improvements in care, specific updated screening methods, or cutting edge cancer research)

High-grade, invasive bladder cancer remains one of the most deadly cancers in the United States. Once it invades the muscle wall of the bladder, even with optimal multimodal therapy (surgery and chemotherapy), nearly half of patients still die from their disease. Furthermore standard surgery for muscle invasive bladder cancer entails removing the entire bladder and reconstructing the urinary tract. This is a complex, highly morbid operation with perioperative death rates in the 2-5% range and more than 60% of patients will experience some complication associated with surgery. Because of the danger and morbidity associated with muscle invasive bladder cancer, many treatment strategies have been proposed to treat non-muscle invasive

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bladder cancer and prevent progression. The current standard for treatment of high-volume, low grade or high-grade non-invasive bladder cancer is with surgical resection followed by intravesical therapy with BCG (a tuberculosis related vaccine) that cross-primes the immune response to fight the primary cancer and prevent recurrence. Unfortunately, though many show an initial response, more than 50% of the patients will show progression of the disease within 5 years and are left with limited options for non-invasive treatment. In addition, some patients fail to respond to BCG all together, resulting in the need for radical cystectomy urinary diversion and the above-mentioned complications. Furthermore, because of the high-risk nature of the operation, many patients are not surgical candidates. These patients are left with very few options and are often relegated to symptomatic relief only.

We believe our approach will potentially have tremendous benefits to patients diagnosed at both early and late stages of bladder cancer. We know that bladder cancer responds to immunotherapy (based on the success of BCG). We also know that the BCG vaccine is not optimized for targeting bladder cancer cells (as it is a tuberculosis vaccine and functions by indirectly priming the immune system). By using a tumor targeted vaccine and adjuvants specifically designed to stimulate an immune response (that overcomes tolerance), we will provide a plan to develop a therapy that could either augment the success or BCG or even succeed where BCG has failed. We see a role for our new therapy in several clinical settings. First in the setting of newly diagnosed, intermediate or high risk bladder cancer. These patients often progress to muscle invasive disease and represent a large population of patients. Furthermore, we see a role for those who are not surgical or chemotherapy candidates with aggressive disease who have failed other treatment options. This promising technology could help many people in Minnesota since it is estimated that over 1000 Minnesotans are diagnosed with bladder cancer every year.

5. Description of the program’s specific action steps with regard to timelines and completion of project.

This project builds on the work pioneered by John Ohlfest in the design of autologous tumor cell vaccines for fighting cancer. In collaboration with the Ferguson lab, Ohlfest identified adjuvants that can overcome some of the limitations of tumor cell vaccines by activating key cytokines to increase the population of antigen specific T cells. The approach has become well known in the field of veterinary science for treating canine meningioma and is moving forward towards human clinical trials for glioblastoma. The strategy taken here extends and applies this technology to take advantage of the known susceptibility of bladder cancer to the immune response (as demonstrated by the use of BCG) to create a new vaccine for this disease. The primary focus of the first year of this project is on the design and development of the vaccine using patient donor samples and animal models to evaluate the efficacy and formulate the optimal vaccine for patient care.

Objective 1: Demonstrate susceptibility of bladder cancer cells to autologous tumor cell-based immunotherapy using ex vivo studies and realistic animal models.

Dr. Weight will collect tumor samples and blood from patient donors (with consent during a normal course of therapy) for use in these studies. The tumor cells will be cultured to

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sonicated to produce tumor lysate or irradiated to produce apoptotic bodies for inclusion in the vaccine. The vaccine will contain autologous tumor antigens, stimulatory nanoparticles, and small molecule adjuvants developed specifically for cancer therapy. The vaccine formuation will be evaluated using patient blood through a fairly simple process by which we measure the immune response of the patient to the vaccine (and gauge the tumor killing potential of the treatment). This is done by harvesting CD14+ monocytes from blood which are subsequently treated with GM-CSF and IL-4 to derive immature dendritic cells (iDC). Dendritic cells are antigen presenting cells which prime and drive the immune response. The iDC culture is then treated with vaccine to produce mature antigen presenting (AP) cells for the study. The activity of the “vaccinated” APs is measured by treatment of patient blood (in particular peripheral blood lymphocytes) containing whole tumor cells. The generation of CD8+ T cells that are specifically activated towards tumor cells is then measured as a function of Granzyme B and interferon- production. These are markers of cytotoxic T cell function and immunogenicity towards the patient’s bladder cancer cells. The experiments will be applied to evaluate vaccine formulation and efficacy, and to perform comparisons with BCG.

The anticancer efficacy of the vaccine will also be evaluated using the MBT-2 murine bladder cancer cells implanted in C3H immune-competent mice. These studies will provide critical pre-clinical data for use in developing a clinical trials protocol and for evaluating the optimal vaccination strategy. Anticancer vaccination can be performed either prior to or post tumor inoculation. Administration of treatments following the appearance of a palpable tumor is more relevant to the clinical setting. However, it has been suggested that anticancer vaccination performed pre-inoculation may represent a situation where a non-metastasized primary tumor has been resected, leaving only a few residual tumor cells. In view of these possible clinical scenarios, we will evaluate the efficacy of therapy initiated pre and post tumor inoculation.

For initiating treatments pre-inoculation, the vaccine will be given one week prior to tumor inoculation. Mouse MBT-2 bladder cancer cells (luciferase transfected) tumors (single-cell suspensions of 2 x 105 viable cells in 100 µl HBSS) will be injected subcutaneously in the flank region. Progression of primary tumors will be determined by measuring the tumor volume using Vernier calipers. For initiating treatments post-inoculation, MBT-2 tumors will be inoculated first. When tumor volumes reach ~100 mm3, vaccination will be initiated. In all the cases, tumor volumes and animal survival will be used as primary markers of treatment efficacy. Body weight of treated animals will be monitored closely to determine any potential toxicity caused by the treatments. Animals treated with vehicle, tumor cells alone, tumor cells + blank NPs, blank NPs alone will be used as controls.

In order to further elucidate the mechanism of action, we will evaluate the tumors from treated animals for immune response. Tumor cell proliferation will be determined by Ki-67 staining while induction of apoptosis will be determined by staining for activated caspase-3 in tumor sections. We will also stain the tumor sections for CD4+ and CD8+ T-cells as well as for perforin and granzyme B (mediators of T-cell-induced cell death). These studies will provide strong mechanism-based, preclinical evidence for the proposed strategy of creating an in vivo whole cell vaccine to treat bladder cancer.

Objective 2: Complete Phase I clinical trials protocol to initiate clinical trials of autologous tumor cell vaccine for bladder cancer using cell processing and adjuvant systems developed at the University of Minnesota.

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We will work closely with the Center for Translational Medicine (CTM) in the writing a clinical trials protocol (for NIH sponsorship) and the required FDA IND documentation to bring this new therapy to patients as rapidly as possible. Since both the nanoparticle system and autologous cell technology are already FDA approved for use in humans, the translation of this technology to humans should be quite rapid. This documentation will be completed by the end of year one.

6. Description of what will constitute success and how it will be measured at the end of the grant period.

At the end of this project period (1 year) we expect to have an autologous tumor cell vaccine that is suitable for translation to human trials. This is an aggressive goal but certainly possible given the past success of BCG in treating bladder cancer and our expertise in the design of tumor cell vaccines. In addition, we expect to have a Phase I clinical protocol written to initiate the process of translating the technology to patient care. Given that autologous cell-based therapies are FDA approved and the availability of FDA approved resources here at the University of Minnesota, we anticipate a rapid clinical translation of the technology will follow this basic science.

The success of this phase of the project will be evident in the research results:

1. Our studies should show (using patient donor samples) that high levels of immunostimulatory cytokines and tumor reactive antibodies and CD8+ T cells are produced in response to treatment with patient derived vaccination.

2. Our animal models should demonstrate the efficacy of autologous tumor cell vaccination against bladder cancer in a pre-clinical trial setting. In addition, the results will provide definitive evidence for the selection of an optimal vaccine formulation and comparative data with BCG.

3. A complete Phase I clinical trials protocol and a complete FDA IND application for launching human trials.

7. Description of long-term funding plans (if applicable) and how the program will be sustained.

Additional funding for this project will come from NIH for clinical trials. We will work closely with the Center for Translational Medicine in developing an FDA IND and clinical trials protocol that can be implemented at the University of Minnesota or through partnerships with affiliated health care providers/organizations. We will also seek funding through the BrIDGS (Bridging Interventional Development Gaps) program at NIH for the development of second generation formulas for improved vaccinations. While this project will generate significant commercial interest, our first goal is to bring this therapy to patients as quickly as possible to start saving lives and improving health.

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8. Description of the qualifications and experiences of the principal staff members of the project in relation to its purposes and objectives.

Christopher Weight, MD will be responsible for harvesting tumor tissues from donors that are needed for the cell culture work and evaluation of vaccine formulations. He will guide the design of a Phase I clinical trial plan and work closely with Drs. Ferguson and Panyam in vaccine development. Dr. Weight received his medical degree from University of Utah. He completed his residency at Cleveland Clinic and a fellowship and Master’s Degree in Clinical and Translational Research at Mayo Clinic. Dr. Weight has demonstrated a long-term interest in improving our understanding of urologic cancers and optimizing treatment options for patients. He has authored more than 60 peer-reviewed articles or book chapters in this area. While performing research Dr. Weight continues to manage patients with bladder cancer on a daily basis and teach resident physicians and medical students how to care for these complex patients. This fusion of research, teaching and patient care helps Dr. Weight refine and refocus his research questions to lead to translational projects that benefit patients in a timely fashion. Jayanth Panyam, PhD will be responsible for production of the nanoparticles and biological assays supporting vaccine development and the transfer of the technology to MCT for tumor cell culturing under FDA approved guidelines.. Dr. Panyam’s group has developed an exciting novel nanoparticle technology that enables efficient encapsulation of TLR agonists and presentation to immune cells. His laboratory has considerable experience performing biological evaluations of nanoparticle based formulations for in vitro and in vivo anticancer effectiveness. He has authored more than 50 peer-reviewed papers in the general area of nanoparticle-based drug delivery technologies.

David Ferguson, PhD will be responsible for managing the overall progress of the project, including adjuvant synthesis, vaccine production, and the preparation of the IND documents for translation of the technology to a Phase I clinical trial. Dr. Ferguson’s lab has extensive experience in the design and discovery of small molecule adjuvants for use in formulating cancer vaccines. His lab (with John Ohlfest) holds the patent on a small molecule adjuvant that is currently used in the Canine Brain Tumor Program. His lab developed an approach to efficiently synthesize adjuvants with dual signaling activities in triggering cytokine production. He has extensive experience in the design and development of anticancer agents and has published over 60 peer reviewed manuscripts in the field.

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PROPOSAL BUDGET:Provide a detailed budget of the project’s income and expenses, including a narrative description of each category of income and expense.

Title: An Advanced Vaccine for Treating Bladder CancerBudget, 1/1/2014 – 12/1/2014IncomeNone.Expenses

Item

Randy Shaver Cancer Research and Community Fund Request Total Cost

Patient sample collection and preservation 5,000 10,000Biological Assays- tumor cell cultures, T Cell Function 10,000 20,000Animal Costs for Pre-Clinical Trials 10,000 20,000Vaccine Production for Blood Work and Animal Trials 5,000 20,000Completion of Phase I Protocol 0 5,000Completion of FDA IND Documentation 0 5,000

Total: 30,000 $100,000

BUDGET NARRATIVE:

Funds are requested to support tumor cell collections, tissue handling, vaccine production, and animal studies. Supplies and reagents will be used to conduct the biological assays, produce vaccine, purchase test kits to evaluate T cell function and cytokines, and purchase materials for the production of adjuvants and nanoparticles.

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ATTACHMENTS:Complete and submit the attached application form, the evaluation plan summary, a copy of your 501(c)(3) designation letter, list of your board of directors and evidence of board endorsement of this proposal.

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EVALUATION PLAN SUMMARY:

At the end of the project period, we will prepare a written summary of the project that includes an analysis of data gathered using patient donor samples and animal model studies, and an evaluation of the efficacy of autologous vaccination for treating bladder cancer. The report will specifically examine:

1. The success of tumor cell vaccination in stimulating high levels of immunostimulatory cytokines and tumor reactive antibodies and CD8+ T cells using patient donor samples.

2. The efficacy of autologous tumor cell vaccinations against bladder cancer in a pre-clinical animal model.

3. The potential benefits of autologous tumor cell vaccination versus BCG.

4. The completion of documentation to launch Phase I clinical trials and FDA IND approvals.

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Board of Trustees RosterOctober 2012

OfficersThomas G. Olson, Chair

Managing Director, Prime Mortgage

Elizabeth Hawn, J.D., Vice ChairCommunity Volunteer

Susan B. Plimpton, SecretaryRetired Vice President, Marketing Services, Formerly American Express Financial Advisors

Patti Andreini Arnold, Treasurer Retired Chief Operating Officer, University of Minnesota Physicians

Other MembersHonorable Clyde E. Allen Jr. *

Chair, Board of Regents, University of Minnesota

R. Mark Allison * President, WAM FitnessChair, Bob Allison Ataxia Research Center (BAARC)

James G. AndersonChief Administrative Officer Emeritus, Mayo Clinic, Arizona

DeWalt H. (Pete) Ankeny Jr. Retired CEO and Chairman, First Bank System

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McNamara Alumni Center200 Oak Street SE, Suite 300Minneapolis, MN 55455-2030

Phone: 612-625-1440800-922-1663

Fax: 612-625-5673www.mmf.umn.edu

Scott Augustine, M.D.Founder and CEO, Augustine Biomedical & Design

David S. Cannom, M.D. Director of Cardiology, Good Samaritan Hospital, Los AngelesClinical Professor of Medicine, UCLA School of Medicine

Richard A. Carlson, M.D., F.A.C.R.Director, Breast Imaging, Suburban Radiologic Consultants, Ltd., Fairview Southdale Breast Center

Bobbi Daniels, M.D.CEO, University of Minnesota Physicians

Gary L. Davis, Ph.D. * Regional Campus Dean, University of Minnesota Medical School - Duluth

Wendy W. Dayton Vice President, Meadowood Foundation

Timothy J. Ebner, M.D., Ph.D. * Professor and Head, Department of NeuroscienceMax E. and Mary LaDue Pickworth Endowed Chair in Neuroscience

Mark A. Eustis President and CEO, Fairview Health Services

John R. Finnegan Jr., Ph.D. * Dean, University of Minnesota School of Public Health

Barbara L. Forster Community Volunteer, Masonic Cancer Center Community Advisory Board

Aaron Friedman, M.D.Dean, University of Minnesota Medical School – Twin CitiesVice President, Health Sciences, Academic Health Center

Judy GaviserVice President of Corporate Affairs and Communications,American Express Financial Advisors (now Ameriprise), Retired

Stanley M. Goldberg, M.D., F.A.C.S. Surgeon, Colon and Rectal Surgery Associates, Edina, MinnesotaAdjunct Clinical Professor, University of Minnesota Department of Surgery

Peter M. Grant II Partner, Stone Arch Capital, LLC

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Beverly N. Grossman Member, University of Minnesota Medical School Board of Visitors

Susan Gunderson CEO, LifeSourceUpper Midwest Organ Procurement Organization, Inc.

John O. HallbergChief Executive Officer, Children’s Cancer Research Fund

Chris HolmChair, University Pediatrics FoundationChair, UMACH Advisory Committee

Russ HufferPresident and CEO, Apogee, Retired

Eric W. Kaler, Ph.D.President, University of Minnesota

Richard E. Kuntz, M.D. Senior Vice President and President, Medtronic Neurological Gastroenterology and Urology and Obesity ManagementMedtronic, Inc.

John Lindahl Managing General Partner, Norwest Equity Partners

Richard L. Lindstrom, M.D.Founder and Managing Partner, Minnesota Eye Consultants, P.A.Chair, Ophthalmology Advisory Committee

Wesley J. Miller, M.D.Chair, University of Minnesota Department of Medicine

Philip W. Ordway President, Bain Companies, Inc.

Richard Ostlund *, J.D.Chair, University Pediatrics Foundation

Treva Paparella* Executive Director, International Hearing Foundation

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Prakash PuramManaging Director, Chrysalis KPI Inc.Leadership Advisory Board Member, Reshare Inc.

James P. Stephenson, J.D.Partner Attorney, Faegre & Benson, LLP

Martin J. Stillman, M.D., J.D. *President, University of Minnesota Medical Alumni Society

Roby Thompson, Jr., M.D.Chief Executive Officer Emeritus, University of Minnesota Physicians

Selwyn M. Vickers, M.D. Jay Phillips Professor and Chair, University of Minnesota Department of Surgery

Brad WallinMember/Trader, Minneapolis Grain ExchangeBoard Member, Wallin Education Partners

Kevin Warren, J.D., M.B.A.Vice President of Legal Affairs & CAO, Minnesota Vikings

Brian Wenger, J.D.Chair - Commercial Department, Briggs and Morgan

Dodd Wilson, M.D.Retired, Dean and Chancellor of University of Arkansas for Medical Sciences

Charles F. Wiser, Jr. Retired owner, Vanguard Travel

Key:**= Executive Committee Member+ = Ex Officio Member‐

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