Development of cancer vaccines

Wings of Karen Vaccine (WOKVAC)—a vaccine to prevent breast cancer

WOKVAC is a vaccine that targets 3 proteins that are highly expressed on most breast cancers as well as most types of “pre-invasive” breast lesions.  We have shown that vaccination with WOKVAC is safe and effective in preventing the development of breast cancer.  We have started a Phase I study of WOKVAC in patients with a previous history of Stage II and Stage III breast cancer.  The clinical trial will determine the optimal dose for the vaccine and will determine whether we can generate an immune response that will protect patients against breast cancer for years.  Funding will support completion of this trial and analysis of immune responses.  

Vaccine targeting breast cancer stem cells—stopping the growth of triple negative cancer

STEMVAC is a vaccine that is directed against 5 proteins that are present in nearly all breast cancer stem cells. We have shown that STEMVAC is safe and effective as a vaccine and is particularly effective in inhibiting the growth of triple negative breast cancer. We will are completing a Phase I trial of STEMVAC in patients with Stage III and IV breast cancer and hope to eventually test whether STEMVAC will prevent breast cancer.  However, we have preliminary data that combination of STEMVAC with new immunotherapy agents that have been shown to boost immunity is effective in treating advanced stage disease.  Funding will support the development of a clinical trial of STEMVAC vaccination in combination with antibody therapy directed against “immune checkpoints” for the treatment of triple negative breast cancer.  

Breast cancer specific polyfunctional T-cells for cancer therapy—creating super T-cells to eradicate breast cancer  

Studies by our group have shown that breast cancer specific T-cells can be isolated from a patient’s blood, expanded in the laboratory to high numbers, and infused back into the patient providing high levels of tumor specific immunity. We have recently discovered an expansion method for T-cells that cause the outgrowth of “polyfunctional” T-cells.  These T-cells are capable of potently killing tumors. In mouse models polyfunctional T-cell infusion in advanced stage breast cancer results in complete resolution of the tumor.  The goal of this project would be to develop a Phase I clinical trial of the approach, immunizing women with a vaccine directed against a common breast cancer antigen, harvesting their tumor specific T-cells, expanding the T-cells in the laboratory to make them polyfunctional and infusing the T-cells to induce a clinical response.

Mary L. (Nora) Disis, MD Athena Distinguished Professor of Breast Cancer Research, American Cancer Society Clinical Research Professor, Associate Dean, Translational Science, University of Washington School of Medicine, Professor, Medicine, Adjunct Professor Pathology and Obstetrics and Gynecology, University of Washington, Member, Fred Hutchinson Cancer Research Center

Finding a Solution When Hormone Therapy Fails 

Deservedly, there is much attention focused on women with certain less common but very aggressive breast cancers – Her2 positive or so called Triple Negative (missing estrogen (ER), progesterone (PR), and Her2 receptors). However, the majority of recurrent or advanced breast cancers, even in young women, still fall into the most common category, ER positive. Not uncommonly, anti-estrogen strategies work for a while in these advanced cancers, but they eventually stop being effective at controlling the disease forcing these women to consider chemotherapy instead. Women with ER+, resistant breast cancers strongly deserve more options that directly target mechanisms serving as the basis for the resistance.
 

The Kemp and Gadi laboratories at the Fred Hutchinson Cancer Research Center have identified a promising framework to discover more targets in patients with tumors that formerly responded to endocrine therapy. Much of the resistance in ER+ breast cancer does not result from widespread new mutations throughout the cancer genome. Instead, certain pivotal proteins involved in the regulation of the genome are behind the resistance process. This type of research is termed cancer epigenetics. Dr. Kemp’s group has been studying one such epigenetic modifying gene called CTCF for decades and has shown very recently how this gene when altered on its own can result in rampant dysregulation of ER+ breast cancers helping them become resistant to anti-estrogen medicines in as many as 70% of such cases. Despite this high rate, no organized effort exists to target this particular mechanism.

Teaming up their laboratories, Gadi and Kemp are poised to change this field. Using specialized techniques, tumors can now be cultured directly from patients with metastatic disease that has become resistant to standard therapies and be studied in the laboratory using genetic techniques to understand the rewiring of the cancer cells. This type of research is called functional genetics and the Gadi and Kemp laboratories are world leaders in this field. Once these rewired networks are uncovered, new cancer drug targets emerge. These targets are verified using a variety of unique and common techniques to prove they are real vulnerabilities for the cancer (to minimize false leads). Using either already available drugs repurposed for killing these cancer cells or developing entirely new drugs, Gadi and Kemp hope to provide more options to treat or prevent ER resistant breast cancer. 

Chris Kemp, Ph.D. Member, Human Biology Division, Fred Hutchinson Cancer Research Center UW Affiliate Professor, Department of Pathology, UW Affiliate Professor, Department of Environmental and Occupational Health Sciences, School of Public Health 

VK Gadi, MD, PhD,Associate Professor of Medicine, Division of Oncology, University of Washington,Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Associate Member, Public Health Sciences Division, Fred Hutchinson Cancer Research Center

Detection of breast cancer genes

Whole Genome Sequencing for High-Risk Breast Cancer Families

The discoveries of BRCA1 and BRCA2 have changed breast cancer prevention and treatment in ways I would not have believed possible when I began this work 40 years ago. It is now possible for women to learn if they carry cancer-predisposing mutations in BRCA1 and BRCA2, and if so, to take steps to prevent breast and ovarian cancer. Furthermore, for the many women whose mothers or sisters carried such mutations and died of breast cancer, but who do not carry the mutation themselves, genetic knowledge brings tremendous relief.

However, one of our greatest frustrations is to discover that a family severely affected with breast cancer carries no mutation in BRCA1, BRCA2, or any of the known breast cancer genes. In our project sponsored by Wings of Karen, we are carrying out whole genome sequencing of DNA from breast cancer patients in these families, using DNA obtained from a small amount of blood. Our participants are women who developed breast cancer when they were young and who have at least two relatives who also developed breast cancer.

Our goal is to reveal unknown mutations in the non-coding regions of the genome. Our results so far indicate that whole genome sequencing provides the best opportunity in decades to identify novel mutations and new mechanisms for inherited breast cancer.

Our results will allow breast and ovarian cancer preventive measures to be taken by women in families for whom the genes causing breast cancer are currently unknown. A new gene identified in one family can easily be tested in many other families. Therefore, this project has the potential to improve patient care in the next few years by yielding a more comprehensive genomic profile of breast cancer predisposition. The short-term goals are to better identify women at risk, in order to enable them to undertake preventive measures. The long-term goals are to contribute to the design of new prevention strategies and provide a better understanding of the biological pathways involved in breast cancer development.

We thank our Wings of Karen friends very much for your continued support. This project could not have begun without you.  Your contribution this year will enable more genes and mutations to be identified, growing our understanding ofinherited breast cancer andaccelerating treatment and prevention for those facing breast cancer everywhere.

Mary-Claire King, PhD, American Cancer Society Professor, Department of Medicine and Department of Genome Sciences, University of Washington 

Gene Engineering for Long-term Control of Breast Cancer 

At present, standard treatment for breast cancer patients involves either removing or destroying the malignant cells. These genetically unstable cells are a moving target for therapies, which explains why many cancer patients experience recurrence with treatment-resistant disease. 

A tumor’s mass is made up of not just malignant cells but also white blood cells and tumor-associated macrophages (TAMs). TAMs are essential to the tumor’s growth and its ability to evade immune response, but TAMs also create an opportunity to attack the tumor with a new kind of gene therapy. 

Cancer’s Achilles’ Heel: TAMs and Long-term Tumor Control 

We have found a way to introduce new cancer therapy genes, via a simple intravenous injection, that have the ability to kill TAMs and surrounding malignant cells. 

Tumors recruit blood stems cells from which TAMs originate. When we transfer cancer therapy genes into blood stem cells, the tumor recruits these new, genetically engineered cells. Upon entering the tumor, the therapeutic gene is activated, producing toxins that kill the TAMs and the cancer cells and enabling us to control tumor growth long-term. If we can control or cure breast cancer in experimental models, our hope is this approach also will work in breast cancer patients. 

Andre Lieber, M.D., Ph.D.
UW Professor of Medicine, Division of Medical Genetics UW Adjunct Professor, Department of Pathology 

Hans-Peter Kiem, M.D., FACP
UW Professor of Medicine, Division of Oncology
UW Adjunct Professor, Department of Pathology
Associate Director of Transplantation Biology and Member, Clinical Research Division, Fred Hutchinson Cancer Research Center