Proposal for Dr. Czerniecki's Stand Up To Cancer Dream Team

Targeted Vaccine and Immune Approaches for the Treatment and Prevention of Breast Cancer

Project Summary Statement: Cancer development is a stepwise process requiring multiple cellular participants, ranging from recently-described pluripotent cancer stem cells to cells of the immune system. All participating cells are interconnected by a complex network of molecular pathways that can affect tumor growth and behavior. Besides estrogen, critical pathways for breast cancer development include those associated with the HER family of transmembrane receptors and insulin growth factor-1 (IGF-1) receptors.  For example, HER-2/neu is over-expressed in luminal tumors that either expresses estrogen receptors (Luminal B) or are estrogen receptor-negative (HER-2/neu phenotype).  These HER-2/neu-expressing phenotypes are associated with early breast cancer development, increased stem cell number and a poor overall prognosis.  A related family member, HER-1 (EGFR), is expressed by a large proportion of so-called “triple negative”, or basal-type tumors. This phenotype, which is also associated with poor outcome and decreased survival, is found in large percentages of young patients, African-American females, and carriers of the BCRA1 gene mutation. The over-expression of both HER and IGF receptor family members clearly enhances disease aggressiveness because the signaling pathways activated by these receptors can regulate the expression of genes that control properties of invasiveness, metastasis, and resistance to chemotherapy.  It is probable that that these qualities are particularly exemplified by the pluripotent breast cancer stem cells. Successful vaccination against signaling elements of these disease-enhancing molecular pathways would offer many advantages.  For example, it might allow us to prevent cancer entirely in selectively-targeted, high-risk populations. Alternatively, it could destroy cells within well-established tumors that bear stem cell characteristics, potentially crippling a tumor’s capacity for self-regeneration and resistance to conventional therapies. At the very least, such a strategy could cull a heterogeneous tumor population of the most dangerous cells, and through a process of vaccine-induced immunoediting, leave only residual populations that are more indolent and amenable to conventional therapy.  It has been demonstrated that vaccine-induced cellular and humoral immune responses can be generated against several of these tumor-associated molecules including HER-2/neu.  An exciting advance was made when HER-2/neu peptide-loaded autologous DCs specially activated with Toll-like receptor (TLR) agonists to secrete high levels of IL-12 were used to immunize subjects with early breast cancer (ductal carcinoma in situ-DCIS) prior to surgical intervention. We observed vaccine-induced immunoediting of HER-2/neu expression in residual tumor at the time of surgical resection with evidence of shrinkage of tumor area in about half of these subjects. There was also preliminary evidence for vaccine-induced immunoediting of previously occult disease in the contralateral breast, as well as apparent long term immune memory. Given the highly encouraging success of this proof-of-principle, we plan to expand the repertoire of vaccine targets to include other critical signaling pathway components (e.g. HER-1, IGF-1, cyclinB1 and survivin). Inclusion of these and other targets associated with aggressive phenotypes would expand the range of breast cancer phenotypes targeted by vaccination. Equally important for producing practical vaccines would be to simplify them by investigating possible non-cell based vaccine approaches that use TLR agonists to activate DC in vivo. Equally important is to devise investigational approaches aimed at gaining a better understanding of the tumor microenvironmental factors critical for successful vaccination and tumor eradication, including role of myeloid suppressor DC and T reg.  As molecular and individualized approaches to medicine develop, vaccination may be deployed as preventatives in identified high-risk patients, or in conjunction with targeted drugs and antibodies to supplement their effectiveness or to complement them by checking molecular avenues of escape. 
Specifically we plan to:

1. Conduct a series of translational clinical trials in various stage breast cancer patients with the theme of immune-targeting molecular pathways associated with aggressive phenotypes, using cellular (DC) and non-cellular TLR activated vaccine approaches to determine whether immunization can impact treatment or prevention of breast cancer recurrence. Selected aggressive phenotype targets include HER family members, IGF-1 receptors, survivin, or cyclin b1.
2. To develop TLR 8 agonist adjuvants for the continued generation of breast cancer vaccines and further generate proteins and peptides derived from molecules involved in breast cancer development and metastasis that can be used for clinical vaccines while developing novel immune monitoring techniques with EPIMAX to follow the immune response to vaccination.
3.  In preclinical models investigate interactions in the tumor microenvironment including myeloid suppressor DC and T reg that can impact the success of targeted vaccine approaches and further elucidate mechanisms to enhance T cell function for the treatment of breast cancer and apply these approaches to future vaccination programs.

Clinical Impact: Our previously published work shows it possible to identify important aggression-associated tumor targets and use innovative vaccine approaches to successfully immunoedit tumor phenotype. By expanding the repertoire of potential targets and gaining further insight into immune regulation we expect to develop and validate vaccine approaches that can 1) reduce recurrence rates of surgically-resectable tumors by eliminating residual cancerous cells; 2) eliminate or cripple the capacity of more advanced tumors to cause disease; 3) reduce or eliminate self-regeneration by destroying cancer stem cells; 4) reduce tumor mass prior to surgery as a breast-conserving strategy. We expect that the developed approaches would complement existing surgical, radiological and chemotherapeutic approaches to reduce recurrence and morbidity resulting from disease.

Timeline toward clinical impact: In the next five years we would be able to determine whether vaccine targeted approaches for at least HER-2/neu, HER-1, IGF-1, cyclin B1 and survivin can have clinical impact in treating and preventing recurrence of aggressive breast cancer phenotypes. We would develop TLR agonists as adjuvants for vaccination. We would understand how to better accomplish vaccination in a tumor bearing host manipulating vaccination and inhibitory cells or molecules in the tumor environment.
Expertise and Key personnel: (Currently this group has not worked together and formed specifically for this SU2C cause. It consists of the leading breast cancer immunology scientists in the country).
TEAM LEADER 1: Brian J. Czerniecki, M.D, PhD (University of Pennsylvania).
TEAM LEADER 2: Nora Disis, M.D. (University of Washington Cancer Center).
(Both team leaders have experience in translating immunologic approaches to breast cancer.)

TEAM PRINCIPAL 1: Gary K. Koski, Ph.D. (Cleveland Clinic).

TEAM PRINCIPAL 2: Peter Cohen, M.D. (Mayo Clinic)

TEAM PRINCIPAL 3: Elizabeth M Jaffee, MD, (Johns Hopkins University)

TEAM PRINCIPAL 4: Suzanne Ostrand-Rosenberg, PhD, (University of Maryland Baltimore Campus)

TEAM PRINCIPAL 5: Karolina Palucka, MD, PhD (Baylor Institute of Immunology)

ADVOCATES: Uschi Keszler Founder of Pennies in Action for Breast Cancer Vaccine Research
Carol Gekoski Breast Cancer Survival Participant in Breast Cancer Vaccine study