Vascular Targeting Therapy for Breast Cancer

Institution: Sidney Kimmel Cancer Center
Investigator(s): Albert Deisseroth, M.D., Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0159 Award: $288,728
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2006)
Women with high risk breast cancer still succumb to their disease despite existing programs of adjuvant chemotherapy and hormonal therapy. Thus, new approaches for adjuvant therapy are needed. Increased expression of the Her-2-Neu oncogene correlates with recurrence, metastasis and resistance to adjuvant therapy. The immune response is tolerant of self-antigens like Her-2-Neu, since they have been present on epithelial cells since birth. Our laboratory has developed a vaccine strategy which can target markers unique to tumor vasculature as well as to Her-2-Neu vaccine, which can suppress the growth of breast cancer cells.

The central hypothesis of the proposed research is that targeting the immune response directly to the blood vessels which supply the breast cancer will reduce the rate of recurrence of breast cancer after surgery. Our laboratory has developed a vaccine strategy that has been shown to induce an immune response to the Her-2-Neu receptor even in older test animals (which, like older humans, usually have a weakened immune response to vaccine). Our lab has now shown for the first time that it is possible to suppress the growth of breast cancer by directing the immune response against the blood vessels in breast cancer, a novel and powerful therapeutic strategy that could ultimately reduce the loss of life due to breast cancer.

Our new vaccine is designed to trick the immune system into responding as if a viral infection is occurring. The viral infection is the strongest stimulus for activating the immune response. In this instance, the virus is engineered so that it is covered by markers (antigens) for the blood vessels of breast cancer tissue and by Her-2-Neu. We propose to test if a combined vaccine against the tumor blood vessels and breast cancer cells can prevent the development of breast cancer in a mouse which is genetically engineered for spontaneous development of breast cancer. In this model, breast cancer takes a long time to develop, just as in human beings.

Be believe that our approach has novel elements that may allow success, despite the difficulties in mounting an effective immune response against breast cancer. The first innovative aspect is the development of an immune response against the blood vessels feeding the breast cancer tissue. The second novel aspect of this strategy is to combine the vaccine against the blood vessels of the tumor tissue with a vaccine against the breast cancer cells themselves. The third novel aspect of this approach is to combine these vaccine approaches with conventional adjuvant chemotherapy. Our laboratory has shown that delivery of chemotherapy during the vaccination process actually enhances the immune response induced by the vaccines. If this strategy were introduced into established programs of adjuvant chemotherapy, the success rate after surgery could go up, without any added toxicity.

Final Report (2008)
Overview: The original goals of the grant focused on how to integrate chemotherapy sensitization vector therapy (with the AdCDIRESE1A/ip5FC vector) with a vaccine therapy (with the Ad-sig-TAA/ecdCD40L vector platform) directed to breast cancer cells and their tumor vasculature. In June, 2007, we expanded the research to include the study of combined chemotherapy sensitization vectors and vaccine vectors targeted to the breast cancer stem cells as well as to the tumor vasculature.

The work completed showed that the combination of the chemotherapy sensitization vector and the vaccine vector induced greater levels of immune response and cancer suppression than either alone. The Ad-sig-hMUC-1/ecdCD40L vaccine vector suppressed the cancer stem cell and thereby cancer growth. The AdCDIRESE1A chemotherapy sensitization vector was successfully targeted to breast cancer tumor vasculature.

Barriers that were Overcome:

We intend to continue this work to combine the chemotherapy sensitization vector that targets breast cancer vasculature with the vaccine vector which targets the breast cancer stem cell.

Symposium Abstract (2007)
Recent analyses of influenza vaccination clinical data shows that there is no survival advantage above the age of 55 and a 4 fold lower antibody response to the multivalent inactivated particle influenza vaccination in individuals over the age of 55. This poor response to vaccines may be due to decreased numbers of antigen na´ve CD8 and CD4 T cells, and the acquisition of functional defects in CD4 helper cells, like decreased expression of the CD40L in activated CD4 cells. In order to develop a method to overcome these defects in the immune response in older individuals, we have designed an adenoviral vector (Ad-sig-TAA/ecdCD40L) for the in vivo activation and tumor antigen loading of dendritic cells (DCs). This adenoviral vector encodes a fusion protein composed of an aminoterminal tumor associated antigen (TAA) fragment fused to the extracellular domain (ecd) of the CD40 ligand (CD40L) at the carboxyl terminal end. Two sc injections of this vector have broken tolerance to breast cancer specific tumor associated antigens in two separate TAA.Tg transgenic mouse models (mice transgenic for rat Her-2-Neu (rH2N) and human MUC-1 (hMUC-1)). Her-2-Neu and MUC-1 are tumor associated antigens which are overexpressed in poor prognosis breast cancer as well as in adenocarcinomas of the prostate, ovary, colon and lung. Overexpression of the MUC-1 is an predictor or poor prognosis which is independent of grade and stage. MUC-1 is expressed on the tumor stem cell or tumor initiating population in breast cancer. The immunoprotection induced by this vaccine extends for over a year and is independent of CD4 cells. We showed that the sc injection of the hMUC-1/ecdCD40L protein following the sc injection of the Ad-sig-TAA/ecdCD40L vector (this vector prime-protein boost is called VPP) increases the levels of both the cellular and humoral immune response over that achievable with just the vector injections alone in the hMUC-1.Tg mice. The antibodies from hMUC-1 VPP vaccinated mice bind to biopsy specimens of human cancers of the breast and prostate. Importantly, the VPP vaccination can induce an immune response even in 18 month old mice which completely suppresses tumor growth in old (18 month old) mice. The Ad-sig-rH2N/ecdCD40L vaccination suppresses the evolution of spontaneous breast cancer in the rH2N.Tg mouse model. The Ad-sig-TAA/ecdCD40L/ecdCD40L vector prime-TAA/ecdCD40L protein boost vaccine can also be used to induce a humoral and cellular immune response against antigens (Annexin A1) which are specific for the luminal membrane of tumor vascular endothelial cells. The Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost strategy may be of value in the prevention and treatment of breast cancer as well as other epithelial neoplasms and infectious diseases.

Chemotherapy Targeted to Cancer Tissue Potentiates Antigen-specific Immune Response Induced by Vaccine for In Vivo Antigen Loading and Activation of Dendritic Cells.
Periodical:Molecular Therapy
Index Medicus: Mol Therapy
Authors: Akbulut H, Tang Y, Akbulut KG, Maynard J, Deisseroth A.
Yr: 2008 Vol: 16 Nbr: 10 Abs: Pg:1753-60