Cell-Based Immunotherapy for Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Nabila Jabrane-Ferrat, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6KB-0116 Award: $120,811
Award Type: New Investigator Awards
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2000)
Successful immunotherapy and tumor rejection has been reduced in many cases to the creation of appropriate inflammation. Although the immune system can discriminate between self and non-self antigens, this paradigm may not make sense in the context of immunity to tumors. A newly arising tumor may display novel antigens, but this is not enough to alert the immune system because\ they are not seen as a danger. We postulate that by incorporating genes to create a "danger signal" within the tumor itself, we can activate a T cell and train the immune system to see the tumor as a source of danger. To achieve our goals, we will express molecules that are involved in recognition and presentation as well as recruitment of immune cells. Tumor cells will be able to display tumor antigen (signal 1) and stimulate effector cells (signal 2). These phenomena will lead to the activation of an immune attack against tumor cells and hopefully result in tumor clearance. We will develop and evaluate several promising vaccine strategies, including retrovirus and cell-based vaccines. We will rigorously evaluate and optimize these vaccine strategies in vitro. Results from these studies will lead us towards the best strategy or strategies to use in obtaining an overall objective of developing an effective, appropriate immunotherapy for breast cancer.


Final Report (2003)
Breast cancer progresses despite the aggressive multi-modal therapies used in the clinic. Innovative treatments such as immunotherapy provide avenues to improve the prognosis of breast cancer. Cancer vaccines are of great interest not only to treat existing cancer but also to prevent recurrence at new sites, however, the success of immunotherapy is lessened in many cases by because the immune system does not recognize the tumor as foreign even though it might express a novel antigen. The main goal of our study was to develop an immunotherapy that would give a double signal to the immune system, thereby encouraging it to recognize and destroy the tumor cells. We used dicistronic retroviral vectors to transduce the expression of MHC class II antigens and CD80 co-stimulatory molecule, and then created a vaccination vehicle where tumor cells become antigen presenting cell would able to display tumor antigens in the context of MHCII.

In the two years of funding, we accomplished many of the proposed goals. First, we generated different retroviruses encoding either CIITA, B7.1 or interferon gamma. Next, we created a cell line from mammary tumors occurring in HER2 transgenic mice. Tumor cells were then transduced to express either CIITA, B7.1 or interferon gamma and stable clones were generated. Established cell lines were characterized for levels of transduced expression of CIITA, CD80 and their secretion of interferon gamma. Our investigation revealed that transduced cells that expressed CIITA, CD80 or both were able to induce the proliferation of syngeneic lymphocytes in the laboratory. Finally, we have shown that expression of CD80 in a mouse mammary adenocarcinoma cell line reduces its tumorigenicity when grown in the animal compared with the parental MCNeuA cells. Although, all of the mice inoculated with CIITA expressing MCNeuA cells developed tumors, the tumor size was significantly lower than the parental cell line. Coexpression of CIITA with CD80 did not abrogate the protective effect observed with CD80 expressing cells. In fact, it led to enhanced tumor immungenicity. Both CD80 alone or CD80 and CIITA expressing tumor cells were completely rejected when injected into neuTg mice and both induced significant protection against spontaneous mammary tumor development.

Major histocompatibility complex class II transcriptional platform: assembly of nuclear factor Y and regulatory factor X (RFX) on DNA requires RFX5 dimers
Periodical:Molecular and Cellular Biology
Index Medicus: Mol Cell Biol
Authors: Jabrane-Ferrat N, Nekrep N, Tosi G, Esserman LJ, Peterlin BM
Yr: 2002 Vol: 22 Nbr: 15 Abs: Pg:5616-25