Combating Breast Cancer with the Wellderly Immune Repertoire

Institution: Scripps Research Institute
Investigator(s): Brunhilde Felding, Ph.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15IB-0050 Award: $284,718
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2009)

The “Wellderly” are a group of 1000 healthy people in their eighties who never had cancer or any other chronic disease. Our idea is that many of these people have a strong immune system, and that some may have had developing breast cancer cells in their bodies, at some point in time, but successfully produced antibodies that prevented tumor establishment. Our project will tap into the genes of the “Wellderly” and generate a “library” from their immune cells. This library will then be used to fish out antibodies that can inhibit breast cancer cells, particularly those that cause inflammatory breast cancer, the most aggressive form of this disease.

For this project we have established a new breast cancer cell model that includes cell lines from the primary tumor, a local recurrence and a pleural effusion that developed despite chemotherapy and radiation in a young patient with very rapidly progressing inflammatory breast cancer. We will use this new model to address the following questions:

1) Can we identify and isolate antibodies from the Wellderly immune repertoire that inhibit the growth of the aggressive breast cancer cells in culture and tumor development caused by these cells in experimental mice?
2) What are the molecules that these antibodies recognize on the tumor cells, and can we learn from this information how aggressive breast cancer works?
3) How do the tumor cells change while the patient is being treated with chemo and radiation, and what makes the tumor cells survive and escape the therapy?

Our approach is to ‘mine’ the antibody library from the “Welldely” population by first removing antibodies that react with normal breast tissue. Then, we will pull out antibodies that specifically react with the aggressive breast cancer cells. Antibodies that bind to the tumor cells will be tested in culture, to see if they can inhibit tumor cell growth. Promising antibodies will be tested in mice that bear tumors from injecting the human breast cancer cells, to measure if this antibody treatment can stop tumor growth and spreading. Finding out which molecules such antibodies recognize on the tumor cells will help us understand how the cancer cells grow, produce tumors and spread the disease. Finally, we will analyze the gene expression profiles of the breast cancer cells from the primary tumor and the cells that caused the relapse and rapid cancer progression in the patient, even though she had various types of chemotherapy and radiation treatment.

Human antibodies from the “Wellderly” might be directly used in patients or could be optimized for efficient therapy and combination treatments.




Final Report (2010)

The “Wellderly” is a group of 1000 healthy people in their eighties who never had cancer or any other chronic disease. Our idea is that many of these people have a strong immune system, and that some may have developing breast cancer cells in their bodies, at some point in time, but successfully produced antibodies that prevented tumor establishment. Our project will tap into the genes of the “Wellderly” by using a “library” from their immune cells that we generated. The library will be used to fish out antibodies that can inhibit breast cancer cells, particularly those that cause inflammatory breast cancer, the most aggressive form of this disease.

We established a new breast cancer cell model that includes cell lines from the primary tumor, a local recurrence and a pleural effusion that developed despite chemotherapy and radiation in a young patient with very rapidly progressing inflammatory breast cancer. Using this model we identified key changes and novel pathways as likely drivers of the disease. Our progress includes:

  1. Isolating antibodies from a phage display antibody library from the immune repertoire of the “Wellderly” population, which inhibit growth of aggressive inflammatory breast cancer cells.
  2. Analyzing the gene expression profiles of increasingly aggressive and therapy resistant tumor cells from a patient with rapidly progressing inflammatory breast cancer.

Our progress consolidates the scientific and clinical relevance of our initial aims and allowed us to expand our focus on new lead mechanisms as possible disease drivers. Importantly, we also extended the genetic analyses of our progression model and are beginning to understand gains and losses of chromosomal regions in relation to gene expression regulation. We realized that our progression model has tremendous potential for revealing causes and drivers in breast cancer and its progression and treatment resistance. We therefore decided to fully explore this model in this study. In the future, we will broaden the perspective and ask how specific our lead mechanisms are for a particular breast cancer type, or whether the implications are more general.




Symposium Abstract (2010)

Breast cancer diagnosis and treatment have much improved, but some tumor types stubbornly resist therapy. Our goal is to identify novel markers of hard-to-treat breast cancer for the development of novel effective therapies. This is achieved through a combination of two major approaches using our novel model of triple-negative inflammatory and metaplastic breast cancer, the most aggressive type of this disease. In the first approach, we are tapping into the immune repertoire of healthy long-lived people (the wellderly) to identify antibodies that can block breast cancer growth. We hypothesize that many ‘wellderly’ individuals may have encountered developing breast cancer cells in their bodies over the years, but remained clinically disease free over decades - in many cases despite non-favorable genetic disposition and accumulating risk factors encountered over a lifetime. In the second approach, we are comparing the gene expression profiles of variants of our breast cancer cell model that represent increasingly aggressive and treatment resistant stages of the disease.

Our work during the first year of this project has focused on:

Our results identified genes associated with epithelial to mesenchymal transition (EMT) as a predominant set of changes during progression of this triple negative inflammatory and metaplastic breast cancer. Analyses of the adhesive, migratory and invasive properties of these cells indicated that EMT is a major driver of malignant progression in this model. Consistent with this notion, the tumor recurrence and pleural effusion derived tumor cells are strikingly more tumorigenic in SCID mice the cells from the primary breast cancer. Other major changes were seen in cytoskeletal genes, chemokines and their receptors, drug transporter proteins, metalloproteinases and matrix proteins.

Our developments and findings support our original research plan and contribute important new information on mechanisms that drive progression of hard-to-treat triple negative breast cancer. Our analyses have lead to the identification of an array of novel potentially clinically and functionally important markers in this breast cancer type. Our functional validation studies have revealed new leads for possible inhibition of triple-negative breast cancer progression and opened focused avenues for the upcoming, intensive studies on functional molecular pathways that are critical for aggressive breast cancer development.

Finding antibodies that can curb breast cancer growth and identifying their targets, combined with knowledge on the genetic changes that occur during disease progression of hard-to-treat and ultimately unresponsive breast cancer will help understand the nature of aggressive breast cancer, define specific new ways for inhibition, and provide tools for clinical therapy.