Antibody-IL-2 Fusion Protein for Breast Cancer Immunotherapy

Institution: Sidney Kimmel Cancer Center
Investigator(s): Joseph Lustgarten, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4KB-0010 Award: $419,144
Award Type: New Investigator Awards
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (1998)
Cancer immunotherapy relies on the ability of specialized white blood cells called cytolytic T lymphocytes (also called killer T cells) to eradicate tumor cells. These T cells recognize and destroy damaged or foreign cells that make proteins (antigens) that are not produced in an individualís normal cells. However, killer T cells that specifically eliminate tumor cells are not frequently found in cancer patients. Our goal is to manipulate the immune system to produce killer T cells that specifically recognize and eliminate breast tumors. We will focus on three antigens that are found in breast tumors: Her-2/neu, Her-3, and Her4. Her-2/neu and Her-3 are expressed on 25-35% of all breast cancers and are associated with poor prognosis and low survival. It has been proposed that elimination of tumor cells expressing Her-family receptors could improve the effectiveness of drug treatment and prolong survival time.

We have recently generated a fusion protein that is a combination of an antibody and a cytokine (IL2 - a compound necessary for obtaining a vigorous immune response). This fusion protein is targeted to the Her-2/neu protein. We have observed that T cells in the presence of this fusion protein are able to kill target cells in a manner that is independent of the their normal route through the T cell receptor. It is our hypothesis that a treatment protocol using a combination of functional T cells from cancer patients with the anti-Her-2/neu fusion protein will improve the efficiency of immunotherapy for breast cancer. We are trying to recreate a pre-clinical mode that is analogous to the situation in breast cancer patients to test the efficacy of this strategy to control the growth of breast tumors. We will use a mouse model to test the ability of T cells from patients with breast cancer to eliminate the tumor from breast carcinomas cell lines expressing Her-2/neu. In addition, we will generate another fusion protein composed of the ligand for Her-3 and Her4. This work will assist in the development of a new strategy to reinforce the body's defenses against existing tumors.

Final Report (2003)
The major limitation of the existence of tumor specific T-cells within the repertoire is self-tolerance. Such tolerance can disable the capacity of the immune system to respond to antigens by eliminating or energizing T-cells with the potential to recognize tumor associated antigens (TAA). In order to overcome such tolerance we found mechanisms in which T-cells are able to kill target cells in a non-MHC restricted manner in the presence of an antibody-IL-2 fusion protein.

We have generated two different fusion proteins: 1) anti-Her-2/neu-IL-2, 2) Hereguhn-IL-2. With these fusion proteins, T cells are able to recognize tumor cells expressing Her-family receptors (Her-2/neu, Her-3 and Her-4). Her-family receptors are over expressed in breast cancer and are associated with metastatic disease, poor prognosis and low survival. We found that these fusion proteins have the ability to redirect non-tumor specific T cells to the tumor microenvironment inducing the elimination of tumor. Therefore these proteins represent an excellent target for T cell immunotherapy.

In addition, we have demonstrated in a SCID tumor model that the anti-Her-2/neu-IL-2 and Heregulin-IL-2 fusion protein in combination with anti-CD3 stimulated T cells are able to control the growth of tumor in a non-MHC restricted manner. Thus, this immunotherapeutic approach is an alternative strategy to eradicate Her+ tumors especially when tolerance has hampered the immune system.

Redirecting effectors T cells through thier IL-2 receptors
Periodical:Journal of Immunology
Index Medicus: J Immunol
Authors: Lustgarten, J., Marks, J., and Sherman, L.A.
Yr: 1999 Vol: 162 Nbr: 1 Abs: Pg:359-65