Activated Lymphocytes Improve Response to Monoclonal Antibody Treatment of Breast Cancer

Cancer researchers have detailed the mode of action of the monoclonal antibody trastuzumab, the standard treatment for breast cancers that overexpress human epidermal growth factor-2 (HER2/ErbB-2).

The over-expression of HER2/ErbB-2 is the main cause of tumor proliferation in 20 to 30% of breast cancer patients. While trastuzumab has become the drug of choice for treating these patients, its exact mechanism of action had not been fully elucidated. In the current study, investigators at the University of Montreal (Canada) and the Peter MacCallum Cancer Center (East Melbourne, Australia) focused on the molecular events initiated by the binding of trastuzumab to HER/ERB-2.

They reported in the April 26, 2011, issue of the journal Proceedings of the [US] National Academy of Sciences (PNAS) that anti–ErbB-2 monoclonal antibody therapy was dependent on the release of type I and type II interferons but was independent of perforin (a pore-forming protein produced by cytotoxic T cells) or FasL (a transmembrane protein belonging to the tumor necrosis factor (TNF) family that induces apoptosis when it binds with its receptor).

The results of this study contradict the notion that classical antibody-dependent, lymphocyte-mediated cellular cytotoxicity is important for trastuzumab. Rather, they show that trastuzumab treatment of experimental tumors derived from MMTV-ErbB-2 transgenic mice triggered MyD88-dependent signaling and primed IFN-gamma–producing CD8+ T cells. The presence of these activated lymphocytes in tumors enhanced treatment success.

The investigators increased the presence of activated lymphocytes in tumors by adding monoclonal antibodies against programmed death-1 (PD-1) or 41BB (CD137) while treating with trastuzumab. They found that anti–PD-1 or anti-CD137 monoclonal antibodies could significantly improve the therapeutic activity of trastuzumab in immunocompetent mice.

"These findings open another avenue for breast cancer treatment for nearly a third of all women who are affected," said first author Dr. John Stagg, professor of pharmacy at the University of Montreal.

Related Links:
University of Montreal
Peter MacCallum Cancer Center