Enhancing Trastuzumab Therapy with an NK Activating Antibody

Institution: Stanford University
Investigator(s): Ronald Levy, M.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16IB-0095 Award: $224,749
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2010)

Monoclonal antibodies which target cancer are among the most notable scientific advances in the last quarter century. Rapid translation of this research has prolonged the survival of thousands of patients with breast cancer through development of trastuzumab (Herceptin) which targets HER2/neu oncogene expressing breast cancers. Despite the promising activity of trastuzumab, the response rate among patients with advanced cancer is suboptimal. The anti-tumor activity of trastuzumab is dependent, in part, upon the patient’s immune response, which recognizes and destroys antibody-bound tumor cells. Specifically, this tumor-killing mechanism is through antibody dependent cell-mediated cytotoxicity (ADCC) whereby a natural killer (NK) cell bearing an Fc receptor binds to the antibody-targeted tumor cell and ultimately mediates the killing function. Unfortunately, conventional cytotoxic chemotherapies (e.g. antracyclines) induce myelosuppression, decreasing the population of NK cells, thereby reducing the efficacy of ADCC. Thus, therapies which augment NK cell function uniquely offer the ability to improve activity of monoclonal antibodies without increasing toxicity to non-cancer cells. We have recently demonstrated that ADCC function can be augmented and target cell killing can be enhanced by a second antibody against CD137, an NK “activating” cell surface molecule.

Thus, in this project we will test whether triggering the activation marker, CD137, on NK immune cells will enhance the anti-tumor efficacy of trastuzumab therapy against HER2/neu expressing breast cancer. First, we will demonstrate increased NK cell expression of CD137 following NK cell exposure to trastuzumab-targeted breast cancer. Second, we will investigate if stimulation of activated NK cells with anti-CD137 antibody enhances cytotoxicity against trastuzumab-targeted breast cancer in cell models. Finally, we will determine if treatment of xenografts (a mouse model) of human breast cancer is enhanced by anti-CD137 antibody together with trastuzumab.

Of the women with HER2-positive metastatic breast cancer, 60% do not respond to trastuzumab-based combination chemotherapy, and significant cardiac toxicity has been observed. Therefore, even though significant advances in cancer treatment have been made through monoclonal antibody therapy, there exists a substantial need for improvement. We are confident that the underlying biological rationale for combination of trastuzumab with a CD137 antibody will result in enhanced anti-breast cancer efficacy.

Final Report (2011)

Natural killer (NK) cells are fundamental effector cells mediating antibody-dependent cell-mediated cytotoxicity (ADCC). As the anti-tumor activity of trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER-2/neu, is due in part to ADCC, strategies which enhance NK cell function may improve trastuzumab’s clinical efficacy against HER-2/neu overexpressing tumors. Here we demonstrate that NK cell stimulation with an agonistic mAb against CD137, a co-stimulatory receptor, enhances trastuzumab-dependent cytotoxicity against HER-2/neu overexpressing breast cancer cells. In in-vitro and multiple in-vivo models, including xenotransplanted human breast cancer cell lines and a human primary breast tumor, combination of trastuzumab and anti-CD137 mAbs has potent and HER-2/neu-specific anti-breast cancer activity. These findings support further investigation of dual antibody therapies which selectively target the tumor and enhance the anti-tumor immune response.

The major accomplishments of this work include demonstration of:

  1. Trastuzumab induces CD137 upregulation on human NK cells following exposure to HER2-positive tumor cells,
  2. Anti-CD137 agonistic mAb increases trastuzumab-mediated NK cell cytokine secretion and trastuzumab-dependent NK cell-mediated cytotoxicity, and
  3. Anti-CD137 agonistic mAb enhances anti-breast cancer activity of trastuzumab in-vivo.

We are hopeful this work will translate to a Phase I clinical trial in breast cancer as it is currently being planned in lymphoma in the near future.

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer
Periodical:Journal of Clinical Investigation
Index Medicus: J Clin Invest
Authors: Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, Colevas AD...Levy
Yr: 2012 Vol: 122 Nbr: 3 Abs: Pg:1066-1075