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    Research Grants Awarded

    Targeting Her2 Signalling By Alphaviral-Based Immunotherapy Plus Tyrosine Kinase Inhibition

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    This proposal seeks to test a novel combination of HER2 targeted therapies against trastuzumab-refractory breast cancer. Although trastuzumab-based therapy yields significant clinical benefits for HER2-overexpressing, metastatic breast cancers, refractory disease develops within 1 year. Recently, the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib, when combined with capecitabine, was reported to yield a higher response rate and time to progression than capecitabine alone, but the responses are transient in most. Nonetheless, these tumors continue to overexpress HER2, suggesting that other approaches for targeting HER2 such as immunotherapies that activate anti-HER2 T cells and antibodies may have efficacy. We have previously demonstrated the safety and immunogenicity of vaccines consisting of autologous dendritic cells loaded with protein fragments of HER2, but more recently have developed vaccines based on alphaviral particles containing RNA encoding the extracellular and transmembrane domains of HER2 (called VRP-ECD-TM) that are more efficient to produce, store, and administer. Alphaviral particles are notable for their ability to direct the production of large amounts of the antigenic protein within dendritic cells after injection, leading to potent immune responses. In murine models, VRP-ECD-TM induces antigen-specific immune responses that are able to slow the progression of implanted HER2 expressing tumors. An important observation from mice immunized against HER is that, in addition to T cell responses, antibodies are induced that are capable of binding to HER2 and causing immune mediated cellular destruction. Remarkably, sera from immunized mice also inhibit signaling through HER2 and a synergistic effect against HER2 signaling occurs when the sera from immunized mice are combined with lapatinib. We hypothesize that immunization against HER2 in the setting of lapatinib-based therapy will result in enhanced antitumor immunity and clinical response in patients with advanced, trastuzumab-refractory breast cancer. We will conduct a clinical trial to test this hypothesis by combining VRP-ECD-TM with the standard lapatinib plus capecitabine regimen. Our specific aims are: Aim 1. Perform a phase I/II clinical trial of HER2 encoding alphaviral replicon particle immunization with lapatinib-based therapy in trastuzumab (HerceptinTM) refractory HER2-overexpressing metastatic breast cancer; Aim 2. Investigate the cellular immunologic response to HER2 following immunization; Aim 3. Investigate the humoral response to the immunization by ELISA and the effect on signaling pathways of the induced antibodies. Successful completion of these aims is expected to provide considerable clinical benefit by providing a means to prolong the efficacy of lapatinib-based therapy, and will also be a scientific catalyst by providing a proof of principle about a new paradigm for combination targeted therapies that will have significance for other breast cancer clinical scenarios and other malignancies. Finally, from the antibody containing sera induced after immunization against HER2, we expect to develop new reagents such as antibodies capable of affecting other aspects of HER function such as interactions with HER3.

    Lay Abstract:
    This proposal seeks to develop and test a new way of targeting HER2+ breast cancers by combining immune therapy with anti-signaling therapy. Although great strides have been made in the treatment of HER2+ breast cancers with drugs such as the antibody trastuzumab (Herceptin) and the small molecule tyrosine kinase inhibitor lapatinib (Tykerb), the cancer eventually progresses in most. Importantly, though, the breast cancer continues to overexpress HER2, suggesting that other ways of targeting HER2 such as cancer vaccines that can activate T cells and antibodies against HER2 might be useful treatments. We have tested a series of such vaccines and found them to have few side effects and to activate the immune system. More recently we have developed vaccines which consist of virus-like particles that contain the genetic material which encodes pieces of HER2 called VRP-ECD-TM. These are more efficient to produce, store, and administer. In mice engineered to express HER2 in their tissues and which have been implanted with HER2+ tumors, vaccination against HER2 induces immune responses that are able to slow tumor growth. As expected, the antibodies induced by the vaccine can kill tumor cells by binding complement which punches holes in the cell membrane, a typical way that antibodies function. Remarkably, the antibodies in the serum of vaccinated mice could also inhibit signaling through HER2 and had an effect that was greater still when combined with lapatinib. We hypothesize that immunization against HER2 in the setting of lapatinib-based therapy will result in enhanced antitumor immunity and clinical benefit in patients with advanced, trastuzumab-refractory breast cancer. We will conduct a clinical trial to test this hypothesis by combining the VRP-ECD-TM with the standard lapatinib plus capecitabine regimen. Our specific aims are: Aim 1. Perform a phase I/II clinical trial of HER2 encoding alphaviral replicon particle immunization with lapatinib-based therapy in trastuzumab (HerceptinTM) refractory HER2-overexpressing metastatic breast cancer; Aim 2. Investigate the cellular immunologic response to HER2 following immunization; Aim 3. Investigate the humoral (antibody) response to the immunization and the effect that these antibodies have on signaling through the HER2 molecule. We will also determine if the antibodies have functions different than trastuzumab such as preventing HER2 and HER3 from joining together, an event that otherwise causes potent activation of the breast tumor. Completion of these aims will not only provide a strategy to prolong and enhance the benefits of lapatinib-based therapy, but will also demonstrate a principle about combination targeted therapies that will have significance for other breast cancer scenarios and other malignancies. Finally, we expect to develop new reagents such as antibodies capable of affecting other aspects of HER function such as interactions with HER3. We envision the development of future drugs with a greater ability to inhibit HER2+ breast cancers based on these antibodies and combination therapies.