Despite improvements in the treatment of women with metastatic breast cancers (MBC), there are no curative treatment options. For the 20-25% of women with MBC who are HER2/neu (HER2) 3+, Herceptin(r) has become a mainstay of treatment in combination with chemotherapy. New approaches, however, are needed that will prolong progression-free survival (PFS) and overall survival (OS) for the 75-80% of the MBC patients who are HER2 0-2+ and are not eligible for Herceptin(r). In our previous phase I clinical trial, we have administered anti-CD3 activated T cells (ATC) "armed" with anti-CD3 x anti-HER2/neu bispecific antibody (HER2Bi) to women with both HER2-positive and HER2-negative MBC to determine their safety and the maximum tolerated dose. Arming ATC with HER2Bi makes every T cell into a HER2-specific cytotoxic T lymphocyte (CTL) with the potential to induce high levels of specific cytotoxicity that is independent of HER2 receptor-mediated mechanisms and thus, HER2 expression levels. Indeed, evaluation of immune responses in our phase I clinical trial patients suggests that infusions of Her2Bi-armed ATC induce robust immune responses regardless of the patient's HER2 status. Here, we propose a phase II trial that combines primary oncologist's choice of chemotherapy (ChemoT) consisting of 4 cycles or 4 months of followed by lymphodepletion with low dose fludarabine (Flu) and cyclophosphamide (Cy) before giving multiple infusions of Her2Bi-armed ATC to treat patients with MBC having HER2/neu 0, 1+, or 2+ amplification levels. The efficacy of the combined therapy for the entire group as measured by PFS (primary endpoint) will be compared to a median time to progression of 6 months derived from the literature for second line chemoT for MBC. We hypothesize that if Her2Bi-armed ATC infusions are capable of reversing the immunosuppressed-state of the patient, then infusions of Her2Bi-armed ATC after ChemoT will further enhance anti-tumor immunity directed at residual disease and improve progression free survival and tumor responses. Additionally, by lymphodepletion with Flu and Cy, we will provide an opportunity for the infused armed ATC to expand in vivo after infusion and thus, enhance MBC-specific immune-mediated cytotoxicity and/or to persist to develop central memory for tumor antigens.
In Aim 2, we will also evaluate functional and phenotypic immunological changes in peripheral blood and/or at the tumor site.
Aim 3 is designed to develop correlates between the systemic or tumor site immune responses monitored in Aim 2 and clinical outcomes in Aim 1. We predict that this approach involving Her2Bi-armed ATC-mediated anti-tumor "immunization" following second line chemotherapy for MBC will improve clinical outcomes.
In order to improve progression free survival in women with stage IV Her2/neu (0, 1 or 2+) metastatic breast cancer (MBC), we proposed to combine second line chemotherapy for MBC with lymphodepletion with using low dose fludarabine and cyclophosphamide followed by 8 infusions of 10 billion anti-CD3 activated T cells armed with anti-CD3 x anti-Her2/neu bispecific antibody given twice a week for 4 weeks (Aim 1). Sequential Immune function tests on the blood and tumor sites will be performed to monitor immune responses (Aim 2) and to develop clinical correlates (Aim 3).
|Lum, L G; Thakur, A; Pray, C et al. (2014) Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: a pilot study. Bone Marrow Transplant 49:73-9|
|Yano, Hiroshi; Thakur, Archana; Tomaszewski, Elyse N et al. (2014) Ipilimumab augments antitumor activity of bispecific antibody-armed T cells. J Transl Med 12:191|
|Lum, Lawrence G; Thakur, Archana; Liu, Qin et al. (2013) CD20-targeted T cells after stem cell transplantation for high risk and refractory non-Hodgkin's lymphoma. Biol Blood Marrow Transplant 19:925-33|
|Zitron, Ian M; Thakur, Archana; Norkina, Oxana et al. (2013) Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies. BMC Cancer 13:83|
|Thakur, Archana; Schalk, Dana; Tomaszewski, Elyse et al. (2013) Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE2 dependent pathway. J Transl Med 11:35|
|Thakur, Archana; Schalk, Dana; Sarkar, Sanila H et al. (2012) A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother 61:497-509|
|Thakur, Archana; Sorenson, Carly; Norkina, Oxana et al. (2012) Activated T cells from umbilical cord blood armed with anti-CD3 ýý anti-CD20 bispecific antibody mediate specific cytotoxicity against CD20+ targets with minimal allogeneic reactivity: a strategy for providing antitumor effects after cord blood transplant Transfusion 52:63-75|
|Lum, Lawrence G; Thakur, Archana (2011) Targeting T cells with bispecific antibodies for cancer therapy. BioDrugs 25:365-79|
|Thakur, Archana; Norkina, Oxana; Lum, Lawrence G (2011) In vitro synthesis of primary specific anti-breast cancer antibodies by normal human peripheral blood mononuclear cells. Cancer Immunol Immunother 60:1707-20|
|Thakur, Archana; Lum, Lawrence G (2010) Cancer therapy with bispecific antibodies: Clinical experience. Curr Opin Mol Ther 12:340-9|
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