Alpha Omega Alpha Honor Medical Society

2012 Research Abstract

Use of High Affinity FcR-expressing T Cells in Recognition and Destruction of Cancer Tumors in vivo

Investigators: Tamara Aghamolla, Degui Geng, and Eduardo Davila

Mentor: Eduardo Davila, PhD, Greenebaum Cancer Center, Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland

Cytotoxic T cells have the ability to recognize and destroy malignant tumor cells by presenting peptides that are derived from tumor-associated antigens (TAA) in a complex with the major histocompatibility complex (MHC) class I molecules. Thus, cytotoxic T cells have been utilized for cancer immunotherapy treatments, specifically through Adoptive Cell Therapy (ACT). Unfortunately, the clinical efficiency of ACT for tumor patients is still limited because the isolation and expansion of naturally occurring TAA-specific T cell clones is labor-intensive, time consuming, and technically difficult due to the few number of TAA-specific T cells found and their anergic nature. Here, we have developed an adaptable gene platform that confers immune cell specificity to various cancer types that can be used in combination with vaccines composed of TAA-specific IgGs or with the infusion of tumor-reactive antibodies. Human and mouse T cells were transduced with a chimeric antigen receptor (CAR) containing the high-affinity IgG Fc Receptor (FcγRIII; FcγRI); an activation signal (CD3) and costimulatory signals (CD28; 4-1BB) that promote T cell survival and proliferation. Various antibodies currently in clinical use including trastuzumab (αHer-2; TzAb), cetuximab (αEGFR; Ctx), and rituximab (αCD20; Rtx) were tested for their ability to bind tumor cells, activate T cells, and induce anti-tumor effects in vitro and in vivo. T cell functionality was proven in vitro by efficient target lysis and cell proliferation in response to antibodies in both the presence and absence of tumor cells. Combinatorial treatment with FcR-T cells and TzAb successfully delayed the progression of an established mouse breast cancer tumor expressing Her-2 in vivo as compared with TzAb or FcR-T cells alone. These findings demonstrate that the use of the high-affinity FcR-T cells in conjunction with TAA-specific IgGs has the potential to re-direct T cells to eliminate malignant tumor cells against various cancer types in patients.

Updated on September 6, 2012.

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