Adoptive cell therapy using primary T lymphocytes with genetically engineered T cell receptors against melanoma and glioma

Over the past few decades, our knowledge of tumor immunology and the role antitumor immune responses play in tumor recognition and eradication has greatly increased and led to immunotherapies being investigated as a promising strategy for cancer treatment. Current clinical studies with various immunotherapies have shown promising results, including therapy with adoptive cell transfer (ACT) of T lymphocytes. T cell immunotherapy is highly attractive because T cells have the ability to selectively recognize and destroy malignant neoplastic cells. Although a promising approach, one of the limitations encountered clinically is the difficulty isolating and expanding tumor-specific T lymphocytes from patients. This limitation may be circumvented by genetically engineering T lymphocytes to express antigen-specific T cell receptors (TCR). The goal of this work was to investigate adoptive T cell therapy using primary T lymphocytes modified to express genetically engineered T cell receptors against murine melanoma and glioma. In chapter 2, a new SIYRYYGL (SIY) peptide-expressing murine glioma cell line (GL261-SIY) was generated as a model to investigate strategies to improve adoptive T cell therapy for brain tumors. Our findings demonstrated successful development of this new cell line as determined by surface expression of SIY antigen and effective peptide presentation to T cells in vitro resulting in T cell activation and induction of cytotoxic T cell activity. In vivo, T cell infiltration of brain tumors and long-term survival benefits with adoptive transfer of transgenic and TCR-modified T cells was examined. In chapter 3, ACT of MHC class I-redirected CD4+ helper T cells was evaluated in a subcutaneous murine melanoma tumor model. TCRs specific for MHC class I-restricted antigens were introduced into CD4+ cells to assess whether high affinity TCRs, in the nanomolar affinity range, could provide an enhanced antitumor response compared to micromolar affinity wild type TCRs. Our study revealed improved survival and long-term immunity with CD4+ T cells expressing high affinity MHC class I-restricted TCRs. T cell therapy with CD4+ T cells (alone or in combination with CD8+ T cells) for the treatment of murine glioma and melanoma resulted in development of graft-versus-host disease (GVHD) in some mice. In chapter 4, mice affected by GVHD were studied in detail. Clinical signs, physical GVHD presentation, and GVHD-associated histopathology were dissected to better understand the mechanisms and factors involved in the in vivo interactions between the transferred T cell populations and the affected host tissue. Overall, this work examined adoptive therapy with ex vivo activated T cells expressing wild type or high affinity genetically engineered TCRs for the treatment of established tumors in mice, as well as GVHD development secondary to T cell therapy. The findings in these collective studies demonstrate that immunotherapy with CD8+ and CD4+ T cells expressing gene-modified TCRs is a distinct strategy to optimally exploit cytotoxic T lymphocyte (CTL) effector functions and helper T cell functions. T cell immunotherapy is a very powerful therapeutic approach for treatment of cancer with the potential of driving potent antitumor responses capable of achieving life-changing clinical benefits for patients.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Soto, Carolina

Contributors dc:contributor

• Roy, Edward J.
• Ceman, Stephanie S.
• Kranz, David M.
• Olivero, William C.

• Cancer Immunotherapy
• Tumor Targeting
• T cell receptors (TCR)
• T cell
• Melanoma
• Adoptive Cell Therapy
• Glioma

Statement dc:rights

• Copyright 2012 Carolina Soto

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/42476

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/42476