ACT of T cell receptor (TCR) gene- modified T cells specific to tumor antigens (Ags) is currently in clinical trials for patients with advanced malignancies. Transduction (Tdx) of human and murine T cells with our retroviral vector encoding the TIL 1383I TCR genes allows for recognition and killing of HLA-A2+, Tyrosinase (Tyr)+ melanoma cells in vitro and in vivo. Limitations to the efficacy of autologous ACT include: less potent activity of transferred cells in vivo, possibly due to the immunosuppressive tumor microenvironment or to the altered biology of cells from a cancer patient. Another limitation is the monospecificity of the transferred cells, which could lead to immune escape variants; therefore, it is vital to build upon this therapy to achieve better and more durable clinical responses. Therapeutic efficacy of cancer vaccines has been shown to correlate with mounting a broad systemic anti-tumor response through induction of cross priming. A phase I clinical trial in collaboration with Dr. Keld Kaltoft, administered intratumoral injections of irradiated, allogeneic, MART-1-specific T cells into stage IV melanoma patients. Two of fifteen patients had regression of non-injected lesions and two patients developed vitiligo, suggesting induction of systemic anti-tumor immunity and generation of T cells specific to additional melanoma Ags. We propose to use intratumoral injection of Tyr TCR transduced (Td) allogeneic T cells as an alternate approach to systemic infusion of Tyr TCR Td autologous T cells to enhance host immune activation and overcome the immunosuppression that prevents destruction of tumors. We hypothesize that intratumoral injection of Tyr TCR Td allogeneic T cells will promote pro-inflammatory cytokine responses and lytic activity, leading to a favorable anti-tumor environment that facilitates epitope spreading and cross priming against additional melanoma Ags and results in regression of distant, untreated tumor lesions.
In Aim II, to further enhance anti-tumor responses and elicit cross priming, we will genetically modify Tyr TCR Td T cells to overcome the immunosuppressive tumor microenvironment and to boost adaptive immune responses. By understanding mechanisms that maximize T cell function within the tumor microenvironment and generate systemic anti-tumor immunity, we can improve upon the therapeutic efficacy and safety of T cell-based immunotherapies.

Public Health Relevance

ACT of T cell receptor gene- modified T cells specific to tumor antigens is currently in clinical trials for patients with advanced malignancies. Transduction of human and murine T cells with our retroviral vector encoding the TIL 1383I TCR genes allows for recognition and killing of HLA-A2+, Tyrosinase+ melanoma cells in vitro and in vivo, however there are limitations to the efficacy of autologous T cell transfer. Because the therapeutic efficacy of cancer vaccines has been shown to correlate with mounting a broad, systemic anti-tumor response through induction of cross priming, we propose to use intratumoral injections of Tyr TCR transduced T cells from an allogeneic source as an alternate approach to systemic infusion of Tyr TCR Td autologous T cells to enhance host immune activation and overcome the immunosuppression that prevents destruction of tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA206507-01A1
Application #
9195273
Study Section
Special Emphasis Panel (ZRG1-OBT-J (21)L)
Program Officer
Mcneil, Nicole E
Project Start
2016-07-18
Project End
2019-07-17
Budget Start
2016-07-18
Budget End
2017-07-17
Support Year
1
Fiscal Year
2016
Total Cost
$30,370
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153