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IL-12 genetic immunotherapy for lung cancer

Institution: University of California, Los Angeles
Investigator(s): Steven Dubinett, M.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8IT-0035 Award: $75,000
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
Lung cancer is the leading cause of cancer death in men and women in the United States. New therapies are needed for lung cancer to either prevent or treat its spread throughout the body. This research focuses on boosting the immune system against lung cancer by using specialized immune enhancing cells called dendritic cells. This new form of therapy uses dendritic cells that are removed from the blood, activated in test tubes, and then injected into lung tumors. This type of therapy is able to completely cure mice with cancer. In order to develop dendritic cell immunotherapy for patients with lung cancer, this research focuses on determining how this therapy works in mice with lung cancer. This is research that can be translated from laboratory studies into clinical trials in patients with lung cancer. Thus, results of this study may have a major impact on the treatment of lung cancer.

Final Report
Overall objective and hypothesis In this proposal we hypothesize that autologous dendritic cells (DC), when transduced with an adenoviral vector expressing the IL-12 gene (DC-AdIL-12), can be used to stimulate specific and therapeutic anti-tumor immunity without the need for priming with a tumor antigen ex vivo. In preliminary studies, the intraturnoral injection of these gene modified DC into established murine tumors induced specific antitumor responses both locally and at metastatic sites. Animals treated in this manner not only experienced complete tumor regression, but were protected from subsequent tumor challenge. We hypothesize that the autologous tumor provides access to the entire repertoire of available antigens, both increasing the likelihood of a response and reducing the potential for phenotypic modulation. The overall goal of this proposal is to use murine models to determine the immuunologic mechanisms by which DC-AdIL-12 mediates tumor eradication.

The problem to be investigated Lung cancer, with an overall 5-year survival of less than 15%, is the leading cause of cancer-related death in the United States. This statistic has changed minimally in the last 20 years and new therapeutic strategies are clearly needed. While various methods of immune stimulation have shown promise in the past, none have proven clinically effective for lung cancer. We now have a clearer understanding of the problem: while lung cancers express tumor antigens, they are ineffective as antigen presenting cells. In fact, the tumor's lack of costimulatory molecules, in combination with the tumor's production of inhibitory factors, promotes a state of specific T cell anergy. Our efforts to produce an effective cancer therapy are therefore focused on methods to restore tumor antigen presentation. Dendritic cells (DC) are bone marrow-derived leukocytes characterized by the following important parameters: high level expression of major histocompatibility complex (MHC) and co-stimulatory molecules, the ability to take-up and process antigens, the ability to secrete immunostimulatory cytokines, and the capacity to use all of these features to activate and expand antigen specific T cells. Recent clinical trials have shown that DC, when appropriately armed with a tumor antigen (Ag), can promote antitumor immunity and clinically significant tumor regression.

Work accomplished in Specific Aims We have made progress in both specific aims and found that the intratumoral administration of cytokine gene modified DC leads to systemic tumor reduction that is accompanied by trafficking to regional and systemic lymph nodes.

We are currently evaluating the phenotype of the DC requisite for antitumor responses.
Publications

1kBa gene transfer is cytotoxic to squamous cell lung cancer cells and sensitizes them to TNFa-mediated cell death
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Batra RK, Guttridge DC, Brenner DA, Dubinett SM, Baldwin AS, Boucher RC ART
Yr: 1999 Vol: 21 Nbr: Abs: Pg: 238-245

T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function
Periodical: Journal of Immunology Index Medicus:
Authors: Sharma S, Stolina M, Lin Y, et al ART
Yr: 1999 Vol: 163 Nbr: Abs: Pg: 5020-5028

THC-mediated, IL-10 dependent suppression of anti-tumor immunity in murine lung cancer
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Zhu L, Sharma S, Stolina M, et al ART
Yr: 1999 Vol: 159 Nbr: A404 Abs: Pg:

1KBa gene transfer into lung cancer cells induces cytotoxicity and apoptosis
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Batra RK, Guttridge DC, Brenner DA, Dubinett SM, Boucher RC ART
Yr: 1999 Vol: 159 Nbr: A237 Abs: Pg:

Intratumoral administration of cytokiine gene-modified dentritic cells augments specific antitumor immunity and achieves systemic tumor eradication
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller PW, Sharma S, Stolina M, et al ART
Yr: 1999 Vol: 159 Nbr: A238 Abs: Pg:

Mechanisms of IL-10-mediated suppression of antigen presentation in lung cancer
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Sharma S, Stolina M, Lin Y, Zhu L, Miller PW, Dubinett SM ART
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 512

Transfer of IL-10 overproducing lymphocytes reverses the antitumor effects of cyclooxygenase 2 inhibition
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Stolina M, Sharma S, Lin Y, et al ART
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 77

Intratumoral administration of cytokine gene-modified dendritic cells augments antigen prsentation and processing in non-small cell lung cancer
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Miller PW, Sharma S, Stolina M, Zhu L, Dubinett SM ART
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 86

Antisense inhibition of cyclooxygenase-2 blocks invasion and promotes apoptosis in non-small cell lung cancer (NSCLC)
Periodical: Cancer Gene Therapy Index Medicus:
Authors: Dohadwala M, Luo J, Lin Y, Sharma S, Stolina M, Dubinett SM ART
Yr: 1999 Vol: 6 Nbr: Abs: Pg: S3

Increased radioisotope uptake in non-small cell lung cancer following transfection with the sodium/iodide symporter gene
Periodical: Cancer Gene Therapy Index Medicus:
Authors: Huang M, Kogai T, Lin Y, et al ART
Yr: 1999 Vol: 6 Nbr: Abs: Pg: S21

Intratumoral administration of adenoviral interleukin-7 gene-modified dendritic cells augments specific antitumor immunity and tumor eradication
Periodical: Human Gene Therapy Index Medicus:
Authors: Miller PW, Sharma S, Stolina M ART
Yr: 2000 Vol: 11 Nbr: Abs: Pg: 53-65

Specific inhibition of cyclooxygenase 2 restores antitumor by altering the balance of IL-10 and IL-12 synthesis
Periodical: Journal of Immunology Index Medicus:
Authors: Stolina M, Sharma S, Lin Y, et al ART
Yr: 2000 Vol: 164 Nbr: Abs: Pg: 361-370

Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells
Periodical: Journal of Immunology Index Medicus:
Authors: Kiertscher SM, Luo J, Dubinett SM, Roth MD ART
Yr: 2000 Vol: 164 Nbr: Abs: Pg: 1269-1276

Adenoviral gene transfer is inhibited by soluble factors in malignant pleural effusions
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Batra RK, Dubinett SM, Henkle BW, Sharma S, Gardner BK ABS
Yr: 2000 Vol: 22 Nbr: Abs: Pg: 1-8

SLC/6Ckine mediates T-cell-dependent antitumor responses in vivo
Periodical: Journal of Immunology Index Medicus:
Authors: Sharma S, Stolina M, Luo J, et al ART
Yr: 2000 Vol: 164 Nbr: Abs: Pg: 4558-4563

Tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway
Periodical: Journal of Immunology Index Medicus:
Authors: Zhu L, Sharma S, Stolina M, et al ART
Yr: 2000 Vol: Nbr: Abs: Pg:

New gene and cell-base therapies for lung cancer
Periodical: Seminars in Respiratory and Critical Care Medicine Index Medicus:
Authors: Batra RK, Sharma S, Dubinett SM ART
Yr: 2000 Vol: Nbr: Abs: Pg:

Tumor antigens in thoracic malignancies
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Dubinett SM, Batra RK, Miller PW, Sharma S ART
Yr: 2000 Vol: Nbr: Abs: Pg:

Cyclooxygenase-2-dependent invasion and apoptosis resistance in non-small cell lung cancer (NSCLC)
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: ART
Yr: 2000 Vol: 161 Nbr: 3 Abs: Pg: A677

Role of GM-CSF and IL-4 in the development of dendritic cell (DC) subsets and their localization in spleen of mice
Periodical: American Association for Cancer Research Index Medicus:
Authors: Basak SM, Trejo DT, Stolina M, Dubinett SM, Roth MD ART
Yr: 2000 Vol: 41 Nbr: Abs: Pg: 2

Lung cancer cyclooxygenase-2 dependent inhibition of dendritic cells maturation and function
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Stolina M, Sharma S, Zhu L, Dubinett SM ART
Yr: 2000 Vol: 41 Nbr: Abs: Pg: 619

Intratumoral dendritic cell based genetic immunotherapy for lung cancer
Periodical: Methods in Molecular Genetics Index Medicus:
Authors: Sharma S, Yang K, Dubinett SM ART
Yr: 0 Vol: Nbr: Abs: Pg: