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Mobilized dendritic cells for lung cancer

Institution: Stanford University
Investigator(s): Edgar Engleman, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0229 Award: $950,821
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Non-small cell lung cancer (NSCLC) represents the most common form of lung cancer and, like most forms of lung cancer, the single greatest risk factor for NSCLC is cigarette smoking. Unfortunately, NSCLC cannot be reversed by cessation of smoking and currently available treatment (surgery and chemotherapy) provides only limited benefit. In fact, only 15% of patients with NSCLC live for 5 years once the diagnosis is made. Because NSCLC is so common and so deadly, more effective treatment is urgently needed. In this project we will develop and test a new approach to the treatment of NSCLC that uses the body’s natural defense system, known as the immune system. This system efficiently defends the body against infectious organisms, which are detected as “foreign” and destroyed, but tumor cells typically evade detection because the differences between them and normal cells are small. Our strategy is to use specialized white blood cells known as dendritic cells (DC) to stimulate the immune systems in patients with NSCLC such that they recognize and destroy the tumor cells. To make this approach possible patients will initially be treated with Flt-3 ligand, a factor that stimulates the production of DC by the bone marrow and causes the release of the newly produced cells into the blood. The DC will then be removed from the blood, “loaded” with a substance called Carcinoembryonic Antigen (CEA) that is produced by and present on NSCLC tumors, and their own cells will be returned to the patients in a manner similar to that used for blood transfusions. Once inside the body, the CEA-loaded DC should behave like a vaccine and stimulate the immune system to recognize and destroy the tumor cells. This approach has already been tested in six patients. The treatment was well tolerated and without serious side effects. Moreover, all of the patients developed immune responses to CEA and 3 patients showed evidence of tumor shrinkage including one patient whose tumor has almost disappeared. In the proposed project this approach will be tested in two clinical trials involving a total of 45 patients with advanced, inoperable NSCLC. In the first trial DC will be used together with a small fragment of CEA to stimulate the immune system. In the second trial DC will be loaded with the entire CEA molecule and, in addition, before the cells are administered to the patients they will be exposed to another substance that increases their potency. During the trials the patients will be monitored closely both to assure their safety and to determine if the treatment affects their tumors. The results should provide a clear indication of how effective this new form of immune therapy is in the treatment of NSCLC. If the results are promising, the same approach could be used to treat other types of cancer.

In vivo manipulation of dendritic cells to induce therapeutic immunity
Periodical: Blood Index Medicus:
Authors: Merad, M, Sugie, T., Engleman, E.G. and Fong, L. ART
Yr: 2002 Vol: 99 Nbr: Abs: Pg: 1676-1682

Langerhans cells renew in the skin throughout life under steady-state conditions.
Periodical: Nature Immunology Index Medicus:
Authors: Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Englema ART
Yr: 2002 Vol: 3 Nbr: Abs: Pg: 1135-1141

Dendritic cell-based cancer immunotherapy.
Periodical: Seminars in Oncology Index Medicus:
Authors: Engleman EG ART
Yr: 2003 Vol: 30 Nbr: Abs: Pg: 23-29

Induction of immunity to tumor-associated antigens following dendritic cell vaccination of cancer patients.
Periodical: Clinical Immunology Index Medicus:
Authors: Engleman EG, Fong L ART
Yr: 2003 Vol: 106 Nbr: Abs: Pg: 10-15

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs.
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Furumoto K, Soares L, Engleman EG, Merad M ART
Yr: 2004 Vol: 113 Nbr: Abs: Pg: 774-783

DC-based cancer vaccines: lessons from clinical trials.
Periodical: Cytotherapy Index Medicus:
Authors: Brody J, Engleman EG ART
Yr: 2004 Vol: 6 Nbr: Abs: Pg: 122-127