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Morphological and Functional Aspects of Active Specific Immunotherapy of Established Pulmonary Metastases in Guinea Pigs¹

Cancer Metastasis and Treatment Laboratory, National Cancer Institute Frederick Cancer Research Center, Frederick, Maryland 21701

Using active specific immunotherapy, we evaluated the efficacy of syngeneic tumor cell vaccines supplemented with the adjuvant Mycobacterium bovis strain Bacillus Calmette-Guérin against established pulmonary metastases. In a series of experiments, inbred strain 2 guinea pigs were given i.v. injections of 10⁶ syngeneic hepatocarcinoma cells (100 times the minimum lethal dose). Animals were not treated or were treated once a week for 2 weeks with vaccines consisting of 10⁷ cryopreserved, X-irradiated viable tumor cells admixed with 10⁷ live B. Calmette-Guérin and on the third week with a vaccine consisting of 10⁷ tumor cells alone. To assess the limits of tumor burden in this model, we immunized groups of animals on Days 1, 4, 7, or 10 after i.v. tumor challenge. The pulmonary tumor foci ranged from clumps of several cells at Day 1 to nodules between 0.1 and 0.2 mm in diameter at Day 10. By Days 21 to 24 after i.v. tumor challenge, the pulmonary nodules were macroscopic in size, equal to or greater than 0.5 mm in diameter. While significant protection was measured by survival, the effectiveness of this combination of tumor cells plus B. Calmette-Guérin was limited by tumor burden. Morphological evaluation of pulmonary tumor foci in treated animals revealed mononuclear cell infiltration characteristic of a cell-mediated hypersensitivity reaction in the time interval between the first and second immunization. By the time of the third immunization, the nodules had progressed to a marked histiocytosis with fibrosis and central necrosis. It is possible not only that these specific immunological reactions accomplish a significant reduction of the tumor mass but that the host-mononuclear cell infiltrate disrupts the organized histological architecture of metastatic clones, perhaps by the release of soluble factors such as lymphokines. This disruption of the organized histological architecture of the metastatic clones creates a state in which the tumor cells may be more vulnerable or exposed, by destroying the anatomic barriers that allow the tumor to escape disruption by a variety of antitumor agents. This report suggests that multimodality therapy such as post-surgical active specific immunotherapy would be enhanced in combination with other antitumor agents, which on their own would be limited by the anatomical organization of micrometastatic nodules.

¹ Research sponsored by the National Cancer Institute, Department of Health and Human Services, under Contract N01-CO-75380 with Litton Bionetics, Inc. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

² To whom requests for reprints should be addressed.

Received 2/23/81. Accepted 6/30/81.

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