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Immunotherapy with Biochemically Dissociated Fractions of Propionibacterium acnes in a Murine Ovarian Cancer Model¹

Division of Gynecologic Oncology [J. S. B., N. F. H., R. M. K., T. P., R. M. E., L. D. L.], and Departments of Microbiology and Immunology [A. K. L., J. Z.], Medicine, and Surgical Pathology [R. K. N.], UCLA School of Medicine, Los Angeles, California 90024; the Department of Medicine, Wadsworth VA Hospital [A. K. L.], Los Angeles, California 90073; and Ribi ImmunoChem Research, Inc. [J. L. C.], Hamilton, Montana 59840

The antitumor effect of two strains of Propionibacterium acnes (PA_I and PA_II) and chemically derived fractions from the whole bacterial cell were studied using a murine ovarian teratocarcinoma (MOT) model. When injected i.p. in high doses (700 to 1400 µg/mouse), both strains produce survival of a significant proportion of tumor-bearing mice (30 to 90%). On a weight to weight basis, however, PA_I was significantly more effective than PA_II.

PA_I and PA_II were extracted using pyridine, which yielded four fractions, i.e., pyridine-extracted strains PA_I and PA_II (PA-PE_I and PA-PE_II, respectively) which are composed of the cell wall material extracted by pyridine, and the residues of PA-PE_I and PA-PE_II (PA-R_I and PA-R_II, respectively) which are composed of the residue material following the chemical extraction. The chemical composition of PA-PE_I was different from that of PA-PE_II (the latter had proportionately three times as many carbohydrates and one-third of the protein content of the former) and so were their antitumor properties in the MOT model. PA-PE_I had markedly reduced antitumor effect when compared to the untreated cell on a per weight basis. Furthermore, curability was only seen when using a high dose (1400 µg/mouse).

By contrast, the cell wall components extracted by pyridine from PA_II (PA-PE_II) had powerful antitumor effects, i.e., >50% of mice given 1400-µg injections survived. The material contained in PA-PE_II was further fractionated on the basis of its organic solubility in chloroform:methanol solvent. The water-soluble and solvent-insoluble fractions retained most of the antitumor effects of PA-PE_II, while the water-insoluble and solvent-soluble fractions were only moderately effective, suggesting that the active moiety(ies) was associated with the nonlipid components of this fraction.

Both residue fractions (PA-R_I and PA-R_II) were as effective on a per weight basis in controlling the growth of 10⁵ tumor inoculum as were whole untreated cells. However, periodate oxidation of PA-R_I resulted in complete loss of its antitumor effects.

When surviving mice that had no evidence of tumor persistence following a tumor challenge (10⁵ MOT cells) and i.p. treatment with PA were subsequently rechallenged with 10⁴ tumor cells, survival was significantly prolonged, as compared to tumor-challenged (10⁴ MOT) naive mice. In addition, 10 to 20% of these rechallenged mice had complete eradication of the tumor inoculum (no evidence of disease for >120 days). These results suggest that mice previously exposed to PA are still capable of resisting the growth of a lethal tumor rechallenge given >50 days after the primary inoculation. Studies to elucidate the immunological basis for the rejection of a tumor rechallenge are currently under way.

¹ Supported by Grant CA 12800 from the National Cancer Institute, NIH, Bethesda, MD, by grants from the California Institute for Cancer Research and the Concern Foundation, and by research funds of the Veterans Administration.

² To whom requests for reprints should be addressed.

Received 10/17/83. Accepted 2/ 2/84.

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