Induction of immune-mediated regression of tumors by chemoablative or photodynamic therapy.

C. Dees, J. Harkins, T.C. Scott and E.A. Wachter.

Photogen Technologies, Inc., Knoxville, TN USA

In contrast to conventional cancer treatments that suppress immune competence, photodynamic therapy (PDT) of tumors stimulates the production effective anti-tumor immunity. We examined the production of antitumoral immunity following chemoablation of an intradermal hepatoma or after photodynamic therapy by PH-10 (a halogenated xanthene). The ability of therapy with PH-10 to stimulate an immune mediated removal of an existing tumor was also determined. Intratumoral injection of 1 x 105 hepatoma cells into C57BL/6 immunocompetent mice produced hepatomas in the left flank of 13/15 mice in approximately 2 weeks. PH-10 was delivered per os at a dose of 50 mg/kg body weight, single dose, to 5 mice. Sixteen hours later the tumors were illuminated with 100 J/cm2 green light. All 5 tumors were completely gone 24 hours after illumination. No visible collateral damage was observed in perilesional tissue and animals showed no signs of pain or discomfort at any time. Tumors were unaffected in three mice that were treated with laser illumination alone. All five tumors in mice treated chemotherapeutically (by intratumoral injection of PH-10 alone) also disappeared overnight. Twelve days after tumor treatment 1 x 105 hepatoma cells were introduced intradermally in the right flank of cured mice. No tumors appeared in any mice whose tumor was previously removed by PDT or chemoablation Mice bearing left flank tumors treated by light alone developed a new tumor in the right flank (3/3). A similar challenge was performed in immunodeficient BalbC (nu/nu) nude mice. In contrast to the immunocompentent mice, a second hepatoma was produced in all mice that had a hepatoma removed from the left flank. Mice whose hepatomas had been removed from the left flank were also challenged with B16F10 melanoma cells to see if the antitumor immunity was specific for hepatomas. All immunocompetent mice that had a tumor removed by PDT or chemoablation from the left flank developed melanomas in the right flank after challenge. Chemoablation or PDT removal of large tumors in the left flank of mice stimulated immune-mediated clearance of untreated small tumors in the right flank of immunocompetent mice but not in immunodeficient mice. Successful treatment of naturally occurring tumors using PH-10 is likely to reduce the reoccurrence of tumors at the primary site, reduce metastatic spread and stimulate the immune-mediated removal of remote tumors.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.