Intratumoral BCG therapy of transplanted head and neck tumors in strain 2 guinea pigs

Abstract

The generally unfavorable prognosis associated with advanced squamous cell carcinoma in the head and neck region in humans led us to immunotherapeutic experiments with bacillus Calmette-Guerin (BCG) in inbred guinea pigs with solid growing and lymphogenous metastasizing tumors. The injection of live BCG or BCG cell wall preparation (CWP) into the planum buccale in the guinea pig led to a pronounced local inflammatory reaction. If live BCG or BCG CWP were injected into the planum buccale together with line 10 tumor cells, no growth of the tumor could be observed. Animals treated in this manner developed a tumor-specific immunity. Guinea pigs treated intratumorally with live BCG or BCG CWP in established, 6-day-old tumors of the planum buccale showed regression of the primary tumor and prevention of the development of lymph node metastases. These cured animals also developed a tumor-specific immunity. Guinea pigs with 6-day-old tumors of the planum buccale remained tumor free after surgical removal of the primary tumor and the draining submandibular and cervical lymph nodes (radical operation) whereas locally operated animals (primary tumor excision) developed lymph node metastases. Animals that were tumor free after radical surgery did not develop tumor-specific immunity. Despite insufficiently clarified mechanisms for the induction and effect of BCG immunotherapy, we can state that, with intratumoral BCG therapy, a tumor experimentally placed in the head and neck region is eliminated, regionally manifest metastases are eliminated, and specific tumor immunity can be demonstrated in successfully treated animals.

Tumor regression and induction of anti‐tumor immunity by local chemotherapy of guinea‐pigs bearing a line‐10 hepatocarcinoma

“…Methotrexate, a drug which did not show an immunopotentiating capacity in the local sensitization protocol (Boemgter et al., 1984;Scheper et al, 1987) had no therapeutic effect upon intralesional administration in the day-7 therapy model (Ohanian et al, 1977). In contrast, VP-16 and cis-platinum, cytostatic drugs with strong immunopotentiating properties in local immunopotentiation protocols (Scheper et al, 1987;Limpens et al, 1990a), displayed distinct therapeutic effects when administered intralesionally (Table 111; and Bier et al, 1980). Second, local administration of excessively high doses of cytostatic drugs (daily injections for 3 weeks starting on day 7 of tumor growth) prevented therapeutic benefit and the development of anti-tumor immunity (Ohanian et al, 1977;Bier et al, 1980), arguing against simple tumor eradication as sufficient for curing.…”

“…In contrast, VP-16 and cis-platinum, cytostatic drugs with strong immunopotentiating properties in local immunopotentiation protocols (Scheper et al, 1987;Limpens et al, 1990a), displayed distinct therapeutic effects when administered intralesionally (Table 111; and Bier et al, 1980). Second, local administration of excessively high doses of cytostatic drugs (daily injections for 3 weeks starting on day 7 of tumor growth) prevented therapeutic benefit and the development of anti-tumor immunity (Ohanian et al, 1977;Bier et al, 1980), arguing against simple tumor eradication as sufficient for curing. Third, the therapeutic effectivity of intralesional cis-platinum therapy starting at day 7, and continuing for 3 weeks, could be totally abolished by treating the animals with anti-lymphocyte sera (Bier et al, 1980).…”

“…Second, local administration of excessively high doses of cytostatic drugs (daily injections for 3 weeks starting on day 7 of tumor growth) prevented therapeutic benefit and the development of anti-tumor immunity (Ohanian et al, 1977;Bier et al, 1980), arguing against simple tumor eradication as sufficient for curing. Third, the therapeutic effectivity of intralesional cis-platinum therapy starting at day 7, and continuing for 3 weeks, could be totally abolished by treating the animals with anti-lymphocyte sera (Bier et al, 1980). We recently confirmed this finding using 4-HPCY for intralesional treatment (results not shown).…”

“…This view is supported by early experimental studies with this mode of drug administration. Remarkable cure rates, paralleled by the induction of anti-tumor immunity, have been reported with intralesional cytostatic treatment 7 days after inoculation of the syngeneic line-10 hepatocarcinoma (Bast et al, 1976;Ohanian et al, 1977Ohanian et al, , 1980Bier et al, 1980).…”

Cell-mediated immunity is enhanced by cytostatic drugs continuously released at the site of antigenic stimulation

“…The line-10 hepatocarcinoma, when injected intradermally into syngeneic strain-2 guinea pigs, metastasizes within 7 days into the regional lymph node, and kills the animals within a period of 60-80 days [1,4,5,15]. Intralesional treatment by serial injections of selected cytostatic drugs, starting 7 days after tumor cell inoculation, has been shown to induce regression of this tumor.…”