Abstract

CRM197 and cancer: effects of intratumoral administration

Author(s): Silvio Buzzi, Diego Rubboli, Giorgio Buzzi, Anna Maria Buzzi, Claudio Morisi and Flavio Pironi

Background: Cross-reacting material 197 is a nontoxic mutant of diphtheria toxin that cross-reacts immunologically with the native counterpart. The molecule was recently tested as a systemic anticancer agent with promising results but its exact mechanism of action has remained unclear. Objective: The main goal of this study was to investigate this mechanism through the possible histologic changes induced by direct inoculation of the molecule into a tumor lesion. A secondary objective was to evaluate toxic, hematologic and antitumor effects of the procedure. Methods: Cross-reacting material 197 was administered by injection into accessible lesions of 12 patients with advanced cancer refractory to standard therapies. Two different doses were used according to the maximal diameter of the selected lesions. Lesions up to 2.5 cm were injected with 0.017 mg/day contained in 0.33 ml of a dilution buffer. Lesions up to 5.0 cm were injected with 0.051 mg/day contained in 1.0 ml of dilution buffer. The treatment schedule consisted of six injections administered on alternate days. A biopsy was taken from each selected lesion before the start of treatment and again 15 days later. Results: Toxicities and effects of cross-reacting material 197 on the injected lesion varied according to the patients’ degree of reactivity to diphtheria toxin. Patients with poor reactivity experienced negligible toxicity and no change or minimal change in the number of circulating neutrophils, in the post-treatment histology of their lesions and in the final lesion size. Patients with strong reactivity experienced mild-to-moderate flu-like syndrome, a prominent increase in the number of circulating neutrophils and a dense neutrophilic infiltration of the injected lesion leading to inflammation and, sometimes, to suppuration. Shrinkage of the index lesion ranging from 60 to 100% was observed in three of the patients. Conclusion: Neutrophils seemed to play a crucial role in achieving these results. One patient was available for post-treatment biopsy only at day 30 from the start of treatment. Examination of these specimens evidenced a striking granulomatous reaction surrounding a core of dead and viable tumor cells.