Combined modality radioimmunotherapy. Promise and peril

Single-agent radioimmunotherapy (RIT), although potentially useful for slowing solid tumor growth, has not been effective in curing aggressive tumors, such as breast cancer. These cancers typically have p53 mutations and are less susceptible to apoptosis, the apparent mechanism of cell death from low dose-rate radiation. Thus, synergistic or combined modality radioimmunotherapy (CMRIT) agents are needed to increase radiosensitivity for therapeutic enhancement without additive toxicity.

To assess synergy in CMRIT in a breast cancer xenograft model, we evaluated RGD peptide EMD 121974, an inhibitor of alpha(v)beta(3) integrin; paclitaxel, an antimicrotubule; IMC-C225, a monoclonal antibody to epidermal growth factor receptor (EGFR); and bcl-2 antisense oligonucleotide G3139. Groups of mice received (90)Y-DOTA-ChL6 in combination with each agent. Tumor size, survival, and blood counts were monitored for efficacy and toxicity. Immunopathologic evaluation of apoptosis was performed at selected time points after RIT and RIT + RGD CMRIT.

CMRIT with RGD peptide increased apoptosis and resulted in 57% cures, compared with 0% cures with RIT alone. CMRIT with paclitaxel after RIT increased cures to 88%, compared with 25% cures with RIT before paclitaxel administration. CMRIT with IMC-C225 resulted in up to 20% cures if given before RIT. A time-dependent increase in toxicity was observed with IMC-C225 after RIT. CMRIT with bcl-2 antisense G3139 resulted in no cures and an increased rate of regrowth compared with RIT alone.

Some combined modality therapies resulted in higher numbers of cures, while others decreased cures and responses and increased toxicity compared with RIT alone. These results support the potential for CMRIT but illustrate the complexity of predicting the efficacy and toxicity and the importance of the relationship between dose and sequence of administration.