Low-dose radioimmunotherapy ((90)Y-PAM4) combined with gemcitabine for the treatment of experimental pancreatic cancer.
OBJECTIVE
Monoclonal antibody PAM4 is reactive with the MUC1 mucin as expressed by >85% of human pancreatic cancers. Significant antitumor effects have been demonstrated using radiolabeled PAM4 for radioimmunotherapy (RAIT) of experimental pancreatic cancer. The goal of the present study was to determine whether the addition of low-dose (90)Y-PAM4 RAIT to a clinically relevant regimen of gemcitabine chemotherapy would provide enhanced antitumor efficacy over that observed by chemotherapy alone without the addition of significant toxicity to normal tissues.


METHODS
Mice bearing human pancreatic tumor xenografts (CaPan1) were administered three cycles of gemcitabine chemotherapy (1000 mg/m(2)/week for 3 weeks with 1 week off) concomitant with (90)Y-labeled PAM4 RAIT (25 micro Ci; 10% of the single agent MTD) given at weeks 0, 4, and 7. Control groups of mice received chemotherapy alone, (90)Y-PAM4 RAIT alone, or an equidose of (90)Y-labeled nontargeting control antibody with and without gemcitabine.


RESULTS
Mice that received (90)Y-PAM4 RAIT with gemcitabine had tumors that were significantly smaller in size than all of the other treatment groups (P < 0.005). A median survival of 24 weeks was achieved in mice that received the combined treatment versus 10 weeks for mice that received only gemcitabine (P < 0.001) and 16 weeks for mice that received only (90)Y-PAM4 RAIT (P < 0.040). The combined treatment regimen was well tolerated.


CONCLUSIONS
A combined chemoimmunotherapy and RAIT approach using gemcitabine and low-dose (90)Y-PAM4 provided significantly increased antitumor efficacy than was observed for each treatment arm given alone. Importantly, the enhanced antitumor efficacy was achieved with minimal toxicity to normal tissues. These studies provide justification for clinical trials using the combined modality treatment for patients with pancreatic cancer.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D015021:Yttrium Radioisotopes; D003841:Deoxycytidine; D000093542:Gemcitabine