Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy.
OBJECTIVE
Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm(3) before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy.


METHODS
Mice bearing 300-mm(3) subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon alpha) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume.


RESULTS
Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm(3). More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy.


CONCLUSIONS
These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.
Sega
Emanuela I
EI
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Lu
Yingjuan
Y
Ringor
Michael
M
Leamon
Christopher P
CP
Low
Philip S
PS
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002352:Carrier Proteins / Q000276:immunology*; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000627:therapeutic use; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000627:therapeutic use; D006241:Haptens / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000276:immunology*; D011878:Radiotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D011897:Random Allocation; D011956:Receptors, Cell Surface / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D047368:Tumor Burden
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D006241:Haptens; D007376:Interleukin-2; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D007371:Interferon-gamma; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate