Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.
OBJECTIVE
Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases.


METHODS
The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT.


RESULTS
Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells.


CONCLUSIONS
The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.
Demaria
Sandra
S
Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. demars01@med.nyu.edu
Kawashima
Noriko
N
Yang
Anne Marie
AM
Devitt
Mary Louise
ML
Babb
James S
JS
Allison
James P
JP
Formenti
Silvia C
SC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D003037:Cobalt Radioisotopes; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011879:Radiotherapy Dosage; D015996:Survival Rate
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D003037:Cobalt Radioisotopes; C556707:Ctla4 protein, mouse; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents