Potentiation of adoptive immunotherapy by cis-diamminedichloroplatinum(II), but not by doxorubicin, on a disseminated mouse lymphoma and its association with reduction of tumor burden.
The therapeutic effect of a combination therapy employing syngeneic anti-tumor immune T lymphocytes and either doxorubicin (DX) or cis-diamminedichloroplatinum II (DDP) was tested on BALB/c mice bearing a disseminated, weakly immunogenic lymphoma (YC8) which metastasizes mainly to the liver. Therapy with specific tumor-immune lymphocytes alone cure 80-100% mice bearing 3-day established tumors. The same effector cells, however, were less effective in mice at a more advanced stage of the disease (day 5) and ineffective when treatment was further delayed (day 7). Chemotherapeutic treatment alone with DX or DDP given i.p. at the maximal tolerated doses was less effective than immune lymphocytes on 3-day tumors since cures were very seldom observed, but both drugs prolonged survival time even when administered on day 7. While DX did not enhance the antitumor effect of immune lymphocytes on 5-day tumors, the association of DDP with immunotherapy by giving the 2 modalities sequentially according to the two sequences (i.e., chemotherapy before immunotherapy and vice versa) with a 2-day interval, was significantly more effective than each treatment alone. Like mice cured by immunotherapy alone, most of the animals cured by chemo-immunotherapy developed a systemic transplantation immunity to the tumor as revealed by the specific rejection of a second lethal tumor challenge 90 days after the first tumor inoculum. The higher activity of DDP compared with DX in potentiating the effect of immunotherapy was shown to be associated with a greater reduction of tumor burden in the liver, whereas the 2 drugs gave a similar reduction of tumor burden in other organs, as determined from bioassay of tumor-bearing organs of chemotherapy-treated mice. These results indicate that combination of chemotherapy with immunotherapy may improve the effects of each treatment alone, and that the synergistic effect is associated with the reduction of the tumor load in the main organ (liver) of tumor dissemination.
Formelli
F
F
Division of Experimental Oncology B, Istituto Nazionale Tumori, Milan, Italy.
Rossi
C
C
Sensi
M L
ML
Parmiani
G
G
D000818:Animals; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D007116:Immunization, Passive; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology*
D004317:Doxorubicin; D002945:Cisplatin