The requirement of multimodal therapy (vaccine, local tumor radiation, and reduction of suppressor cells) to eliminate established tumors.
OBJECTIVE
Numerous immune-based strategies are currently being evaluated for cancer therapy in preclinical models and clinical trials. Whereas many strategies look promising in preclinical models, they are often evaluated before or shortly following tumor implantation. The elimination of well-established tumors often proves elusive. Here we show that a multimodal immune-based therapy can be successfully employed to eliminate established tumors.


METHODS
This therapy consists of vaccines directed against a self-tumor-associated antigen, the use of external beam radiation of tumors to up-regulate Fas on tumor cells, and the use of a monoclonal antibody (mAb) to reduce levels of CD4+CD25+ suppressor cells.


RESULTS
We show here for the first time that (a) antigen-specific immune responses induced by vaccines were optimally augmented when anti-CD25 mAb was given at the same time as vaccination; (b) anti-CD25 mAb administration in combination with vaccines equally augmented T-cell immune responses specific for a self-antigen as well as those specific for a non-self antigen; (c) whereas the combined use of vaccines and anti-CD25 mAb enhanced antigen-specific immune responses, it was not sufficient to eliminate established tumors; (d) the addition of external beam radiation of tumors to the vaccine/anti-CD25 mAb regimen was required for the elimination of established tumors; and (e) T cells from mice receiving the combination therapy showed significantly higher T-cell responses specific not only for the antigen in the vaccine but also for additional tumor-derived antigens (p53 and gp70).


CONCLUSIONS
These studies reported here support the rationale for clinical trials employing multimodal immune-based therapies.
Kudo-Saito
Chie
C
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Schlom
Jeffrey
J
Camphausen
Kevin
K
Coleman
C Norman
CN
Hodge
James W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011878:Radiotherapy; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D015375:Receptors, Interleukin-2