Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2.
The purpose of this investigation was to evaluate the occurrence of autoimmune toxicities associated with the administration of low-dose IL-2 in conjunction with vaccines for melanoma. Ninety-three patients with stage IIB, III, or IV melanoma were enrolled in three clinical trials and received anti-melanoma vaccines on days 1, 8, 15, 29, 36, and 43. The vaccines comprised peptide-pulsed dendritic cells, autologous tumor cells with GM-CSF in Montanide ISA-51, or synthetic peptides with GM-CSF in Montanide ISA-51. In conjunction with the vaccines, all patients were administered 3 x 10(6) IU/m2/d IL-2 subcutaneously for 42 days, either days 8 to 49 or 29 to 70. Clinical and laboratory data from these studies were reviewed in aggregate to evaluate the occurrence of autoimmune toxicities. Of 91 evaluable patients, vitiligo was documented in 6 patients (7%). In addition, one patient experienced transient severe insulin-dependent diabetes that resolved after discontinuing IL-2, and another experienced an exacerbation of his pre-existing diabetes; these occurrences are consistent with an autoimmune insulitis. Four occurrences (4%) of transient minor ocular toxicity were documented, but no autoimmune ocular toxicities or changes in visual acuity were found. Of 55 evaluable patients, 14 experienced thyroid abnormalities (25%). These were attributed to an autoimmune thyroiditis, which was supported by findings of antithyroid antibodies in three of the seven patients evaluated. Overall, autoimmune toxicities affecting several organ systems were observed in patients receiving melanoma vaccines in conjunction with low-dose IL-2. None of these toxicities caused major long-term effects, though one was acutely life-threatening and others contributed to treatment-related morbidity. Peptide- or cell-based vaccines administered in combination with low-dose IL-2 appear to be capable of breaking tolerance to self-antigens; despite the associated toxicities, these combinations may still be useful to administer as an immunotherapy for cancer. However, careful monitoring for autoimmune toxicities should be incorporated in future clinical studies incorporating low-dose IL-2.
Department of Surgery/Division of Surgical Oncology, University of Virginia, Charlottesville, Virginia 22908, USA.
Kimberly A
KA
Chianese-Bullock
Elizabeth M H
EM
Woodson
Huimin
H
Tao
Scott A
SA
Boerner
Mark
M
Smolkin
William W
WW
Grosh
Patrice Y
PY
Neese
Priscilla
P
Merrill
Gina R
GR
Petroni
Craig L
CL
Slingluff
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005128:Eye Diseases / Q000139:chemically induced / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D007111:Immunity, Cellular / Q000276:immunology; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D008297:Male; D008353:Mannitol / Q000031:analogs & derivatives / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D009829:Oleic Acids / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014820:Vitiligo / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009829:Oleic Acids; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; C477385:montanide ISA 51; D008353:Mannitol; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D014442:Monophenol Monooxygenase