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.