Focus on FOCIS: Interleukin 2 treatment associated autoimmunity

Abstract

A patient from the University of Pittsburgh is presented who developed autoimmunity during IL-2 based combination therapy. IL-2 was originally described as a “T cell growth factor” capable of expanding previously activated T cells, enhancing the cytotoxicity of antigen-specific cytotoxic T cells and NK cells. High dose Interleukin 2 (HDIL2) is now FDA-approved for therapy of patients with metastatic melanoma and renal cell carcinoma, based on its ability to induce durable responses in 5–10% of patients. The antitumor effect of HDIL2 is incompletely understood, but it appears that this regimen alters the balance of immigrant T effector cells in relation to T suppressor cells. It promotes a less immunosuppressive tumor microenvironment, inducing tumor regression in a subset of patients that is yet to be defined. The antitumor activity of IL-2, as for other agents that promote durable antitumor activity against melanoma such as interferon alpha and anti-CTLA4 antibody, is frequently associated with development of autoimmunity as observed in this patient. We present studies investigating the mechanisms for the therapeutic benefit of HDIL2 in melanoma.

Introduction

A 60 year old Caucasian male with a prior history of non-insulin dependent diabetes mellitus, hypercholesterolemia, and hypertension but no known autoimmune disease presented to the emergency room with acute onset of right flank pain. Whole body CT scan revealed calcified left lung nodules and ipsilateral hilar lymph nodes felt to be consistent with prior granulomatous disease but there were several noncalcified lung nodules, noted bilaterally and a 5.1 × 3.2-cm heterogeneous right adrenal mass, with streaking extending into the right perinephric fat that were interpreted as recent hemorrhage from the right adrenal gland. Fig. 1A shows a representative section from a CT scan of the patient's noncalcified lung nodules. Screening blood workup was unremarkable, including hematologic, renal, and hepatic function tests, as well as LDH and uric acid that were normal. The patient underwent laparoscopic adrenalectomy with pathologic examination revealing metastatic melanoma. Shortly thereafter the patient developed a non-specific hand tremor. Brain MRI confirmed not only the presence of a 16 mm right cerebellar nodule, but also 4 additional parietal lesions. Fig. 1D shows a representative section from an MRI scan of the brain, revealing the parietal lesions. The patient completed stereotactic radiosurgery for all five brain lesions with control at one month, and was subsequently enrolled into a phase II clinical trial of sequential chemotherapy with the oral alkylating agent temozolomide (75 mg/m²/day orally on a 21 out of 28 day schedule) followed by high-dose cytokine therapy with bolus IV administration of interleukin-2 (HDI, 600,000 U/kg/dose intravenously every 8 h, maximum 14 doses over 5 days). Each cycle included one course of temozolomide and one course of HDI. The patient had a partial response to the regimen after 2 cycles (Figs. 1B, E). However after 2 more cycles he developed a new pulmonary metastasis and was therefore taken off study. The patient completed a total of four 5-day hospitalizations for HDI, and a total of four 21-day cycles of temozolomide.

After a month, the patient was enrolled on another clinical protocol that involved administration of an HLA-A2⁺ restricted gp100 melanoma vaccine. Immediately before enrollment the patient first noted depigmentation that was originally localized to areas of his face, but over the ensuing 5 months this vitiligo-like depigmentation spread to his neck, upper chest, and upper extremities. Figs. 2A, B show the development of vitiligo in the patient's neck and upper chest. The patient has not received any therapy for 16 months and has no evidence of melanoma 25 months following his original enrollment into the combination of temozolomide-HDI under study in this trial UPCI 03-137 (Figs. 1C, F).

In summary, in this patient with widespread metastatic melanoma with brain metastases (AJCC stage M1c), the combination of HDIL2 with temozolomide resulted in partial response following two cycles and minor disease progression after two additional cycles. Approximately one month following discontinuation of the temozolomide-HDI regimen the patient developed progressive vitiligo-like depigmentation and shortly thereafter, he was enrolled into a gp100 peptide vaccine study. Given the short interval between the discontinuation from the temozolomide-HDI regimen and the onset of vitiligo, the patient's original objective response to the temozolomide-HDI based therapy, and the lack of any association between vitiligo and temozolomide therapy in melanoma, we suggest that the onset of vitiligo-like depigmentation in this case was an HDI-mediated phenomenon.