Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study

Abstract

Background: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.

Methods: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses).

Results: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.

Conclusions: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.

FIG. 1

Computed tomography scans illustrating disease status before treatment (upper panels) and after treatment (lower panels) for patients treated with anti–CTLA-4 antibody and IL-2. Arrows on pretreatment scans denote sites of disease. (A) Patient 4: regression of disease in the mediastinum. (B) Patient 8: regression of disease in the right axilla and latissimus dorsi. (C) Patient 12: regression of disease in the left lung. (D) Patient 14: regression of disease in subcutaneous tissue of the face and submandibular lymph nodes. (E) Patient 15: regression of disease in the abdominal wall. (F) Patient 19: regression of disease in subcutaneous tissue and an inguinal lymph node. R, right.

FIG. 1

Computed tomography scans illustrating disease status before treatment (upper panels) and after treatment (lower panels) for patients treated with anti–CTLA-4 antibody and IL-2. Arrows on pretreatment scans denote sites of disease. (A) Patient 4: regression of disease in the mediastinum. (B) Patient 8: regression of disease in the right axilla and latissimus dorsi. (C) Patient 12: regression of disease in the left lung. (D) Patient 14: regression of disease in subcutaneous tissue of the face and submandibular lymph nodes. (E) Patient 15: regression of disease in the abdominal wall. (F) Patient 19: regression of disease in subcutaneous tissue and an inguinal lymph node. R, right.

FIG. 1

Computed tomography scans illustrating disease status before treatment (upper panels) and after treatment (lower panels) for patients treated with anti–CTLA-4 antibody and IL-2. Arrows on pretreatment scans denote sites of disease. (A) Patient 4: regression of disease in the mediastinum. (B) Patient 8: regression of disease in the right axilla and latissimus dorsi. (C) Patient 12: regression of disease in the left lung. (D) Patient 14: regression of disease in subcutaneous tissue of the face and submandibular lymph nodes. (E) Patient 15: regression of disease in the abdominal wall. (F) Patient 19: regression of disease in subcutaneous tissue and an inguinal lymph node. R, right.

FIG. 1

Computed tomography scans illustrating disease status before treatment (upper panels) and after treatment (lower panels) for patients treated with anti–CTLA-4 antibody and IL-2. Arrows on pretreatment scans denote sites of disease. (A) Patient 4: regression of disease in the mediastinum. (B) Patient 8: regression of disease in the right axilla and latissimus dorsi. (C) Patient 12: regression of disease in the left lung. (D) Patient 14: regression of disease in subcutaneous tissue of the face and submandibular lymph nodes. (E) Patient 15: regression of disease in the abdominal wall. (F) Patient 19: regression of disease in subcutaneous tissue and an inguinal lymph node. R, right.

FIG. 1

Computed tomography scans illustrating disease status before treatment (upper panels) and after treatment (lower panels) for patients treated with anti–CTLA-4 antibody and IL-2. Arrows on pretreatment scans denote sites of disease. (A) Patient 4: regression of disease in the mediastinum. (B) Patient 8: regression of disease in the right axilla and latissimus dorsi. (C) Patient 12: regression of disease in the left lung. (D) Patient 14: regression of disease in subcutaneous tissue of the face and submandibular lymph nodes. (E) Patient 15: regression of disease in the abdominal wall. (F) Patient 19: regression of disease in subcutaneous tissue and an inguinal lymph node. R, right.

FIG. 2

(A) Colonoscopic view of bowel edema and ulceration in the descending colon of patient 29, who experienced autoimmune colitis. (B) Histopathologic analyses revealed focal active colitis (upper panel) with crypt destruction, loss of goblet cells, and neutrophilic infiltrates in the crypt epithelium (lower panel) (original magnification: upper panel, ×20; lower panel, ×60).