IL-2: the first effective immunotherapy for human cancer

Abstract

The ability of IL-2 to expand T cells with maintenance of functional activity has been translated into the first reproducible effective human cancer immunotherapies. The administration of IL-2 can lead to durable, complete, and apparently curative regressions in patients with metastatic melanoma and renal cancer. The growth of large numbers of tumor-infiltrating lymphocytes with in vitro anti-cancer activity in IL-2 has led to the development of cell transfer therapies that are highly effective in patients with melanoma. The genetic modification of T cells with genes encoding αβ TCRs or chimeric Ag receptors and the administration of these cells after expansion in IL-2 have extended effective cell transfer therapy to other cancer types.

FIGURE 1.

Upper panel, Fifty-six–year-old male with metastatic renal cell cancer to the liver and subcarinal lymph nodes was treated with high-dose bolus IL-2 in January 1994. Patient underwent a complete regression of all disease and remains disease-free 20 y later. Upper middle panel, Fifty-four–year-old male with metastatic melanoma to the lungs and liver was treated with autologous TILs plus IL-2 following a lymphodepleting regimen in December 2003. The patient underwent a complete regression of all disease and remains disease-free >10 y later. Lower middle panel, Fifty-year-old male with follicular non-Hodgkin’s lymphoma at multiple sites in the abdomen, mediastinum, and axillary lymph nodes treated with genetically engineered autologous peripheral lymphocytes expressing a gene encoding an anti-CD19 chimeric Ag receptor in May 2009. The patient underwent a dramatic regression of all disease following two cycles of treatment and is progression-free >4 y later. Lower panel, Sixty-seven–year-old female with metastatic synovial sarcoma to the lung and right pelvis treated with genetically engineered autologous peripheral lymphocytes expressing a gene encoding a TCR reactive with the NY-ESO-1 cancer testes Ag in August 2010. The patient was treated in August 2010 and has undergone a dramatic partial regression now ongoing >3 y later.

FIGURE 2.

Objective response rates (using Response Evaluation Criteria in Solid Tumors criteria) using various forms of cancer immunotherapy of patients with metastatic melanoma treated in the Surgery Branch at the National Cancer Institute. Only anecdotal responses have been seen utilizing cancer vaccine approaches. A response rate of 2.6% was seen using 541 different vaccines in 440 patients with metastatic cancer (84). Using an anti-CTLA Ab, a response rate of ~15% was seen but varied with the dose and schedule of administration (85). Utilizing IL-2 response rates of ~15% were seen that increased to 34% when IL-2 was given following ACT. The response rates increased to 49% when cell transfer was preceded by a nonmyeloablative chemotherapy (NMA) consisting of cyclophosphamide (60 mg/kg 2×) and fludarabine (25 mg/kg 5×) and was increased to 72% when cells were transferred following NMA plus 12 Gy TBI. The years of these reports are shown on the bottom line of the figure.