Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209–217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA⋆A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209–217(210M) plus incomplete Freund’s adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. Results The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine–interleukin-2 group, as compared with the interleukin-2–only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P = 0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P = 0.008). The median overall survival was also longer in the vaccine–interleukin-2 group than in the interleukin-2–only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P = 0.06). Conclusions In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.)

SllmmaryTo expand the spectrum of recognition of effector lymphocytes and to redirect them towards predefined targets, we have altered the specificity of human tumor-infiltrating lymphocytes (TIL) through stable modification with chimeric receptor genes consisting of single-chain antibody variable regions linked to the 3' subunit common to the immunoglobulin (Ig)G and IgE Fc receptors. Using either hapten or ovarian carcinoma-specific monoclonal antibodies, we constructed chimeric receptor genes and retrovirally introduced them into CD8 + TIL. Redirected TIL specifically lysed trinitrophenyl-labeled Daudi or a human ovarian carcinoma cell line (IGROV-1), and secreted granulocyte/macrophage colony-stimulating factor upon stimulation with the appropriate antigen. This strategy may allow new approaches towards the adoptive immunotherapy of cancer in humans.A limitation in the use of adoptive cellular immunotherapy for cancer lies in the difficulty in obtaining specific tumor-infdtrating lymphocytes (TIL) for many histologic types of cancer. In contrast, many mAbs have been described that bind tumor-associated antigens shared by tumors of the same histology. Two approaches have been attempted to combine the effector function of T cells with the antitumor specificity of antibodies. One is destruction of tumor by bispecific antibodies possessing dual specificity for both the target and the immune cell (1, 2). However, the use of bispecific antibodies for therapy is limited by the inaccessibility of many solid tumors to antibody penetration (3) and dissociation of antibody from the lymphocyte membrane in a relatively short period of time (4). A second approach involves the construction of chimeric receptors containing the V regions of antibodies joined to the C regions of the TCR (5-9). Because antigen binding by most antibodies requires both light and heavy V region chains (V. and VL), and TCR function requires both oe and (or 3//8) chains, this approach necessitates the coexpression of two chimeric genes. While the stable expression of multiple genes has been possible in transformed T cells and hybridomas, it has been difficult in primary T cells. To overcome these problems, we have constructed chimeric receptor genes containing VL/V. single-chain V domains (scFv) from mAbs linked to the Fc receptor-associated 3, chain (10). The scFv, which consists of VL bridged to V. via a flexible linker, has been demonstrated to have similar binding affinities and specificities compared to natural Fab fragments (11). The 3, chain is the signal transdudng subunit of both the high affinity IgE receptor (FceRI) of mast cells and basophils, and of the low affinity receptor for IgG (Fc3,RIII), expressed primarily by macrophages and NK cells (12). The 3, subunit is very similar in structure and function to the CD3~" chain and in fact can form heterodimers with it in some T and NK cells (13). The scFv-3, design that we have used for the present studies combines antibody recognition and T cell signaling in one continuous gene, and has be...

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HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.