Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8 + T-cell immune responses, and modulation of CD4 + CD25 + FoxP3 + regulatory T-cell (Treg) numbers were secondary end points. Experimental Design: Three patients with colon cancer, four with non^Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specificT-cell responses was observed after therapy. Tregs as detected by expression of CD4+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. Conclusions: Ipilimumab treatment depressedTreg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8 + T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

IntroductionIL-15 is a proinflammatory cytokine that stimulates T and natural killer (NK) cell activity and induces the expression of TNF-␣, IL-1␤, and other inflammatory chemokines. 1-4 IL-15 is important for the maintenance of long-lasting, high-avidity T-cell responses directed at invading pathogens by supporting the survival of CD8 ϩ memory T cells. In addition, IL-15 also inhibits IL-2-induced activation-induced cell death. 5-7 IL-15 signals through the heterotrimeric IL-15 receptor that includes a private IL-15-specific receptor subunit IL-15R␣, the IL-2/IL-15R␤ subunit (CD122) that is also shared with the IL-2 receptor, and the common ␥-chain (␥ c ) receptor that is shared by IL-2, IL-4, IL-7, IL-9, and IL-21. 3,8 IL-15 binds to IL-15R␣ with high affinity (K d of ϳ 1 ϫ 10 Ϫ11 M). 9 Under physiologic conditions, IL-15 does not act as a secreted molecule but rather is trans-presented on the cell surface of activated monocytes and dendritic cells as part of an immunologic synapse to T and NK cells that express IL-2/IL15R␤ and ␥ c . 10 Abnormalities of IL-15 expression have been implicated in many autoimmune disorders, including rheumatoid arthritis, 11 psoriasis, 12 celiac disease, 13 inflammatory bowel disease, 14 and multiple sclerosis, 15 as well as in select lymphoid malignancies and diseases associated with human T-cell lymphotropic virus 1 infection. 16 In celiac disease, abnormal expression of IL-15R␣ was found to be associated with abnormal IL-15 expression, and together they contribute to the pathogenesis of the disease. 17 This highlights the importance of IL-15R␣ for the function of IL-15.Large granular lymphocyte (LGL) leukemia represents a spectrum of lymphoproliferative diseases that are characterized by abnormal clonal expansions of mature T or NK cells. 18 Based on the cellular origin, LGL leukemia can be divided into T-cell LGL leukemia and NK-cell LGL leukemia. The majority of patients with T-cell LGL leukemia have a clinically indolent course. However, a significant fraction will develop neutropenia, anemia, recurrent bacterial infections, autoimmune disorders, or symptomatic splenomegaly. 19 Neutropenia, the most common hematologic disorder associated with T-LGL leukemia, is the major reason for these patients seeking medical attention. 18 Approximately 70% to 80% patients with T-LGL leukemia develop neutropenia and may be predisposed to infection. Anemia is the second most common hematologic disorder associated with T-LGL leukemia. Another common association is autoimmunity, with rheumatoid arthritis occurring most often. 20,21 Rheumatoid arthritis has been reported in approximately one-third of T-LGL leukemia patients. Although it has been suggested that LGL leukemic cells represent cytotoxic T lymphocytes activated by chronic antigenic stimulation, the molecular mechanisms that lead to LGL leukemia are unknown. The wide association of LGL leukemia with hematologic and autoimmune disorders suggests the possibility of a common pathogenesis in LGL leukemia and their hematologic disorders ...

Interestingly, the addition of an anti-IL-2R-␣ monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/ IL-9, and the downstream Janus kinase/ signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. IntroductionAdult T-cell leukemia (ATL) that is caused by human T-cell lymphotropic virus I (HTLV-1) is an aggressive malignancy of CD4-and CD25-expressing leukemia, and lymphoma cells. ATL is a heterogeneous disease that can be divided broadly into 4 stages: smoldering, chronic, lymphoma, and acute-type ATL. The common clinical manifestations of ATL are skin lesions, hypercalcemia, immunologic anergy to antigen stimulation, and cells with "flowerlike" nuclei in the circulation. Smoldering/chronic ATL patients have normal or mildly increased white blood cell counts with a variable number of leukemic cells in the circulation and are generally associated with a better prognosis. Patients with acutetype ATL have organ dysfunction associated with circulating leukemic cells and are generally associated with a poor prognosis. The mechanisms underlying the progression from smoldering/chronic stage to the acute stage are unknown; however, the accumulation of molecular mutations is thought to play a role in this progression.Although the pathogenesis of ATL is unknown, the virally encoded regulatory protein, HTLV-1 Tax, seems to play a central role in the initial leukemogenesis of ATL. Hasegawa et al demonstrated that overexpression of Tax in immature thymocytes induced leukemia/lymphoma in mice with clinical, pathologic, and immunologic features characteristic of ATL after a long latency. 1 Subsequently, Ohsugi et al 2 showed that Tax is able to promote oncogenesis not only with immature T cells, but also with mature T cells. Both experiments highlighted the importance of Tax in the initial development of ATL.Beyond the in vivo mouse models, numerous in vitro studies have demonstrated the essential role of Tax in ATL initiation and shed light on the mechanism of Tax-mediated cellular transformation. 3 Tax deregulates the expression of genes involved in cellular proliferation, cell-cycle control, and apoptosis through physical interaction with cellular elements, including transcription factors such as nuc...