Explore the vast range of titles available.

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3. It is unknown whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy or whether activation of any particular Treg subset correlates with clinical outcome. Here, we evaluated Treg population subsets that were induced in patients with melanoma following HD IL-2 therapy. We identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). This Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS(+) Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS(+) Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS(+) Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS(+) Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome.

High dose (HD) IL-2 treatment is a potent form of immunotherapy that can induce durable complete responses in a fraction of metastatic melanoma patients. Its initial purpose was to activate the expansion and anti-tumor responses of NK cells. However, the efficacy of HD IL-2 in achieving this has been relatively limited due to two main reasons. First, IL-2 preferentially expands CD4+CD25+Foxp3+ T-regulatory cells (Tregs) constitutively expressing the high affinity IL-2R consisting of CD25 together with the IL-2Rβ and the common gamma chain rather than NK cells and effector T cells that are mostly CD25-negative and express mostly the IL-2Rβγ lower affinity receptor. In particular, we found that a highly suppressive CD25hi Treg subset expressing ICOS expands the most in response to IL-2. Second, HD IL-2 can be highly toxic by causing vascular leak syndrome due to a surge in pro-inflammatory cytokines and by its indirect activation of CD25 expressing endothelial cells facilitating NO release. Here, we characterized whether a mutant form of IL-2 (F42K) that preferentially binds to the lower affinity IL-2Rβγ complex can be an alternative to wild-type (WT) IL-2 therapy. We first tested the effects of equivalent concentrations of WT IL-2 on PBMC from healthy donors and melanoma patients for 6 or 14 days in vitro. F42K-treated PBMC produced much lower pro-inflammatory cytokines such as IL-6, IL-1α and IFN-γ, and VEGF than WT IL-2. Importantly, F42K selectively expanded NK cells with a decreased expansion of ICOS+ Tregs. In comparison to treatment with WT IL-2, F42K also induced increased NK cell activation by up-regulating the NK activation markers NKp30, NKp44 and TIM-3, but not NKG2D, CD226 and inhibitory KIR molecules such as CD158a and CD158b. F42K also enhanced survival of these highly activated NK cells and prevented apoptosis by inducing a higher expression of Bcl2 than WT IL-2. Furthermore, F42K increased NK cell cytotoxicity against breast cancer and melanoma cells than WT IL-2 associated with TRAIL and granulysin up-regulation in both CD56hi and cytotoxic CD16+CD56+ NK cell subsets. Using a hydrodynamic gene therapy (HGT) approach, C57BL/6 mice treated with plasmids encoding F42K had an earlier, more robust and persistent NK cell expansion in vivo with a dramatic reduction in the expansion of CD4+CD25+Foxp3+Tregs than WT IL-2 plasmid therapy. Lastly, we found that F42K was equally able to expand TILs from melanoma patients as WT IL-2. Our results suggest that F42K has great potential as a non-toxic substitute for WT IL-2 as a cytokine therapy for cancer by potently activating NK cells without Treg expansion either as a monotherapy or in combination with other therapies such as adoptive cell therapy.

Liposarcomas are soft tissue sarcomas of adipocyte origin. We describe a case of a dedifferentiated retroperitoneal liposarcoma with an unusual presentation on recurrence as a large, multicystic tumour. The patient was a 72-year-old woman who had undergone multiple treatments including two prior resections. For her most recent locoregional disease recurrence, the patient was offered surgical debulking for symptom palliation. At this operation, performed after two cycles of chemotherapy, the tumour cyst fluid was analysed and found to have a predominance of immune cells with no identifiable malignant cells. This case and the results of our tumour cyst fluid analysis raise several interesting considerations for the management of this unique situation in a rare disease.

Cancer immunotherapy has become an important area for the future development of cancer therapy; this includes T-cell-based therapies that involve adoptive transfer of autologous T cells derived from the tumors or peripheral blood of cancer patients, vaccines, oncolytic virus therapy, and immunomodulatory antibodies and ligands. Here, we summarize the current approaches and clinical data in the field of adoptive T-cell transfer therapy using tumor-infiltrating lymphocytes (TILs) for metastatic melanoma. We also discuss current knowledge on the mechanism of transferred TILs in mediating tumor regression and the growing need for and recent advances in the identification of predictive biomarkers to better select patients for TIL therapy. The current technical limitations of current TIL expansion methods for out-scaling are discussed as well as how these are being addressed in order to further “industrialize” this form of cell therapy. Lastly, how TIL adoptive transfer can be incorporated into the current melanoma treatment continuum, especially as combination therapy with other immunomodulators and targeted drugs, is discussed.

High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3. It is unknown whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy or whether activation of any particular Treg subset correlates with clinical outcome. Here, we evaluated Treg population subsets that were induced in patients with melanoma following HD IL-2 therapy. We identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). This Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. [ICOS.sup.+] Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of [ICOS.sup.+] Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer [ICOS.sup.+] Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the [ICOS.sup.+] Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome.

In this paper, the authors evaluated Treg population subsets that were induced in patients with melanoma following high-dose (HD) IL-2 therapy. They identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). The Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF- beta . ICOS super( +) Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS super( +) Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS super( +) Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS super( +) Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome.

In this paper, the authors evaluated Treg population subsets that were induced in patients with melanoma following high-dose (HD) IL-2 therapy. They identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). The Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS^sup +^ Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS^sup +^ Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS^sup +^ Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS^sup +^ Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome.

Repetitive vaccinations with dendritic cell (DC)-based vaccines over long periods of time can break pre-existing tolerance to tumors and achieve clinically relevant immune response. This requires a large number of DCs to be generated under good manufacturing protocol, which is time- and cost intensive. Thus, producing a large numbers of DCs at one time point and cryopreserving these cells in ready-for-use aliquots for clinical application may overcome this constraint. This could also reduce batch-to-batch variations. In this study, we generated DCs from bone marrow obtained from BALB/c mice. Some of the generated DCs were cryopreserved before conducting various tests. There were no significant differences in the morphology and phenotype between cryopreserved and freshly generated DCs. Both types of DCs pulsed with tumor lysate (TL) from 4T1 murine mammary cancer cells (DC+TL) possessed a similar capacity to stimulate the proliferation of T-cells. In addition, cryopreserved and fresh DC pulsed with TL showed similar tumor growth inhibition patterns. Both DCs induced initial retardation of tumor growth (p<0.05) and prolonged the survival (p<0.05) of tumor-bearing mice treated with DC+TL as compared with nontreated control mice. Cryopreserved DCs shared similar therapeutic efficacy to fresh DCs, and this finding lends supports the routine use of cryopreserved DCs in future clinical trials.