Dendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of ...activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.
Cancer vaccines: Where are we going? CEBON, Jonathan
Asia-Pacific journal of clinical oncology,
March 2010, Letnik:
6, Številka:
s1
Journal Article
Recenzirano
The discovery that the immune system can distinguish molecular targets on cancer cells has led to efforts to develop cancer immunotherapeutics that can improve the recognition and effective ...elimination of tumor cells. Several types of tumor antigens are recognized by T lymphocytes, which are classified according to patterns of gene expression or protein distribution. Of particular interest is the group of molecules known as cancer‐germline or cancer‐testis antigens. As the relationship between the immune system and cancer has become clearer, so too have the challenges in designing effective cancer immunotherapeutics: (i) antigens need to be specifically selected based on ideal characteristics, such as tissue distribution that is restricted to tumors; (ii) selected antigens need to be combined with adjuvant agents that enhance their immunogenicity and yield robust responses; (iii) vaccination should be timed to pre‐empt the development of regulatory suppressive immune mechanisms; and (iv) if suppressive regulatory mechanisms do arise, specific antagonists may be needed to enhance pro‐immune outcomes. These challenges are shaping current and future research in this area.
Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that ...knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex; and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.
BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the ...anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.
Loss-of-function mutations in the gene coding for perforin (
) markedly reduce the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells, causing immunosuppression and ...impairing immune regulation. In humans, nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic
mutations. The partial inactivation of PRF1 due to mutations that promote protein misfolding or the common hypomorphic allele coding for the A91V substitution have been associated with lymphoid malignancies in childhood and adolescence. To investigate whether
mutations also predispose adults to cancer, we genotyped 566 individuals diagnosed with melanoma (101), lymphoma (65), colorectal carcinoma (30) or ovarian cancer (370). The frequency of
genotypes was similar in all disease groups and 424 matched controls, indicating that the
status is not associated with an increased susceptibility to these malignancies. However, four out of 15 additional individuals diagnosed with melanoma and B-cell lymphoma during their lifetime expressed either PRF1
or the rare pathogenic PRF1
variant (p = 0.04), and developed melanoma relatively early in life. Both PRF1
- and PRF1
-expressing lymphocytes exhibited severely impaired but measurable cytotoxic function. Our results suggest that defects in human PRF1 predispose individuals to develop both melanoma and lymphoma. However, these findings require validation in larger patient cohorts.
To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in ...patients with colorectal carcinoma.
Patients with colorectal carcinoma were infused with 131IhuA33 (400 MBq: 10 mCi) and 125IhuA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated.
There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of 131IhuA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2beta) between dose levels (mean +/- SD, 86.92 +/- 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 +/- 8.1 hours. Quantitative tumor uptake ranged from 2.1 x 10(-3) to 11.1 x 10(-3) %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion.
huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.
This study identifies type I IFNs as activating cytokines in a serum-free system in which human dendritic cells (DC) were generated from CD34+ progenitor cells. After 14 days of culture in GM-CSF, ...TNF-alpha, and IL-4, CD34+ progenitors gave rise to a population of large, immature DC expressing CD1a and CD11b but lacking CD14, CD80, CD83, CD86, and CMRF44. During the next 2 wk, this population spontaneously matured into nonadherent, CD1a(low/-), CD11b(low/-), CD14-, CD80+, CD83+, CD86+, CMRF44+ DC with high allostimulatory activity in the MLR. To examine which factors influenced this maturation, 25 different cytokines or factors were added to the immature DC culture. Only type I IFNs (alpha or beta) accelerated this maturation in a dose-dependent manner, so that after only 3 days the majority of large cells acquired the morphology, phenotype, and function characteristics of mature DC. Furthermore, supernatants from cultures containing spontaneously maturing DC revealed low levels of endogenous IFN production. Because of the similarity of the activation of DC in our culture system with the phenotypic and functional changes observed during Langerhans cells activation and migration in vivo, we investigated the effect of IFN-alpha on human Langerhans cell migration. IFN-alpha also activated the migration of human split skin-derived DC, demonstrating that this effect was not limited to DC derived in vitro from hemopoietic progenitor cells. DC activation by type I IFNs represents a novel mechanism of immunomodulation by these cytokines, which could be important during antiviral responses and autoimmune reactions.
Background and Objectives
The aim of this study was to perform a retrospective analysis of survival rates and determine prognostic indicators for patients who underwent definitive surgical resection ...of stage IV melanoma.
Methods
Patients included were those who underwent complete resection of metastatic melanoma. Data was analyzed using IBM SPSS 2.0. Survival estimates were derived from Kaplan‐Meier, log‐rank, and Breslow tests.
Results
The study population (n = 95) consisted of 60 males and 35 females. Median overall survival (OS) from the first metastasectomy was 49 months (95% confidence interval, 31‐67 months). OS at 1, 2, and 5 years was 92%, 87%, and 50% respectively. Predictors of survival included clear surgical margins compared to patients with positive margins (median OS 53 vs 20 months,
P = .026). A preoperative neutrophil to lymphocyte ratio less than 5 experienced a median OS of 65 months compared to 15 months (
P = .006; multivariable analysis for OS: hazard ratio 3.590,
P = .009).
Conclusion
This study's results are consistent with previous findings demonstrating favourable long‐term outcomes following selective resection of metastatic melanoma. In addition to achieving clear surgical margins, a low preoperative neutrophil to lymphocyte ratio was associated with improved outcomes. These factors may help identify surgical candidates.
Over most of the 20th century, immunotherapy for cancer was based on empiricism. Interesting phenomena were observed in the areas of cancer, infectious diseases, or transplantation. Inferences were ...made and extrapolated into new approaches for the treatment of cancer. If tumors regressed, the treatment approaches could be refined further. However, until the appropriate tools and reagents were available, investigators were unable to understand the biology underlying these observations. In the early 1990s, the first human tumor T cell antigens were defined and dendritic cells were discovered to play a pivotal role in antigen presentation. The current era of cancer immunotherapy is one of translational research based on known biology and rationally designed interventions and has led to a rapid expansion of the field. The beginning of the 21st century brings the possibility of a new era of effective cancer immunotherapy, combining rational, immunological treatments with conventional therapies to improve the outcome for patients with cancer.
Since the early 1990s, numerous cancer Ag have been defined and for a handful of these there is now some clinical experience, which has made it possible to assess their value as targets for cancer ...immunotherapy. The cancer-testis Ag have been particularly attractive because their expression is limited to cancer and virtually no non-malignant cells apart from germ cells and trophoblast. Among these, NY-ESO-1 has been the focus of our attention. The exceptional immunogenicity of this Ag coupled with its widespread distribution among many cancer types make it a very good vaccine candidate, with the potential to be used in vaccines against many types of malignancies. This article reviews emerging knowledge about the biology of NY-ESO-1 and experience with the early clinical development of vaccines directed against NY-ESO-1. These early studies have yielded a wealth of information about the immunology of NY-ESO-1 and set the scene for future clinical strategies for immune targeting of cancer.
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