T cell priming by high avidity neoantigens in lymph nodes augments adoptive immunotherapy.

Does Hypergammaglobulinemia Predispose to Secondary Solid Tumors in Patients with Chronic Lymphocytic Leukemia?.

Background Occurrence of second hematologic malignancies in patients with chronic lymphocytic leukemia (CLL) is well known, but development of secondary solid tumors has not been well documented. Isolated case reports indicate that CLL patients may have a predisposition to develop solid tumors. There is not enough literature available to support this hypothesis. We here intend to study the incidence of secondary solid tumors in CLL patients with regard to their treatment and immunoglobulin levels. Methods We reviewed the medical records of 323 CLL patients over the last 20 years at Veterans Affairs Medical Center, Kansas City. Broadly, the patients were divided into two groups, the group that received chemotherapy for CLL (74/323) versus the group that did not receive treatment (249/323), and their median immunoglobulin levels were also documented. Patients who developed secondary hematologic malignancies were excluded from this study. Results The overall incidence of solid tumors was found to be 14.8% (48/323). In the chemotherapy-treated CLL, the incidence of solid tumors was 18% (14/74) compared with 13.6% (34/249) in the nontherapeutic group (p value .12). The most common malignancies noted were gastrointestinal malignancies, genitourinary tumors, and skin cancers, including melanomas. Interestingly, CLL patients who developed secondary solid tumors had a higher median IgG levels (1,010 g/L) when compared with those who did not develop secondary tumors (738 g/L, p value Conclusion Our study shows that there is a higher overall incidence of secondary solid tumors in patients with CLL when compared with the incidence in the general population. There is no significant increase in the incidence of therapy-related solid tumors in CLL patients. Upward drift in immunoglobulin levels should raise a suspicion for diagnosis of secondary solid tumors in patients with CLL. More studies are warranted to confirm this finding.

Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity

CD8+ T Cells: Foot Soldiers of the Immune System

The mTOR Kinase Determines Effector versus Memory CD8+ T Cell Fate by Regulating the Expression of Transcription Factors T-bet and Eomesodermin

Solid tumors in patients treated for Hodgkin's disease: a report from the German Hodgkin Lymphoma Study Group

Tumor Associated Antigen Reactive Donor T Cells As Elementary Components of Streptamer Isolated Multi-Antigen Specific T Cells

CD8 Coreceptor-Independent T Cell Stimulation Induces High Avidity CTL In the Presence of IL-21

The article reviews the key approaches to the use of modified response evaluation criteria in solid tumors (mRECIST) in patients with hepatocellular carcinoma and discusses its main strengths and features. According to the evaluation by mRECIST, complete response is defined as the disappearance of any intratumoral arterial enhancement in all target lesions. A partial response is defined as 30% decrease in the sum of the longest diameters of viable tumor target lesions compared with its baseline sum. Disease progression signifies a ≥20% increase in the sum of the longest diameters of viable tumor target lesions compared with nadir. Stable disease is defined as neither partial response nor progression.

Predicting lymph node output efficiency using systems biology

The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

A major barrier to cancer vaccines as therapy is the many tolerance mechanisms inhibiting the activation of cancer-specific T cells. Higher avidity T cells have been shown to be more strongly affected by tolerance signals leaving the potential for lower avidity T cells to be effective. These signals as well as co-regulatory signals strongly affect T cell activation, function, and survival in vivo. Our study aims to identify tolerance mechanisms and co-regulatory signals in lower avidity CD8+ T cells as compared to other cells within a T cell repertoire specific for the same cancer antigen. We used the HER-2/neu (neu-N) transgenic mouse model of spontaneous mammary tumors. Vaccines targeted at the HER-2/neu protein induce T cell responses of differing avidities against the immunodominant epitope RNEU420-429. We created high and low avidity TCR transgenic mice whose high and low avidity tumor-specific T cells can be tracked in the tolerized HER-2/neu mice in vivo. T cells from the high and low avidity TCR transgenic mice were adoptively transferred into neu-N mice under different treatment conditions to evaluate changes in protein expression. Treatment groups included: tumor alone, tumor plus a GM-CSF secreting whole cell vaccine, and tumor plus vaccine plus the T regulatory cell (Treg) depleting agent cyclophosphamide. The combination of the Treg depleting agent and vaccine allows the activation of high avidity T cells including the ability of those T cells to reject tumor. Low avidity T cells do not reject tumor with any of these treatments. We used microarrays to compare gene expression between the high and low avidity T cells in tolerant and non-tolerant environments and found several genes with higher expression in the low avidity Tcells. In particular, cell death pathways were upregulated in the low avidity T cells when compared with high avidity T cells in a tolerant environment. The specific molecules within the cell death pathways that showed the most distinction were CD24, FasL, and DR5. Further analysis confirmed that protein expression of these molecules was also increased on low avidity T cells. We also found that these molecules are more highly expressed on T cells undergoing apoptosis. The increases in proteins involved the cell death pathway on low avidity T cells correlates with our finding that in tolerant mice lower avidity T cells have a shorter survival than higher avidity T cells. These studies also show that T cells expressing these death proteins secrete less effector cytokines, including IFNγ, than T cells that do not express them. Currently these proteins are being targeted therapeutically to determine if the survival and function of low avidity T cells can be altered. Thus, this study should identify novel combinatorial immune-based treatments to enhance the overall anti-tumor activity of cancer vaccines. Citation Format: Chelsea M. Black, Elizabeth M. Jaffee, Todd D. Armstrong. Pro-apoptotic proteins affect survival of tumor-specific low avidity CD8+ T cells in tolerant mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 455. doi:10.1158/1538-7445.AM2013-455

This study aimed to identify potential tolerance signals specific to lower avidity T cells. Cancer vaccines are currently being investigated as a way to activate antigen-specific anti-tumor T cell responses capable of eradicating developing tumors. It is now appreciated that a major barrier to cancer vaccines as therapy are the multiple signals originating from the tumor microenvironment that inhibit the activation of cancer-specific T cells. In addition, the most potent T cells specific for a tumor antigen are often subject to the most potent tolerance mechanisms leaving in place a range of lower avidity T cell sub-populations potentially available for activation. A number of co-regulatory signals play an important role in T cell activation, propagation, function, and/or survival in vivo. However, it is still not clear which mechanisms regulate specific T cell sub-populations within a given T cell repertoire specific for the same cancer antigen. We used the HER-2/neu (neu-N) transgenic mouse model of spontaneous mammary tumors in which vaccines targeted against the HER-2/neu protein induce T cell responses against the immunodominant epitope RNEU420-429 with a range of avidities. We created high and low avidity TCR transgenic mice from which isolated T cells can be tracked in the tolerized HER-2/neu mice in vivo. We first adoptively transferred T cells from the high and low avidity TCR transgenic mice into neu-N mice under different treatment conditions to evaluate the changes in the co-regulatory signaling pathways. Treatment groups included: tumor alone, tumor + a GM-CSF secreting whole cell vaccine, and tumor + vaccine + a T regulatory cell (Treg) depleting agent. The Treg depleting agent cyclophosphamide has been shown to suppress Tregs and allow activation and function of the high avidity T cells but not the low avidity T cells. This suggests that Tregs do not regulate lower avidity T cell populations. The low avidity T cells fail to reject tumor when compared with the high avidity T cells which reject tumor under conditions of vaccine + Treg depletion. We used microarrays to compare signal differences between the high and low avidity T cell populations under each condition, and several genes were identified that were upregulated in the low avidity T cells. Molecules within the survival signaling pathways that specifically demonstrated higher expression were CD24, FasL, and DR5. These molecules were confirmed to have increased protein expression in low avidity T cells when compared with high avidity T cells. Further functional analysis also demonstrated that T cells expressing CD24 and DR5 secrete lower levels of the effector cytokine IFNγ than T cells not expressing those molecules. This increase in proteins involved the cell death pathway correlates with our finding that lower avidity T cells have a shorter survival than higher avidity T cells in the tolerant mice under all treatment conditions. Currently pro-survival therapies are being conducted to determine if survival and function of the low avidity T cells can be altered through modulation of each upregulated pathway. These studies should identify novel combinatorial immune based therapies that engage multiple components of the T cell repertoire and enhance the overall anti-tumor activity of vaccines in vivo. Citation Format: Chelsea M. Black, Todd D. Armstrong, Elizabeth M. Jaffee. Low avidity tumor-specific CD8+ T cells are regulated by increased expression of proapoptotic proteins in tolerant mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B54.

BackgroundCD8+ T cell fate decision refers to the differentiation of a naïve T cell into effector, memory, exhausted, or other fates. Evidence from chronic infection and cancer models suggest that...

The European Association for the Study of the Liver criteria and the modified Response Evaluation Criteria in Solid Tumors are used for assessing the treatment outcomes of hepatocellular carcinoma. We investigated the inter- and intra-observer reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients with advanced hepatocellular carcinoma treated with sorafenib. A total of 99 patients with treatment-naive advanced hepatocellular carcinoma receiving sorafenib were included. The κ-values for the inter- and intra-observer agreement of the treatment response were calculated. Inter-observer agreement for baseline tumour number was excellent, as reflected by the high κ-value. The κ-statistics showed "excellent" concordance between the 2 sets of measurements by observer A regarding the overall responses using the European Association for the Study of the Liver criteria (κ=.948, agreement rate=84.8%) and modified Response Evaluation Criteria in Solid Tumors (κ=.944, agreement rate=83.8%; all P<.001). In addition, high κ-values indicated concordance between the first sets of measurements by observers A and B (κ=.991 by the European Association for the Study of the Liver criteria and .988 by modified Response Evaluation Criteria in Solid Tumors, all P<.001). When agreements in radiological overall responses between the 2 sets of measurements by observer B and between the second sets of measurements by observers A and B were calculated, similar results regarding high κ-values (>.8) were obtained. The reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in assessing treatment outcomes was high in patients with advanced hepatocellular carcinoma treated with sorafenib.