Strategies for Cancer Vaccine Development

Treating cancer with vaccines has been a challenging field of investigation since the 1950s. Over the years, the lack of effective active immunotherapies has led to the development of numerous novel strategies. However, the use of therapeutic cancer vaccines may be on the verge of becoming an effective modality. Recent phase II/III clinical trials have achieved hopeful results in terms of overall survival. Yet despite these encouraging successes, in general, very little is known about the basic immunological mechanisms involved in vaccine immunotherapy. Gaining a better understanding of the mechanisms that govern the specific immune responses (i.e., cytotoxic T lymphocytes, CD4 T helper cells, T regulatory cells, cells of innate immunity, tumor escape mechanisms) elicited by each of the various vaccine platforms should be a concern of cancer vaccine clinical trials, along with clinical benefits. This review focuses on current strategies employed by recent clinical trials of therapeutic cancer vaccines and analyzes them both clinically and immunologically

Heterozygosity at Gm Loci Associated with Humoral Immunity to Osteosarcoma

Familial clustering of osteosarcoma suggests the involvement of genetic factors (1, 2), and the demonstration of a high incidence of osteosarcoma-specific antibodies (3, 4), as well as tumor-specific cell-mediated immunity (5) in patients and their relatives, indicates the involvement of immunological factors in the pathogenesis of this disease. Certain Gm allotypes (genetic markers of IgG) have been shown to be associated with a high relative risk of some forms of cancer. For instance, in Caucasians an unusual Gm haplotype--Gm 1,3;5,13,14--has been found to be associated with neuroblastoma (6), and an increased frequency of Gm (2) has been reported in patients with malignant melanoma (7, 8). A recent report has shown an association of the Gm 1,2; 13,15,16,21 phenotype with lung cancer and primary hepatoma in the Japanese (9). To our knowledge, however, the possible role of Gm allotypes in predisposition to osteosarcoma has not been examined. Immune responsiveness to a variety of antigens in both experimental animals and humans has been shown to be controlled either by major histocompatibility complex (MHC)-linked immune response (Ir) genes or by allotype-linked Ir genes (10-13). In some instances an interactive effect of these two unlinked genetic systems has been observed (12). It is possible that MHC-linked or allotype-linked Ir genes may also influence humoral immunity to tumor antigens. In this report we present evidence for complementary Ir genes controlling immune responses to osteosarcoma-associated antigens (OSAA)

Strong cardiovascular prognostic implication of quantitative left atrial contractile function assessed by cardiac magnetic resonance imaging in patients with chronic hypertension

<p>Abstract</p> <p>Background</p> <p>Progressive left ventricular (LV) diastolic dysfunction due to hypertension (HTN) alters left atrial (LA) contractile function in a predictable manner. While increased LA size is a marker of LV diastolic dysfunction and has been shown to be predictive of adverse cardiovascular outcomes, the prognostic significance of altered LA contractile function is unknown.</p> <p>Methods</p> <p>A consecutive group of patients with chronic hypertension but without significant valvular disease or prior MI underwent clinically-indicated CMR for assessment of left ventricular (LV) function, myocardial ischemia, or viability. Calculation of LA volumes used in determining LA emptying functions was performed using the biplane area-length method.</p> <p>Results</p> <p>Two-hundred and ten patients were included in this study. During a median follow-up of 19 months, 48 patients experienced major adverse cardiac events (MACE), including 24 deaths. Decreased LA contractile function (LAEF_Contractile) demonstrated strong unadjusted associations with patient mortality, non-fatal events, and all MACE. For every 10% reduction of LAEF_Contractile, unadjusted hazards to MACE, all-cause mortality, and non-fatal events increased by 1.8, 1.5, and 1.4-folds, respectively. In addition, preservation of the proportional contribution from LA contraction to total diastolic filling (Contractile/Total ratio) was strongly associated with lower MACE and patient mortality. By multivariable analyses, LAEF_Contractilewas the strongest predictor in each of the best overall models of MACE, all-cause mortality, and non-fatal events. Even after adjustment for age, gender, left atrial volume, and LVEF, LAEF_Contractilemaintained strong independent associations with MACE (p < 0.0004), all-cause mortality (p < 0.0004), and non-fatal events (p < 0.0004).</p> <p>Conclusions</p> <p>In hypertensive patients at risk for left ventricular diastolic dysfunction, a decreased contribution of LA contractile function to ventricular filling during diastole is strongly predictive of adverse cardiac events and death.</p

Long-Term Survival and PSA Control with Radiation and Immunotherapy for Node Positive Prostate Cancer

We describe a patient with node positive prostate cancer treated with radiation, androgen deprivation, and immunotherapy with long-term overall survival and PSA control. ELISPOT immunoassay studies demonstrated PSA specific T-cells prior to starting vaccine therapy suggesting that this positive response may be related to an improved antitumor immune response of the patient, increased immunogenicity of the tumor, or decreased activation of immune escape pathways. Further evaluation of therapeutic cancer vaccines in combination with radiation and hormonal therapy in the definitive management of prostate cancer is warranted

883 An anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human acute myeloid leukemia (AML) cell lines in vitro

BackgroundNEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 and has demonstrated tumor sensitivity and specificity in epithelial cells. Functional analysis has revealed that NEO-201 can engage innate immune effector mechanisms including ADCC and CDC to directly kill tumor cells expressing its target. A recent Phase 1 clinical trial at the NCI has determined both safety and recommended Phase 2 dosing. We have also seen the expression of the NEO-201 target on hematologic cells, specifically Tregs and neutrophils. Due to epitope being expressed both on malignant epithelial cells as well as several hematologic cells, we designed this study to explore the reactivity of NEO-201 against hematological neoplastic cells in vitro.MethodsPhenotypic analysis was conducted by flow cytometry. Cell lines used were six AML (HL60, U937, MOLM13, AML2, IMS-M2 and OCL-AML3), two multiple myelomas (MM) (OPM2, MM1.S), two acute lymphoblastic leukemia (ALL) (SUP-B15, RPMI8402) and four mantle cell lymphoma (MCL) (Jeko-1, Z138, JVM2 and JVM13). Markers used for flow cytometry analysis were CD15, CD45, CD38, CD138, CD14, CD19 and NEO-201. Functional analysis was performed by evaluating the ability of NEO-201 to mediate ADCC activity against AML cell lines using human NK cells as effector cells.Results5 of 6 AML cell lines tested bind to NEO-201 and the% of positive cells were 47%, 99.5%,100%,100% and 97.8% for HL60, U937, MOLM13, AML3 and IMS-M2, respectively. The% of positive cells in the two MM cell line were 99% and 18% for OPM2 and MM1.S, respectively. NEO-201 binding was not detected in the two ALL and the four MCL cell lines tested. Functional analysis has demonstrated that NEO-201 can mediate ADCC activity against the AML cell line (HL60) tested.ConclusionsThis study demonstrates that NEO-201 mAb's target is expressed in most of the AML cell lines tested in vitro. In addition, we have shown it can mediate ADCC activity against HL60 cells (AML). Together, these findings provide a rationale for further investigation of the role of NEO-201 in AML as well as MM, further exploring patient PBMCs and bone marrow samples

DNA-templated assembly of droplet-derived PEG microtissues

Patterning multiple cell types is a critical step for engineering functional tissues, but few methods provide three-dimensional positioning at the cellular length scale. Here, we present a “bottom-up” approach for fabricating multicellular tissue constructs that utilizes DNA-templated assembly of 3D cell-laden hydrogel microtissues. A flow focusing-generated emulsion of photopolymerizable prepolymer is used to produce 100 μm monodisperse microtissues at a rate of 100 Hz (10[superscript 5] h[superscript −1]). Multiple cell types, including suspension and adherently cultured cells, can be encapsulated into the microtissues with high viability ([similar]97%). We then use a DNA coding scheme to self-assemble microtissues “bottom-up” from a template that is defined using “top-down” techniques. The microtissues are derivatized with single-stranded DNA using a biotin–streptavidin linkage to the polymer network, and are assembled by sequence-specific hybridization onto spotted DNA microarrays. Using orthogonal DNA codes, we achieve multiplexed patterning of multiple microtissue types with high binding efficiency and >90% patterning specificity. Finally, we demonstrate the ability to organize multicomponent constructs composed of epithelial and mesenchymal microtissues while preserving each cell type in a 3D microenvironment. The combination of high throughput microtissue generation with scalable surface-templated assembly offers the potential to dissect mechanisms of cell–cell interaction in three dimensions in healthy and diseased states, as well as provides a framework for templated assembly of larger structures for implantation

d-alpha correlation functions and collective motion in Xe+Au collisions at E/A=50 MeV

The interplay of the effects of geometry and collective motion on d-{alpha} correlation functions is investigated for central Xe+Au collisions at E/A=50 MeV. The data cannot be explained with out collective motion, which could be partly along the beam axis. A semi-quantitative description of the data can be obtained using a Monte -Carlo model, where thermal emission is superimposed on collective motion. Both the emission volume and the competition between the thermal and collective motion influence significantly the shape of the correlation function, motivating new strategies for extending intensity interferometry studies to massive particles

d-alpha Correlation functions and collective motion in Xe+Au collisions at E/A=50 MeV

The interplay of the effects of geometry and collective motion on d-$\alpha$ correlation functions is investigated for central Xe+Au collisions at E/A=50 MeV. The data cannot be explained without collective motion, which could be partly along the beam axis. A semi-quantitative description of the data can be obtained using a Monte-Carlo model, where thermal emission is superimposed on collective motion. Both the emission volume and the competition between the thermal and collective motion influence significantly the shape of the correlation function, motivating new strategies for extending intensity interferometry studies to massive particles.Comment: Accepted for publication on Physics Letters

Estimating Infection Attack Rates and Severity in Real Time during an Influenza Pandemic: Analysis of Serial Cross-Sectional Serologic Surveillance Data

This study reports that using serological data coupled with clinical surveillance data can provide real-time estimates of the infection attack rates and severity in an emerging influenza pandemic