The present invention relates to compositions and methods for generating RNA Chimeric Antigen Receptor (CAR) transfected T cells. The RNA- engineered T cells can be used in adoptive therapy to treat cancer.

Rna engineered t cells for the treatment of cancer

The present invention provides an approach for the determination of the activation states of a plurality of proteins in single cells. This approach permits the rapid detection of heterogeneity in a complex cell population based on activation states, expression markers and other criteria, and the identification of cellular subsets that exhibit correlated changes in activation within the cell population. Moreover, this approach allows the correlation of cellular activities or properties. In addition, the use of modulators of cellular activation allows for characterization of pathways and cell populations. Several exemplary diseases that can be analyzed using the invention include AML, MDS, and MPN.

Methods for Diagnosis, Prognosis and Methods of Treatment

The present invention provides an approach for the simultaneous determination of the activation states of a plurality of proteins in single cells. This approach permits the rapid detection of heterogeneity in a complex cell population based on activation states, and the identification of cellular subsets that exhibit correlated changes in activation within the cell population. Moreover, this approach allows the correlation of cellular activities or properties. In addition, the use of potentiators of cellular activation allows for characterization of such pathways and cell populations.

Methods and compositions for risk stratification

Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hon.2137

Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy

The invention provides T cells comprising nucleic caid sequence encoding a chimeric antigen receptor and a nucleic acid sequence encoding an enhancer of T cell priming, compositions including the T cells, and methods of using the T cells to treat diseases associated with the expression of disease-associated antigens.

Enhanced antigen presenting ability of car t cells by co-introduction of costimulatory molecules

In one embodiment, a method includes sending an indicator of an availability of a sample from a sample pool stored in a physical inventory. The sample being included in the sample pool based on an attribute of the sample satisfying a condition associated with the sample pool. An indicator that the sample has been selected from the sample pool for analysis at a first test site included in an array of test sites is received. A rule is retrieved from a rule database based on an experimental parameter value associated with the first test site. At least one of the experimental parameter value associated with the first test site or an experimental parameter value associated with a second test site is modified based on a condition within the rule being satisfied.

Methods and apparatus related to management of experiments

As disclosed herein, the present invention provides for kits and a composition for diagnosis, prognosis, drug discovery, drug development, and patient stratification. The kits can comprise a plurality of binding elements for cell surface markers, and a plurality of binding elements for state-specific intracellular markers. The kits can further comprise a plurality of modulators directed for the particular cell function or signaling pathways. The kits can further include fixatives, permeabilizing agent, buffers, containers, instructions, and software for data analysis/compilation.

Kits for multiparametric phospho analysis

Provided herein are methods, compositions, and kits for determining cell signaling profiles in normal cells and comparing the cell signaling profiles of normal cells to cell signaling profiles from a test sample.

Benchmarks for Normal Cell Identification

Background

Single Cell Network Profiling (SCNP) is a multiparametric flow cytometry-based assay that quantifiably and simultaneously measures changes in intracellular signaling proteins in response to in vitro extracellular modulators at the single cell level. Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder of hematopoietic stem cells that occurs in elderly subjects and is characterized by dysplasia and ineffective hematopoiesis. The functional responsiveness of MDS bone marrow (BM) hematopoietic cells, including functionally distinct myeloid and erythroid precursor subsets, to hematopoietic growth factors (HGF) and the relationship of modulated signaling to disease characteristics is poorly understood.



Methods

SCNP was used first to examine the effects of age on erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF)-induced signaling in myeloid, nucleated red blood cells (nRBC), and CD34 expressing cell subsets in healthy BM (n = 15). SCNP was then used to map functional signaling profiles in low risk (LR) MDS (n = 7) for comparison to signaling in samples from healthy donors and to probe signaling associations within clinically defined subgroups.



Results

In healthy BM samples, signaling responses to HGF were quite homogeneous (i.e., tightly regulated) with age-dependent effects observed in response to EPO but not to GCSF. Despite the relatively small number of samples assayed in the study, LR MDS could be classified into distinct subgroups based on both cell subset frequency and signaling profiles.



Conclusions

As a correlate of underlying genetic abnormalities, signal transduction analyses may provide a functional and potentially clinically relevant classification of MDS. Further evaluation in a larger cohort is warranted. © 2013 International Clinical Cytometry Society

/pdf/age-related-changes-of-healthy-bone-marrow-cell-signaling-in-3kui3frrkg.pdf

Age-related changes of healthy bone marrow cell signaling in response to growth factors provide insight into low risk MDS.

Single Cell Network Profiling (SCNP) to Evaluate the Mechanism of Action of ON 01910.Na, A Novel Clinical Trial Stage Compound.

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