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Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robustin vivoanti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. [ABSTRACT FROM AUTHOR]

Summary Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Here, Ca 2+ /calmodulin-dependent protein kinase II γ (CAMKIIγ) was shown to stabilize the c-Myc protein by directly phosphorylating it at serine 62 (S62). Furthermore, CAMKIIγ was shown to be essential for tumor maintenance. Inhibition of CAMKIIγ with a specific inhibitor destabilized c-Myc and reduced tumor burden. Importantly, high CAMKIIγ levels in patient TCL specimens correlate with increased c-Myc and pS62-c-Myc levels. Together, the CAMKIIγ:c-Myc axis critically influences the development and maintenance of TCL and represents a potential therapeutic target for TCL. [ABSTRACT FROM AUTHOR]

In this study, we identified a CD105+CD90.1−CD133−CD55− (CD133−CD55−) population in the fetal skeletal element that can generate bone and bone marrow. Besides osteoblasts and chondrocytes, the CD133−CD55− common progenitors can give rise to marrow reticular stromal cells and perivascular mesenchymal progenitors suggesting they function as the fetal common skeletal progenitor. Suppression of CXCL12 and Kitl expression in CD133−CD55− common progenitors severely disrupted the BM niche formation but not bone generation. Thus, CD133−CD55− common progenitors are the main source of CXCL12 and Kitl producing cells in the developing marrow. [ABSTRACT FROM AUTHOR]

Human CD8+effector T cells derived from CD45RO+CD62L+precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO+CD62L−precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8+effector T cells derived from CD45RA+CD62L+precursors enriched for naïve and stem cell memory precursors (TN/SCM) with that of TCM. We found that cytotoxic T cells (CTLs) derived from TCMtranscribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from TN/SCM. Higher frequencies of CTLs derived from TCMretained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ScidIL-2RγCnullmice, CD8+TCMderived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8+TCMderived CD19CAR+CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8+TN/SCMderived counterparts. These studies support the use of TCMenriched cell products for adoptive therapy of cancer. [ABSTRACT FROM PUBLISHER]

An abstract of the article "Comparison of Pseudotyped rAAV Vectors for Transduction of Primary Hematopoietic Stem and Progenitor Cells Assayed In Vitro and In Vivo," by Lijing Li, Sarah Hardy, Leslie Smith-Powell, Sai Srinivas, Stephen J. Forman, K. K. Wong and Saswati Chatterjee is presented.

Discusses findings of a study conducted by Cindi M. Morshead et al. which reveals inability to generate hematopoietic progeny from neural stem cells (NSC). Information on functional characteristics of NSC cultures described in the study; Assertion that comparison of study by Morshead et al. with that of Bjornson et al is inappropriate.

A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials. [ABSTRACT FROM AUTHOR]

An abstract of the article "rAAV-2 Transduction of Primitive Human Hematopoietic Stem Cells Capable of Serial Engraftment in Immune Deficient Mice," by Helicia Paz, Leah Santat, Lijing Li, Christie Wong, Stephen J. Forman, K. K. Wong and Saswati Chatterjee is presented.

Background: Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation remains a serious problem. In a clinical trial, we tested the combination of cyclosporine and prednisone with and without methotrexate for the prevention of GVHD. Methods: One hundred fifty patients with either acute leukemia in first complete remission, chronic myelogenous leukemia in first chronic phase, or lymphoblastic lymphoma in first complete remission were enrolled in the study. All the patients were given fractionated total-body irradiation (1320 cGy) and etoposide (60 mg per kilogram of body weight) in preparation for transplantation, and received bone marrow from genotypically histocompatible donors. To prevent GVHD, they were randomly assigned to prophylactic treatment with either cyclosporine, methotrexate, and prednisone or cyclosporine and prednisone without methotrexate. All the patients received standardized supportive care after transplantation, including intravenous gamma globulin. Results: Patients receiving cyclosporine, methotrexate, and prednisone had a significantly lower incidence of acute GVHD of grades II to IV (9 percent) than those receiving cyclosporine and prednisone (23 percent, P = 0.02). Multivariate regression analysis demonstrated that an increased risk of acute GVHD was associated with an elevated serum creatinine concentration (P = 0.006) and treatment with cyclosporine and prednisone alone (P = 0.02). The lower incidence of acute GVHD was not associated with a higher rate of relapse of leukemia or lymphoma. There was no significant difference in disease-free survival at three years between the two treatment groups (64 percent with the three-drug regimen vs. 59 percent with the two-drug regimen, P = 0.57). Conclusions: The combination of cyclosporine, methotrexate, and prednisone was more effective in preventing acute GVHD of grades II to IV than was the combination of cyclosporine and prednisone without methotrexate. (N Engl J Med 1993;329:1225-30.) [ABSTRACT FROM AUTHOR]