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(1) Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis.[TOP]

Pubmed ID :30951849
Publication Date : //
Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

Authors : Teter B, Morihara T, Lim G P, Chu T, Jones M R, Zuo X, Paul R M, Frautschy S A, Cole G M,

(2) A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia.[TOP]

Pubmed ID :30524966
Publication Date : //
Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4 and CD8 T cells, and CAR expression was confirmed by flow cytometry. CAR33VH, similar to My96CAR, demonstrated robust and specific cytotoxicity in short-term and long-term co-incubation killing assays against CD33 AML lines. In overnight cytokine release assays in which CAR T cells were challenged with the CD33 tumor cells HL-60, MOLM-14 and KG-1a, CAR33VH elicited IFN-gamma, TNF-alpha and IL-2. This was seen with CD33 cell lines, but not when CAR T were cultured alone. Studies with a CD33 cell line engineered to stably express the full length CD33 variant 1, or the naturally occurring CD33 splice variant 2, revealed that both CAR33VH and My96CAR, target the V domain of CD33, suggesting a similar therapeutic profile. Colony-formation assays utilizing peripheral blood CD34 hematopoietic stem cells treated with CAR33VH, My96CAR, or with an untransduced T cell control, yielded similar numbers of BFU-E erythroid and CFU-GM myeloid colonies, suggesting a lack of CAR-related overt toxicity. In an AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH and CARMy96 efficiently eliminated tumors. In conclusion, we demonstrate for the first time the feasibility and efficacy of employing human variable domain-only binder derived from a phage display library in an anti-AML CAR design. CAR33VH, comprised of a human heavy-chain variable fragment-only antigen binding domain, was efficient in tumor killing and , and showed comparable functionality to the scFv-based My96CAR.

Authors : Schneider Dina, Xiong Ying, Hu Peirong, Wu Darong, Chen Weizao, Ying Tianlei, Zhu Zhongyu, Dimitrov Dimiter S, Dropulic Boro, Orentas Rimas J,

(3) Antibody-Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non-small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade.[TOP]

Pubmed ID :30206165
Publication Date : //
Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological mechanisms associated with HP have been identified.

Authors : Lo Russo Giuseppe, Moro Massimo, Sommariva Michele, Cancila Valeria, Boeri Mattia, Centonze Giovanni, Ferro Simona, Ganzinelli Monica, Gasparini Patrizia, Huber Veronica, Milione Massimo, Porcu Luca, Proto Claudia, Pruneri Giancarlo, Signorelli Diego, Sangaletti Sabina, Sfondrini Lucia, Storti Chiara, Tassi Elena, Bardelli Alberto, Marsoni Silvia, Torri Valter, Tripodo Claudio, Colombo Mario Paolo, Anichini Andrea, Rivoltini Licia, Balsari Andrea, Sozzi Gabriella, Garassino Marina Chiara,

(4) Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models.[TOP]

Pubmed ID :30185216
Publication Date : //
Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models.

Authors : Rosato Roberto R, Dávila-González Daniel, Choi Dong Soon, Qian Wei, Chen Wen, Kozielski Anthony J, Wong Helen, Dave Bhuvanesh, Chang Jenny C,

(5) CLT030, a leukemic stem cell-targeting CLL1 antibody-drug conjugate for treatment of acute myeloid leukemia.[TOP]

Pubmed ID :30037800
Publication Date : //
The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy. RNA-sequencing analysis on isolated LSCs confirmed C-type lectin domain family 12 member A (CLL1, also known as CLEC12A) to be highly expressed on LSCs but not on normal hematopoietic stem cells (HSCs) or other healthy organ tissues. Expression of CLL1 was consistent across different types of AML. We developed CLT030 (CLL1-ADC), an antibody-drug conjugate (ADC) based on a humanized anti-CLL1 antibody with 2 engineered cysteine residues linked covalently via a cleavable linker to a highly potent DNA-binding payload, thus resulting in a site-specific and homogenous ADC product. The ADC is designed to be stable in the bloodstream and to release its DNA-binding payload only after the ADC binds to CLL1-expressing tumor cells, is internalized, and the linker is cleaved in the lysosomal compartment. CLL1-ADC inhibits in vitro LSC colony formation and demonstrates robust in vivo efficacy in AML cell tumor models and tumor growth inhibition in the AML patient-derived xenograft model. CLL1-ADC demonstrated a reduced effect on differentiation of healthy normal human CD34 cells to various lineages as observed in an in vitro colony formation assay and in an in vivo xenotransplantation model as compared with CD33-ADC. These results demonstrate that CLL1-ADC could be an effective ADC therapeutic for the treatment of AML.

Authors : Jiang Ying-Ping, Liu Bob Y, Zheng Quan, Panuganti Swapna, Chen Ruoying, Zhu Jianyu, Mishra Madhavi, Huang Jianqing, Dao-Pick Trang, Roy Sharmili, Zhao XiaoXian, Lin Jeffrey, Banik Gautam, Hsi Eric D, Mandalam Ramkumar, Junutula Jagath R,

(6) An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia.[TOP]

Pubmed ID :29959143
Publication Date : //
The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine- and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next-generation ADC for AML to improve upon the initial success of Mylotarg.

Authors : Zheng Bing, Yu Shang-Fan, Del Rosario Geoffrey, Leong Steven R, Lee Genee Y, Vij Rajesh, Chiu Cecilia, Liang Wei-Ching, Wu Yan, Chalouni Cecile, Sadowsky Jack, Clark Vanessa, Hendricks Angela, Poon Kirsten Achilles, Chu Wayne, Pillow Thomas, Schutten Melissa M, Flygare John, Polson Andrew G,

(7) A potent tetravalent T-cell-engaging bispecific antibody against CD33 in acute myeloid leukemia.[TOP]

Pubmed ID :29858209
Publication Date : //
Acute myeloid leukemia (AML), the most common acute leukemia in adults and the second most common cancer in children, is still a lethal disease in the majority of patients, but immunologic approaches have improved outcome. Bispecific antibodies (BsAbs) are novel immunotherapeutics that can redirect immune cells against AML. We now report a tetravalent (2+2) humanized BsAb in the immunoglobulin G light chain single chain fragment variable [IgG(L)-scFv] format to engage polyclonal T cells to kill CD33 AML targets. In vitro, this BsAb demonstrated strong antigen-specific T-cell-dependent cell-mediated cytotoxicity (TDCC) with an 50% effective concentration (EC) in the femtomolar range that translated into treatment of established human AML IV xenografts in vivo. Importantly, it could redirect intraperitoneally injected T cells to ablate established and rapidly growing extramedullary subcutaneous AML xenografts in vivo. Furthermore, internalization of CD33 upon BsAb binding was identical to that of a bivalent (1+1) heterodimer, both being substantially less than anti-CD33 IgG. In contrast to the heterodimer, the tetravalent IgG-scFv BsAb was >10-fold more efficient in TDCC of AML cells in vitro and in vivo. This BsAb did not react with and did not kill CD38CD34 hematopoietic stem cells from cord blood. We conclude that the novel anti-CD33 IgG(L)-scFv BsAb construct reported here is a potential candidate for clinical development.

Authors : Hoseini Sayed Shahabuddin, Guo Hongfen, Wu Zhihao, Hatano Miho Nakajima, Cheung Nai-Kong V,

(8) Phenotyping and Target Expression Profiling of CD34/CD38 and CD34/CD38 Stem- and Progenitor cells in Acute Lymphoblastic Leukemia.[TOP]

Pubmed ID :29772458
Publication Date : //
Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34/CD38 LSCs in patients with Ph ALL (n = 22) and Ph ALL (n = 27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41 = 24%), CD22 (12/20 = 60%), CD33 (Siglec-3) (20/48 = 42%), CD52 (CAMPATH-1) (17/40 = 43%), IL-1RAP (13/29 = 45%), and/or CD135 (FLT3) (4/20 = 20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph ALL exhibiting BCR/ABL1, whereas in Ph ALL with BCR/ABL1, LSCs variably expressed CD25 but did not express CD26. In Ph ALL, CD34/CD38 LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34/CD38 and CD34/CD38 cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph and Ph ALL display unique marker- and target expression profiles. In Ph ALL with BCR/ABL1, the LSC-phenotype closely resembles the marker-profile of CD34/CD38 LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.

Authors : Blatt Katharina, Menzl Ingeborg, Eisenwort Gregor, Cerny-Reiterer Sabine, Herrmann Harald, Herndlhofer Susanne, Stefanzl Gabriele, Sadovnik Irina, Berger Daniela, Keller Alexandra, Hauswirth Alexander, Hoermann Gregor, Willmann Michael, Rülicke Thomas, Sill Heinz, Sperr Wolfgang R, Mannhalter Christine, Melo Junia V, Jäger Ulrich, Sexl Veronika, Valent Peter,

(9) Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.[TOP]

Pubmed ID :29621339
Publication Date : //
Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage-HLA-DR-CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides.

Authors : Namkoong Ho, Ishii Makoto, Fujii Hideki, Yagi Kazuma, Asami Takahiro, Asakura Takanori, Suzuki Shoji, Hegab Ahmed E, Kamata Hirofumi, Tasaka Sadatomo, Atarashi Koji, Nakamoto Nobuhiro, Iwata Satoshi, Honda Kenya, Kanai Takanori, Hasegawa Naoki, Koyasu Shigeo, Betsuyaku Tomoko,

(10) Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.[TOP]

Pubmed ID :29515236
Publication Date : //
Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.

Authors : Petrov Jessica C, Wada Masayuki, Pinz Kevin G, Yan Lulu E, Chen Kevin H, Shuai Xiao, Liu Hua, Chen Xi, Leung Lai-Han, Salman Huda, Hagag Nabil, Liu Fang, Jiang Xun, Ma Yupo,