Publications by authors named "James F Sanchez"

44 Publications

The Emerging Role of Extracellular Vesicle-Associated RNAs in the Multiple Myeloma Microenvironment.

Front Oncol 2021 21;11:689538. Epub 2021 Jun 21.

Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, United States.

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells (PCs) that develop at multiple sites within the bone marrow (BM). MM is treatable but rarely curable because of the frequent emergence of drug resistance and relapse. Increasing evidence indicates that the BM microenvironment plays a major role in supporting MM-PC survival and resistance to therapy. The BM microenvironment is a complex milieu containing hematopoietic cells, stromal cells, endothelial cells, immune cells, osteoclasts and osteoblasts, all contributing to the pathobiology of MM, including PC proliferation, escape from immune surveillance, angiogenesis and bone disease development. Small extracellular vesicles (EVs) are heterogenous lipid structures released by all cell types and mediate local and distal cellular communication. In MM, EVs are key mediators of the cross-talk between PCs and the surrounding microenvironment because of their ability to deliver bioactive cargo molecules such as lipids, mRNAs, non-coding regulatory RNA and proteins. Hence, MM-EVs highly contribute to establish a tumor-supportive BM niche that impacts MM pathogenesis and disease progression. In this review, we will first highlight the effects of RNA-containing, MM-derived EVs on the several cellular compartments within the BM microenvironment that play a role in the different aspects of MM pathology. We will also touch on the prospective use of MM-EV-associated non-coding RNAs as clinical biomarkers in the context of "liquid biopsy" in light of their importance as a promising tool in MM diagnosis, prognosis and prediction of drug resistance.
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http://dx.doi.org/10.3389/fonc.2021.689538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255802PMC
June 2021

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Oncolytic herpes simplex virus infects myeloma cells and .

Mol Ther Oncolytics 2021 Mar 18;20:519-531. Epub 2021 Feb 18.

Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Monrovia, CA 91016, USA.

Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138/CD38 plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target.
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http://dx.doi.org/10.1016/j.omto.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940704PMC
March 2021

Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools.

Diagnostics (Basel) 2020 Dec 9;10(12). Epub 2020 Dec 9.

Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA 91010, USA.

Small extracellular vesicles (EVs) are a heterogenous group of lipid particles released by all cell types in physiological and pathological states. In hematological malignancies, tumor-derived EVs are critical players in mediating intercellular communications through the transfer of genetic materials and proteins between neoplastic cells themselves and to several components of the bone marrow microenvironment, rendering the latter a "stronger" niche supporting cancer cell proliferation, drug resistance, and escape from immune surveillance. In this context, the molecular cargoes of tumor-derived EVs reflect the nature and status of the cells of origin, making them specific therapeutic targets. Another important characteristic of EVs in hematological malignancies is their use as a potential "liquid biopsy" because of their high abundance in biofluids and their ability to protect their molecular cargoes from nuclease and protease degradation. Liquid biopsies are non-invasive blood tests that provide a molecular profiling clinical tool as an alternative method of disease stratification, especially in cancer patients where solid biopsies have limited accessibility. They offer accurate diagnoses and identify specific biomarkers for monitoring of disease progression and response to treatment. In this review, we will focus on the role of EVs in the most prevalent hematological malignancies, particularly on their prospective use as biomarkers in the context of liquid biopsies, as well as their molecular signature that identifies them as specific therapeutic targets for inhibiting cancer progression. We will also highlight their roles in modulating the immune response by acting as both immunosuppressors and activators of anti-tumor immunity.
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http://dx.doi.org/10.3390/diagnostics10121065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763630PMC
December 2020

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab.

Blood Adv 2020 10;4(20):5194-5202

The Judy and Bernard Briskin Center for Multiple Myeloma Research.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.
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http://dx.doi.org/10.1182/bloodadvances.2020002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594407PMC
October 2020

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting.

Leukemia 2021 01 16;35(1):189-200. Epub 2020 Apr 16.

Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 91010, USA.

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T-cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex vivo and in vivo. In support of Dara's immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.
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http://dx.doi.org/10.1038/s41375-020-0810-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572537PMC
January 2021

Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study.

Leuk Lymphoma 2020 07 8;61(7):1669-1677. Epub 2020 Apr 8.

Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 and 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.
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http://dx.doi.org/10.1080/10428194.2020.1742900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384948PMC
July 2020

MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Judy and Bernard Briskin Center for Multiple Myeloma Research, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, California, USA.

High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.
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http://dx.doi.org/10.1172/jci.insight.129348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948777PMC
November 2019

Venetoclax and hypomethylating agents in TP53-mutated acute myeloid leukaemia.

Br J Haematol 2019 10 22;187(2):e45-e48. Epub 2019 Aug 22.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.

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http://dx.doi.org/10.1111/bjh.16166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786919PMC
October 2019

Multi-institutional evaluation of MVCT guided patient registration and dosimetric precision in total marrow irradiation: A global health initiative by the international consortium of total marrow irradiation.

Radiother Oncol 2019 12 14;141:275-282. Epub 2019 Aug 14.

Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, USA. Electronic address:

Purpose: Total marrow irradiation (TMI) is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. Although many centers worldwide initiated clinical studies using TMI, currently there is no standard for pretreatment patient setup. To this end, the accuracy of different patient setups was measured using pretreatment imaging. Their impact on dose delivery was assessed for multiple institutions.

Methods And Materials: Whole body imaging (WBI) or partial body imaging (PBI) was performed using pretreatment megavoltage computed tomography (MVCT) in a helical Tomotherapy machine. Rigid registration of MVCT and planning kilovoltage computed tomography images were performed to measure setup error and its effect on dose distribution. The entire skeleton was considered the planning target volume (PTV) with five sub regions: head/neck (HN), spine, shoulder and clavicle (SC), and one avoidance structure, the lungs. Sixty-eight total patients (>300 images) across six institutions were analyzed.

Results: Patient setup techniques differed between centers, creating variations in dose delivery. Registration accuracy varied by anatomical region and by imaging technique, with the lowest to the highest degree of pretreatment rigid shifts in the following order: spine, pelvis, HN, SC, and lungs. Mean fractional dose was affected in regions of high registration mismatch, in particular the lungs.

Conclusions: MVCT imaging and whole body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs (or avoidance structures).
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http://dx.doi.org/10.1016/j.radonc.2019.07.010DOI Listing
December 2019

Leflunomide Synergizes with Gemcitabine in Growth Inhibition of PC Cells and Impairs c-Myc Signaling through PIM Kinase Targeting.

Mol Ther Oncolytics 2019 Sep 17;14:149-158. Epub 2019 May 17.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.

The immunosuppressive agent leflunomide has been used in the treatment of over 300,000 patients with rheumatoid arthritis. Its active metabolite, teriflunomide (Ter), directly inhibits dihydroorotate dehydrogenase (DHODH), an enzyme involved in nucleoside synthesis. We report that Ter not only shows anti-proliferative activity in pancreatic cancer (PC) cells as a single agent but also synergizes with the chemotherapeutic gemcitabine (Gem) in growth inhibition of PC cells. The growth-inhibitory effects of Ter are not solely caused by inhibition of DHODH. Through a kinase screening approach, we identified the PIM-3 serine-threonine kinase as a novel direct target. Subsequent dose-response kinase assays showed that Ter directly inhibited all three PIM family members, with the highest activities against PIM-3 and -1. The PIM-3 kinase was the PIM family member most often associated with PC oncogenesis and was also the kinase inhibited the most by Ter among more than 600 kinases investigated. Ter in PC cells induced changes in phosphorylation and expression of PIM downstream targets, consistent with the effects achieved by overexpression or downregulation of PIM-3. Finally, pharmacological inhibition of PIM proteins not only diminished PC cell proliferation, but also small-molecule pan-PIM and PIM-3 inhibitors synergized with Gem in growth inhibition of PC cells.
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http://dx.doi.org/10.1016/j.omto.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562366PMC
September 2019

Outcomes of Haploidentical Transplantation in Patients with Relapsed Multiple Myeloma: An EBMT/CIBMTR Report.

Biol Blood Marrow Transplant 2019 02 20;25(2):335-342. Epub 2018 Sep 20.

Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% CI, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P =.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P = .001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339830PMC
February 2019

Acute lymphoblastic leukemia as a clonally unrelated second primary malignancy after multiple myeloma.

Leukemia 2019 01 19;33(1):266-270. Epub 2018 Jul 19.

The Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA.

Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67). MM therapy included immunomodulatory agents in all patients and autologous hematopoietic cell transplantation in 10 (77%) patients preceding ALL diagnosis. ALL genetics showed a normal karyotype, TP53 mutation/deletion, and monosomy 7 or 7q deletion in 5, 3, and 2 cases, respectively. Analysis of paired samples of MM and ALL using whole exome sequencing demonstrated that the malignancies arose from different clones. Thus, ALL as a second primary malignancy following MM is not clonally related but could potentially represent a therapy-related leukemia.
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http://dx.doi.org/10.1038/s41375-018-0213-yDOI Listing
January 2019

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma.

Leukemia 2018 Jul 23;32(7):1567-1574. Epub 2018 Feb 23.

Sarah Cannon Research Institute, Nashville, TN, USA.

In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose-limiting. Per 3 + 3 phase I design, an additional three patients were enrolled to DL1, with no further dose-limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll three additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved  ≥ partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥ stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.
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http://dx.doi.org/10.1038/s41375-018-0038-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005710PMC
July 2018

Incidence of Second Primary Malignancies after Autologous Transplantation for Multiple Myeloma in the Era of Novel Agents.

Biol Blood Marrow Transplant 2018 05 12;24(5):930-936. Epub 2018 Jan 12.

Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany.

The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPMs). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPMs, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.006DOI Listing
May 2018

Copper 64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma.

Blood 2018 02 4;131(7):741-745. Epub 2018 Jan 4.

Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA.

As a growing number of patients with multiple myeloma (MM) respond to upfront therapies while eventually relapsing in a time frame that is often unpredictable, attention has increasingly focused on developing novel diagnostic criteria to also account for disease dissemination. Positron emission tomography/computed tomography (PET/CT) is often used as a noninvasive monitoring strategy to assess cancer cell dissemination, but because the uptake of the currently used radiotracer 18fluorodeoxyglucose (F-FDG) is a function of the metabolic activity of both malignant and nonmalignant cells, the results frequently lack sufficient specificity. Radiolabeled antibodies targeting MM tissue may detect disease irrespective of cell metabolism. Hence, we conjugated the clinically significant CD38-directed human antibody daratumumab (Darzalex [Dara]) to the DOTA chelator and labeled it with the positron-emitting radionuclide copper 64 (Cu; Cu-DOTA-Dara). Here, we show that Cu-DOTA-Dara can efficiently bind CD38 on the surface of MM cells and was mainly detected in the bones associated with tumor in a MM murine model. We also show that PET/CT based on Cu-DOTA-Dara displays a higher resolution and specificity to detect MM cell dissemination than does F-FDG PET/CT and was even more sensitive than were bioluminescence signals. We therefore have supporting evidence for using Cu-DOTA-Dara as a novel imaging agent for MM.
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http://dx.doi.org/10.1182/blood-2017-09-807263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814935PMC
February 2018

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.

Mol Ther 2018 01 5;26(1):31-44. Epub 2017 Oct 5.

Department of Hematology & Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope Beckman Research Institute and Medical Center, Duarte, CA 91010, USA.

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8 T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors.
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http://dx.doi.org/10.1016/j.ymthe.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763077PMC
January 2018

Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor-Redirected T Cells Against Multiple Myeloma.

Clin Cancer Res 2018 01 23;24(1):106-119. Epub 2017 Oct 23.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat multiple myeloma-bearing mice as combinatorial therapy. CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991104PMC
January 2018

Preclinical data support leveraging CS1 chimeric antigen receptor T-cell therapy for systemic light chain amyloidosis.

Cytotherapy 2017 07 5;19(7):861-866. Epub 2017 May 5.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA.

Background Aims: Light chain amyloidosis (AL) is a protein deposition disorder that is a result of a plasma cell dyscrasia, similar to multiple myeloma (MM). Immunotherapy is an attractive approach because of the low burden of disease, but the optimal target for AL is unclear. CS1 and B-cell maturation antigen (BCMA) are two potential targets because they are expressed on normal plasma cells and MM cells.

Methods: We performed a prospective study evaluating bone marrow specimens of 20 patients with plasma cell diseases, 10 with AL and 10 with MM. We evaluated the clonal population of plasma cells for BCMA and CS1 expression. We designed a second-generation CS1 chimeric antigen receptor (CAR) construct, comprising a CS1 antigen-specific scFv, shortened hinge region and CD28 costimulatory domain. Purified central memory T cells were activated and transduced with a lentiviral vector encoding the CS1 CAR. Cytotoxicity was evaluated using Cr release assays. Five days after tumor inoculation, NSG mice were injected intravenously with CS1 CAR T cells.

Results: Whereas CS1 is present on the plasma cells of AL patients, we found BCMA expression in AL to be markedly low. CS1 CAR T cells were cytotoxic against CS1 positive tumor cells and induced durable tumor regressions in mice.

Discussion: Our work represents a novel application of CS1-directed CAR T cells while revealing that BCMA would not be a suitable target. We expect AL to be particularly susceptible to CAR T-cell therapy because of the low tumor burden in the bone marrow.
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http://dx.doi.org/10.1016/j.jcyt.2017.03.077DOI Listing
July 2017

Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Chemotherapy in Mantle Cell Lymphoma Patients Is Associated with Higher Rates of Hematopoietic Progenitor Cell Mobilization Failure despite Plerixafor Rescue.

Biol Blood Marrow Transplant 2017 Aug 18;23(8):1264-1268. Epub 2017 Apr 18.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Induction regimens for mantle cell lymphoma (MCL) can be categorized into highly intensive regimens containing cytarabine and less intense regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) or rituximab with bendamustine (R-bendamustine). Prior publications have shown rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) can be associated with stem cell mobilization failures. However, those studies did not include the use of plerixafor as rescue for stem cell mobilization failure. We examined our database of 181 consecutive MCL patients who received upfront therapy from 2005 to 2015 with either R-hyperCVAD or less intense chemotherapy (R-bendamustine and R-CHOP only) regimens to assess impact of frontline chemotherapy on collection of hematopoietic cell progenitors before autologous stem cell transplantation (ASCT). In the preplerixafor era (before August 16, 2009), a significant difference in peripheral blood stem cell (PBSC) collection failure between the R-hyperCVAD (12%) and other chemotherapy (11%) groups was not established. However, in the postplerixafor era, use of R-hyperCVAD chemotherapy was associated with significantly higher rates of hematopoietic progenitor cell collection failures (17%) compared with that observed in the other chemotherapy group (4%; P = .04). The rates of mobilization failure declined to 4% in the postplerixafor era from 11% in the preplerixafor era for patients receiving less intensive chemotherapy. Conversely, the rate of mobilization failure increased in the R-hyperCVAD group from 12% in the preplerixafor era to 17% in the postplerixafor era. Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT.
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http://dx.doi.org/10.1016/j.bbmt.2017.04.011DOI Listing
August 2017

Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology.

Biol Blood Marrow Transplant 2017 Jun 4;23(6):922-929. Epub 2017 Mar 4.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Standard-dose yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20 non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646666PMC
June 2017

Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia.

Biol Blood Marrow Transplant 2017 Apr 10;23(4):618-624. Epub 2017 Jan 10.

Department of Radiation Oncology, City of Hope, Duarte, California.

Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.
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http://dx.doi.org/10.1016/j.bbmt.2017.01.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382014PMC
April 2017

Implications and Management of Central Nervous System Involvement before Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2016 Mar 19;22(3):575-8. Epub 2015 Oct 19.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Acute lymphoblastic leukemia (ALL) with a history of central nervous system (CNS) involvement, either at diagnosis or relapse, poses challenges when the decision is made to proceed with allogeneic hematopoietic cell transplantation (alloHCT), as there is no evidence-based consensus on the best peri-transplantation approach to reduce subsequent CNS relapse risk. Here, we retrospectively analyzed outcomes of 87 patients with ALL and a history of CNS involvement who later underwent alloHCT. Patients with pretransplantation CNS involvement had higher risk of CNS relapse after transplantation (2-year CNS relapse: 9.6% versus 1.4%, P < .0001), inferior event-free survival (EFS) (hazard ratio [HR], 1.52; P = .003), and worse overall survival (OS) (HR, 1.55; P = .003) compared with patients without pretransplantation CNS involvement (n = 543). There was no difference in post-transplantation CNS relapse, EFS, or OS among patients presenting with CNS involvement at diagnosis, those with isolated CNS relapse, and those with combined bone marrow and CNS relapse before HCT. Interestingly, neither pretransplantation cranial irradiation, use of total body irradiation-based conditioning, nor post-transplantation prophylactic intrathecal chemotherapy were associated with a reduction of CNS relapse risk after transplantation. Thus, among the patients in the cohort studied, there was no clear benefit of CNS-directed therapy in the peri-transplantation period among patients who had prior CNS involvement and underwent subsequent alloHCT.
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http://dx.doi.org/10.1016/j.bbmt.2015.10.016DOI Listing
March 2016

Rational domain swaps reveal insights about chain length control by ketosynthase domains in fungal nonreducing polyketide synthases.

Org Lett 2014 Mar 5;16(6):1676-9. Epub 2014 Mar 5.

Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy , Los Angeles, California 90089, United States.

A facile genetic methodology in the filamentous fungus Aspergillus nidulans allowed exchange of the starter unit ACP transacylase (SAT) domain in the nonreduced polyketide synthase (NR-PKS) AfoE of the asperfuranone pathway with the SAT domains from 10 other NR-PKSs. The newly created hybrid with the NR-PKS AN3386 is able to accept a longer starter unit in place of the native substrate to create a novel aromatic polyketide in vivo.
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http://dx.doi.org/10.1021/ol5003384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993715PMC
March 2014

Inhibition of Tau aggregation by three Aspergillus nidulans secondary metabolites: 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde.

Planta Med 2014 Jan 10;80(1):77-85. Epub 2014 Jan 10.

Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.

The aggregation of the microtubule-associated protein tau is a significant event in many neurodegenerative diseases including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activity. We have screened Aspergillus nidulans secondary metabolites containing aromatic ring structures for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol and the previously identified aggregation inhibitor emodin as a positive control. While several compounds showed some activity, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde were potent aggregation inhibitors as determined by both a filter trap assay and electron microscopy. In this study, these three compounds were stronger inhibitors than emodin, which has been shown in a prior study to inhibit the heparin induction of tau aggregation with an IC50 of 1-5 µM. Additionally, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde reduced, but did not block, tau stabilization of microtubules. 2,ω-Dihydroxyemodin and asperthecin have similar structures to previously identified tau aggregation inhibitors, while asperbenzaldehyde represents a new class of compounds with tau aggregation inhibitor activity. Asperbenzaldehyde can be readily modified into compounds with strong lipoxygenase inhibitor activity, suggesting that compounds derived from asperbenzaldehyde could have dual activity. Together, our data demonstrates the potential of 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde as lead compounds for further development as therapeutics to inhibit tau aggregation in Alzheimer's disease and neurodegenerative tauopathies.
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http://dx.doi.org/10.1055/s-0033-1360180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442474PMC
January 2014

Application of an efficient gene targeting system linking secondary metabolites to their biosynthetic genes in Aspergillus terreus.

Org Lett 2013 Jul 10;15(14):3562-5. Epub 2013 Jul 10.

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.

Nonribosomal peptides (NRPs) are natural products biosynthesized by NRP synthetases. A kusA-, pyrG- mutant strain of Aspergillus terreus NIH 2624 was developed that greatly facilitated the gene targeting efficiency in this organism. Application of this tool allowed us to link four major types of NRP-related secondary metabolites to their responsible genes in A. terreus. In addition, an NRP affecting melanin synthesis was also identified in this species.
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http://dx.doi.org/10.1021/ol401384vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833251PMC
July 2013

Molecular genetic characterization of the biosynthesis cluster of a prenylated isoindolinone alkaloid aspernidine A in Aspergillus nidulans.

Org Lett 2013 Jun 24;15(11):2862-5. Epub 2013 May 24.

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.

Aspernidine A is a prenylated isoindolinone alkaloid isolated from the model fungus Aspergillus nidulans. A genome-wide kinase knockout library of A. nidulans was examined, and it was found that a mitogen-activated protein kinase gene, mpkA, deletion strain produces aspernidine A. Targeted gene deletions were performed in the kinase deletion background to identify the gene cluster for aspernidine A biosynthesis. Intermediates were isolated from mutant strains which provided information about the aspernidine A biosynthesis pathway.
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http://dx.doi.org/10.1021/ol401187bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713076PMC
June 2013