bluuebunny/crossref_metadata_2025_split huggingface dataset:
Update on Phase I Clinical Trial of IPI-504, a Novel, Water-Soluble Hsp90 Inhibitor, in Patients with Relapsed/Refractory Multiple Myeloma (MM).
Authors: Siegel David , Jagannath Sundar , Mazumder Amitabha , Vesole David , Borrello Ivan , Sydor Jens , Wright Jim , Patterson Jon , Normant Emmanuel , Adams Julian , Anderson Kenneth , Grayzel David , Richardson Paul 
Published: October 2019

Abstract
Introduction: IPI-504 is a novel, water-soluble Heat Shock Protein 90 (Hsp90) inhibitor. It is the chemical reduction product of 17-AAG, a well-characterized Hsp90 inhibitor. 17-AAG is currently in clinical trials, but suffers from very poor aqueous solubility and must be administered to patients in either suboptimal DMSO formulations, or newer cremophor or emulsion formulations. In contrast, IPI-504 exists as a hydrochloride salt which is soluble in water in excess of 200 mg/mL. Therefore, IPI-504 is 4000-fold more soluble than 17-AAG. It has previously been shown that IPI-504 inter-converts with 17-AAG and exists in a pH and enzyme-mediated dynamic redox equilibrium which has been observed in human clinical trials as well. In preclinical animal studies, IPI-504 has demonstrated in vitro and in vivo anti-tumor effects in a variety of cancers including xenograft and orthotopic models of multiple myeloma (MM).
Methods: An open-label phase I dose-escalation trial of IPI-504 infused on days 1, 4, 8 and 11 of a 21 day cycle is being conducted in patients (pts) with relapsed/refractory MM. IPI-504 is administered to pts in 250cc of normal saline over thirty minutes. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and characterize the pharmacokinetic (PK) and pharmacodynamic (PD) marker effects of IPI-504. Levels of Hsp70 protein were measured as a marker of IPI-504’s biologic activity in peripheral blood leukocytes. Toxicity is evaluated by NCI CTCAE (v3.0) and response by EBMT. An accelerated dose titration design was employed with dose escalation of 100% for the first three dose levels with 1 pt / cohort. The first three pts received 22.5, 45 and 90 mg/m2 respectively. Per protocol, once the 150 mg/m2 level was achieved, dose escalation converted to a modified Fibonacci schema with 3 pts per cohort. Subsequently dose escalation occurred in increments of 66%, 50%, 33% and 25%.
Results: Currently, 15 pts (11 female / 4 male), average age 61.3 years, have been treated. IPI-504 has been well-tolerated at doses ranging from 90 to 300 mg/m2. Patients continue to be enrolled at the 400 mg/m2 dose level. Dose limiting toxicities (DLTs), defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 21 days of treatment, have not been observed to date. Dose escalation will continue until a recommended phase 2 dose is identified. Analysis of PK, safety, tolerability, and biologic response to IPI-504 is ongoing. The above support the planning of further clinical exploration of IPI-504 including combination with agents such as bortezomib that have proven synergistic in animal models of MM.
Phase II Trial of SCIO-469 as Monotherapy (M) or in Combination with Bortezomib (MB) in Relapsed Refractory Multiple Myeloma (MM).
Authors: Siegel David S. , Krishnan A. , Lonial S. , Chatta G. , Alsina M. , Jagannath S. , Richardson P. , Hohl R.J. , Lust J.A. , Bensinger W. , Carrum G. , Moreb J. , Simic A. , Barlogie B. , Maziarz R.T. , Anderson K.C. , Lin J. , Lowe A. , Vetticaden S. , Zhu J. 
Published: October 2019

Abstract
Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance.
Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma.
Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB.
Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB.
Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease.
Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.
In Utero Is Superior to Ex Utero Cord Blood Collection.
Authors: Shpall Elizabeth J. , Karandish Safa , Sadeghi Tara , Hosing Chitra , Garcia Christopher J. , Cherry Michael T. , Walker Julia A. , Denman Corliss R. , Saliba Rima M. , Champlin Richard E. , Fernandez-Viña Marcelo , Cano Pedro , McMannis John D. 
Published: October 2019

Abstract
Cord blood (CB) cells are being used increasingly as a source of hematopoietic support in patients lacking human leukocyte antigent (HLA)-matched family or unrelated donors. 1124 CB units were collected, based on obstetrician preference, with the placenta either in utero or ex utero. If logistically feasible, both an in utero collection followed immediately by an additional ex utero collection once the placenta was delivered was performed. We compared the distribution of the collection parameters shown in the following table, using non-parametric tests [data expressed as median (range)]:
Athough the volume of CB collected was highest with the sequential in utero plus ex utero method, the number of total nucleated cells (TNCs) and CD34+ cells was similar for both the in utero procedures and higher than with the ex utero alone procedure. The number of CB units that had microbial contamination was similar for all three groups: ex utero-0 CB units, in utero-1 CB unit and in utero plus ex utero-1 CB unit. There were no clinical adverse events associated with any of the collection procedures.
Conclusion: In utero collections are safe and result in CB units with significantly higher volumes, TNCs and CD34+ cells than ex utero collections, with no difference in the microbial contamination rate.
CB Parameters Ex Utero (N=390) In Utero (N=334) In+Ex Utero (N=400) In+Ex vs Ex (p) In+Ex vs In (p) In vs Ex (p) Volume (ml) 76.5 88.5 94 <0.0001 0.03 <0.001 (35–199) (45–185) (42–207) Tot Nucleated cells (xE7) 94 115 119 <0.001 0.4 <0.001 (20–267) (36–399) (41–393) CD34+cells (xE6) 2.9 3.4 3.1 0.2 0.16 0.01 (0–30) (0–34) (0–55)
Clinical-Scale Combined CD4/CD8 Depletion for Donor Innate Lymphocyte Infusion (DILI).
Authors: Kunzmann Volker , Smetak Manfred , Weissinger Florian , Birkmann Josef , Einsele Hermann , Wilhelm Martin 
Published: October 2019

Abstract
The ability to selectively deplete or enrich cells of specific phenotype by immunomagnetic selection procedures holds significant promise for application in adoptive immunotherapy protocols. In vitro and in vivo studies demonstrated that MHC-independent effector cells of the innate immune system such as natural killer (NK) cells and γδ T cells have potent anti-tumor activity without inducing Graft-versus-Host disease (GvHD). However, current clinical-scale approaches to reduce the risk of GvHD usually use T-cell depletion (such as CD34+ selection or CD3+ depletion). However, both procedures also deplete γδ T cells which may be advantageous in mediating Graft-versus tumor effects and augmenting innate immune response against infections. Here we present a new method for depletion of T cells with potential GvHD reactivity and simultaneously enrichment of innate lymphocytes (NK cells and γδ T cells) from standard leukapheresis products by using a single-step immunomagnetic protocol which efficiently depletes CD4+ and CD8+ αβ T cells under good manufacturing conditions (GMP). Efficiency of CD4+ and CD8+ T cell depletion from (unstimulated) leukapheresis products (n=6) containing up to 2.0 × 1010 white blood cells, was demonstrated by 4-color flow cytometric analysis (mean log depletion of CD4+ cells: 4.12 (3.17–4.9); mean log depletion of CD8+ cells: 3.77 (2.97–4.54)). In addition to efficient depletion of CD4+ and CD8+ cells, immunomagnetic CD4/CD8 depletion resulted in enrichment of NK cells and γδ T cells (mean NK cell recovery: 38%(19–72), mean γδ T cell cell recovery: 50%(34–79)). In vitro assays of the final product demonstrated that NK cells and γδ T cells preserved their proliferative and cytotoxic capacity. We conclude that simultaneous depletion of CD4+ and CD8+ cells is feasible and can be performed in large scale under GMP conditions with sufficient depletion efficacy of αβ T cells and recovery of functionally intact innate effector lymphocytes (NK cells and γδ T cells) for potential use in adoptive immunotherapy studies.
Improved Survival with Adjuvant Donor Lymphocyte Transfusions Following Allogeneic Stem Cell Transplantation after Reduced Intensity Conditioning for High-Risk AML.
Authors: Schleuning Michael , Schmid Christoph , Koenecke Christian , Hertenstein Bernd , Baurmann Herrad , Schwerdtfeger Rainer , Kolb Hans-Jochem 
Published: October 2019

Abstract
Albeit clinical experience is limited adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation. We report our data on aDLT in high-risk AML. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and aDLT. For aDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression and free of GvHD. 30% of patients (n=46) alive at day +120 fulfilled the criteria for aDLT. They had been transplanted (24 from matched unrelated donors) for refractory (n=11) or relapsed leukemia (n=24) or in CR1 because of unfavourable cytogenetics (n=7) or other unfavourable criteria (n=2) or in CR2 with unfavourable cytogenetics (n=2). Twenty-four patients had an unfavourable karyotype, 10 with complex aberrations. Thirty-one patients with similar disease characteristics and fulfilling similar selection criteria (being alive in CR at d +120, no cGVHD and no history of aGVHD> II°) transplanted during the same time period served as control. Of these 10 pts. were transplanted at a center not using aDLT and 21 at the center in Wiesbaden during 2000 and 2002 prior to the introduction of the protocol at this center. The median time from transplant to first aDLT was 160 days (range 71–303). Median follow up of the surviving transfused patients is 594 days (range 113–1920). Nine patients received 1, 18 patients received 2, and 19 patients received 3 transfusions in escalating doses, containing a median of 1×106, 5×106 and 1×107 CD3+ cells/kg at aDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade II/III acute GvHD developed in 4, and chronic GvHD in 8 patients. So far, 8 (17%) patients have relapsed despite aDLT, as compared to 42% in the control group (Chi-square: p=0.018). Two died of refractory leukemia, whereas 5 achieved a secondary CR following adoptive immunotherapy. At the time of analysis (April 2006), 39/46 patients were alive and all but one patient who is actually receiving adoptive immunotherapy are in CR at a median of 441 days post DLT. The actuarial overall survival two years after transplant is 85% as compared to 53% in the control group and at four years 78% vs. 40%, respectively (p=0.005). In conclusion, aDLT is safe, when given in escalating doses and to a selected group of patients. Results are encouraging, and improved long term survival can be achieved.
A Mouse Model of PR1-CTL Adoptive Cell Therapy Demonstrates Rapid Reduction of Leukemia Burden in Both Bone Marrow and Extramedullary Organs.
Authors: Ma Qing , Wieder Eric D. , Jones Dan J. , Wang Changqing , Li Dan J. , Molldrem Jeffrey J. 
Published: October 2019

Abstract
Cytotoxic T lymphocytes (CTL) specific for a nine amino acid HLA-A2-restricted peptide, PR1 (derived from proteinase 3, P3), are capable of killing leukemia cells and contribute to the elimination of CML. PR1-specific CTL (PR1-CTL) elicited in vitro from healthy donors also can lyse P3-expressing AML blasts. Here, we examined whether PR1-CTL can be adoptively transferred to NOD-SCID/HLA-A2 transgenic mice to eliminate blasts as a preclinical model for PR1-CTL cell therapy for AML. Human AML blasts isolated from bone marrow were transferred into irradiated (200 rad) NOD-SCID/HLA-A2 mice and engrafted in bone marrow at various doses (107, 106, 105) between 2–8 weeks. Human CD45 Ab and mouse CD45.1 Ab were used to identify cells of human origin by FACS and IHC, and human CD33 and CD34 Abs were used to identify AML cells. PR1-CTL were elicited from healthy donors that specifically lysed P3-expressing leukemia. These PR1-CTL were predominantly CD45RA−/CCR7−/CD28+ and maintained an activated effector phenotype following adoptive transfer. Transferred AML blasts were significantly decreased in the bone marrow of mice receiving co-transferred PR1-CTL compared to those that received only AML: 0.5×106 AML cells plus 1×104 PR1-CTL or 0.5×106 AML cells (control) were infused into irradiated mice respectively. Mice were sacrificed at 2–4 weeks post-transfer and tissues were analyzed by FACS and IHC. Bone marrow aspirate from mice that received AML alone had 72–88% blasts in hypercellular marrow, whereas mice that received AML plus PR1-CTL had normal hematopoietic elements and only 10–11% blasts in hypocellular marrow. PR1-CTL also migrated to the secondary lymphoid organs including spleen, peripheral and mesenteric lymph nodes, and in the liver. Leukemia cells also infiltrated extramedullary organs. In the liver, intrasinuosidal and periportal collections of leukemic blasts were associated with vascular damage, and PR-CTL infiltrated these same regions by 2 weeks post-transfer. The PR1-CTL in the bone marrow and liver maintained an effector phenotype similar to the pre-infusion CTL, whereas PR1-CTL in secondary lymph organs such as blood and spleen also contained some cells expressing CCR7 that either reverted to a naïve phenotype or had expanded from the precursor population. By 4 weeks post-transfer, leukemia was no longer evident in the liver, although PR1-CTL remained. In conclusion, we found that PR1-CTL generated in vitro can eliminate the AML cells in NOD-SCID/HLA-A2 mice. PR1-CTL can migrate to sites of disease and maintain their capacity to eliminate leukemic blasts. Surface phenotype of PR1-CTL were consistent with their trafficking pattern in both vascular and end-organ tissues. Our results justify a clinical trial with adoptively transferred PR1-CTL in patients with AML.
Treatment of Established B16 Murine Melanoma Tumors with Tyrp-1 Specific CD4+ Lymphocytes.
Authors: Muranski Pawel , Boni Andrea , Paulos Crystal M. , Irvine Kari R. , Antony Paul A. , Restifo Nicholas P. 
Published: October 2019

Abstract
T-cell mediated response against solid tumors has been mostly associated with CD8+ cytotoxic lymphocytes, which act directly on the MHC class I expressing tumors. In the previously published model, gp-100 melanoma antigen-specific pmel-1 CD8+ T cells required co-administration of IL-2 and vaccine to induce significant regression of poorly immunogenic B16 melanoma in mice. MHC class II restricted CD4+ T-cells (T helpers) may have multiple direct and indirect effects on the immune response, but their role in adoptive cell transfer (ACT) therapy of solid tumors remains mainly undefined and based on highly manipulated models involving foreign antigens. In order to investigate the function of tumor specific CD4+ T-cells we have generated a transgenic mouse expressing a TRP-1 T cell receptor (TCR) directed against class II restricted murine melanocyte differentiation antigen tyrp-1. In vitro expanded TRP1 CD4+ cells secreted Th1-like cytokines upon antigen stimulation and caused direct cytotoxic effect against B16 melanoma. In vivo they mediated a highly effective response against large (>1cm2) B16 melanoma tumors after ACT of as few as 2.5×105 cells/mouse into C57B6 animals, which was associated with a massive tumor infiltration with CD11b+, MAC3+, GR1+ cells. TRP-1 T cells caused partial tumor rejection and prolonged survival in MHC class II−/− hosts implying the ability to directly recognize low level MHC class II on the tumor. This suboptimal effect was significantly enhanced after co-transfer of MHC class II+ APCs into MHC class II−/− hosts allowing for antigen cross- presentation.
Interestingly, Rag1−/− hosts, deficient in all T and B lymphocytes, demonstrated excellent initial response to treatment, but were not cured and succumbed to late relapse of the melanoma. Long-term responses were even more impaired in Rag1−/− γc−/− hosts, while complete and durable cure was observed in TCRα−/−, CD4−/− and C57B6 mice, suggesting involvement of other arms of the adaptive immune system. Similarly, co-transfer of 0.1×106 CD4+ TRP-1 cells and 1×106 CD8+ pmel-1 cells resulted in effective tumor regression, while the same numbers of each cells transferred individually were not sufficient to initiate a rejection. Introduction of tumor-specific CD4+ cells therefore eliminates the previously sine qua non need for co-administration of vaccine and IL-2 for effective treatment with CD8+ pmel-1 cells. Overall, we show that antigen-specific CD4+ T cells are highly effective in mediating the anti-tumor response by causing both the direct anti-tumor effect and by activating innate and adaptive arms of the immune system. These findings suggest that CD4+ T helper cells may play a key role in improving efficacy of ACT immunotherapy as central activators of the anti-tumor response.
A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cdk4/6.
Authors: Baughn Linda B. , Di Liberto Maurizio , Wu Kaida , Toogood Peter , Louie Tracey , Gottschalk Rachel , Niesvizky Ruben , Cho Hearn J. , Ely Scott , Moore Malcolm A.S. , Chen-Kiang Selina 
Published: October 2019

Abstract
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow (BM). Inhibition of Cdk4 and Cdk6 by the Cdk inhibitor, p18(INK4c), is required for the generation of normal, functional plasma cells1. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of Cdk4-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of BM myeloma cells in vivo2. These data identify Cdk4 and Cdk6 as key determinants in the loss of cell cycle control in myeloma and suggest that Cdk4/6 may be effective targets for therapeutic intervention. Here we show that by specific inhibition of Cdk4/6, the orally active small molecule PD 0332991 potently induces G1 arrest in primary BM myeloma cells ex vivo, and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation, and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B cell cancers.