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Austin, TX, United States

Barve M.,Mary Crowley Cancer Research Centers | Wang Z.,Strike Bio Inc. | Kumar P.,Gradalis, Inc. | Jay C.M.,Strike Bio Inc. | And 13 more authors.
Molecular Therapy | Year: 2015

Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5′ RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action. © 2015 The American Society of Gene & Cell Therapy. Source

Han X.Y.,University of Texas M. D. Anderson Cancer Center | Hellerstedt B.A.,Texas Oncology PA | Koller C.A.,University of Texas M. D. Anderson Cancer Center
American Journal of the Medical Sciences | Year: 2010

Lymphocytosis in response to viral infection, such as infectious mononucleosis, rarely exceeds 20 × 10/L in the adult population. Transfusion-acquired cytomegalovirus (CMV) mononucleosis after trauma-related splenectomy may cause prominent lymphocytosis, but the history and timing usually hint at the diagnosis. We describe a case of severe CMV mononucleosis that was acquired naturally decades after splenectomy. Together with the 2 similar cases that we reported recently, these cases all presented as initial diagnostic challenge because of a remote history of splenectomy, a prolonged febrile illness (∼4 weeks), marked lymphocytosis (peak 27.9 × 10/L), and undetectable or weakened anti-CMV IgM antibody response. The diagnosis was eventually established through detection of circulating CMV antigen or DNA and a year or longer follow-up with serial determination of IgM and IgG antibodies. Two similar cases were also identified in the literature and reviewed. Although the impaired IgM response may confuse the diagnosis, it correlates well with recent studies showing that human blood IgM memory B cells are circulating splenic marginal zone B cells; asplenic or splenectomized individuals, irrespective of the underlying cause, have undetectable IgM memory B cells. Together, these findings suggest that distant or recent postsplenectomy CMV mononucleosis represents a distinct clinicopathologic syndrome resulting from poor control of early viremia because of the lack of both splenic filtration and the typical brisk IgM response. For the practicing clinician, recognizing these features may aid timely diagnosis and treatment. Copyright © 2010 Southern Society for Clinical Investigation. Source

Olivares J.,Mary Crowley Cancer Research Centers | Kumar P.,Gradalis, Inc. | Yu Y.,Gradalis, Inc. | Maples P.B.,Gradalis, Inc. | And 12 more authors.
Clinical Cancer Research | Year: 2011

Purpose: On the basis of the hypothesis that the combined expression of immunostimulatory granulocyte macrophage colony stimulating factor (GM-CSF) and antitumor suppressor TGF-β2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, we constructed an expression plasmid [the tumor-associated glycoprotein(TAG) plasmid] that coexpressesGM-CSF and TGF-β2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine. Experimental Design: Patients undergoing resection were enrolled. Freshly harvested autologous tumor cells were mechanically and enzymatically disaggregated, then electroporated with the TAG vector. The resulting vaccine was irradiated, then aliquoted and cryopreserved until the time of injection. Patients received a minimum of 5 to a maximum of 12 monthly intradermal injections. Immune function was monitored at baseline and at months 3 and 6. Results: Vaccine manufacturing efficiency was 84% (32/38). Twenty-three patients received at least 1 vaccination. There were no grade 3 or 4 toxicities, and grade 1 and 2 events were local in nature. Seventeen of 21 patients had stable disease (SD) at month 2 or later as their best response, and 1 patient with stage IVa malignant melanoma achieved a complete response (CR) following 11 vaccinations and remains without evidence of disease 2 years following initiation of therapy. Six of 13 patients displayed a positive enzymelinked immunospot (ELISPOT) response to autologous TAG vaccine at week 12 including 3 patients with prolonged SD or CR. The 3 other patients survived through week 24, as compared with none of the 7 ELISPOT-negative patients. Conclusions: On the basis of safety and clinical and immunologic results, further evaluation of bifunctional vaccines is warranted. © 2011 AACR. Source

Raftopoulos H.,Monter Cancer Center | Laadem A.,Celgene | Hesketh P.J.,Tufts University | Goldschmidt J.,Blue Ridge | And 9 more authors.
Supportive Care in Cancer | Year: 2016

Purpose: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. Methods: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline. Results: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. Conclusions: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA. © 2015, The Author(s). Source

Ghisoli M.,Mary Crowley Cancer Research Centers | Barve M.,Mary Crowley Cancer Research Centers | Schneider R.,Mary Crowley Cancer Research Centers | Schneider R.,Gradalis, Inc. | And 15 more authors.
Molecular Therapy | Year: 2015

We report on 12 consecutive patients with advanced/metastatic Ewing's sarcoma who were treated as a separate cohort of a phase 1 trial of FANG autologous immunotherapy (1 × 10 6 -2.5 × 10 7 cells/intradermal injection each month for minimum 4 months). Safety and clinical response were monitored. Patient immune response to unmodified autologous tumor cells was assessed by gamma interferon-enzyme-linked immunospot (γIFN-ELISPOT) assay using peripheral blood mononuclear cells from baseline (pretreatment) and multiple postvaccination time points. None of the 12 patients (47 vaccinations) developed grade 2/3/4 drug-related toxicity. Median product release granulocyte-macrophage colony-stimulating factor expression was 1,941 pg/10 6 cells, and TGFβ1and TGFβ2 knockdown were 99 and 100%, respectively. Eight patients were assessed for ELISPOT response to autologous tumor cells at baseline and all (100%) were negative. In contrast, follow-up ELISPOT response at month 1 or month 4 (one patient) after FANG was positive in all eight patients. One patient achieved a partial tumor response (38% tumor reduction, RECIST 1.1). The Kaplan-Meier estimated survival of these 12 patients at 1 year was 75%. In this phase 1 study in patients with Ewing's sarcoma, FANG immunotherapy was well tolerated, elicited a tumor-specific systemic immune response in all patients, and was associated with favorable 1-year survival. Further clinical testing is indicated. © 2015 The American Society of Gene & Cell Therapy. Source

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