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1.
Haematologica ; 103(3): 531-539, 2018 03.
Article in English | MEDLINE | ID: mdl-29242294

ABSTRACT

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400).


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Interleukin-12/antagonists & inhibitors , Interleukin-23 Subunit p19/antagonists & inhibitors , Th1 Cells/immunology , Th17 Cells/immunology , Ustekinumab/administration & dosage , Adult , Aged , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Transplantation, Homologous , Ustekinumab/adverse effects , Young Adult
2.
Haematologica ; 102(5): 948-957, 2017 05.
Article in English | MEDLINE | ID: mdl-28104702

ABSTRACT

Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Interleukin-2/therapeutic use , T-Lymphocytes, Regulatory/drug effects , Adult , Aged , Antibiotics, Antineoplastic/therapeutic use , Drug Administration Schedule , Female , Graft vs Host Disease/diagnosis , Graft vs Host Disease/prevention & control , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Sirolimus/therapeutic use , Survival Analysis , T-Lymphocytes, Regulatory/metabolism , Transplantation, Homologous , Treatment Outcome , Young Adult
3.
Clin Cancer Res ; 18(11): 3163-9, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22496272

ABSTRACT

PURPOSE: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. EXPERIMENTAL DESIGN: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. CONCLUSION: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.


Subject(s)
Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Small Cell Lung Carcinoma/drug therapy , Sulfonamides/therapeutic use , Aged , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Antineoplastic Agents/adverse effects , Disease-Free Survival , Female , Humans , Male , Middle Aged , Recurrence , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Thrombocytopenia/chemically induced
4.
J Clin Oncol ; 29(7): 909-16, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21282543

ABSTRACT

PURPOSE: Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors. PATIENTS AND METHODS: Patients enrolled to intermittent dosing cohorts received navitoclax on day -3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring. RESULTS: Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume. CONCLUSION: Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies.


Subject(s)
Aniline Compounds/administration & dosage , Genes, bcl-2/drug effects , Neoplasms/genetics , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Sulfonamides/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Aniline Compounds/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/drug therapy , Neoplasms/mortality , Prognosis , Risk Assessment , Small Cell Lung Carcinoma/mortality , Sulfonamides/adverse effects , Survival Analysis , Treatment Outcome
5.
Clin Cancer Res ; 16(13): 3485-94, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-20479064

ABSTRACT

PURPOSE: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer. EXPERIMENTAL DESIGN: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics. RESULTS: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for >or=12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells. CONCLUSIONS: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade.


Subject(s)
Androstadienes/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Aged , Aged, 80 and over , Androstadienes/adverse effects , Androstadienes/pharmacokinetics , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , CTLA-4 Antigen , Drug Administration Schedule , Female , Humans , Inducible T-Cell Co-Stimulator Protein , Maximum Tolerated Dose , Middle Aged , Neoplasms, Hormone-Dependent/drug therapy , T-Lymphocytes/immunology
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