Jakob Dupont

Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses

Purpose: Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. Experimental Design: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. Results: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. Conclusions: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.

Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas

B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.

Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade >2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Human telomerase reverse transcriptase (hTERT) is overexpressed in most human tumors, making it a potential target for cancer immunotherapy. hTERT-derived CTL epitopes have been identified previously, including p865 (RLVDDFLLV) and p540 (ILAKFLHWL), which are restricted by the human leukocyte antigen (HLA) class I A*0201 allele. However, it remains a major challenge to efficiently and consistently expand hTERT-specific CTLs from donor peripheral blood T lymphocytes. To bypass the need for generating conventional antigen-presenting cells (APC) on an autologous basis, we investigated the potential ability of fibroblast-derived artificial APCs (AAPC) to activate and expand HLA-A*0201-restricted CTLs. We show here that AAPCs stably expressing HLA-A*0201, human beta(2)-microglobulin, B7.1, intercellular adhesion molecule-1, and LFA-3, together with either p540 and p865 minigenes or the full-length hTERT, effectively stimulate tumoricidal, hTERT-specific CTLs. hTERT-expressing AAPCs stimulated both p540 and p865 CTLs as shown by peptide-specific cytolysis and tetramer staining, indicating that hTERT is processed by the AAPCs and that the two peptides are presented as codominant epitopes. The level of cytotoxic activity against a panel of tumors comprising hematologic and epithelial malignancies varied, correlating overall with the level of HLA-A2 and hTERT expression by the target cell. Starting from 100 mL blood, approximately 100 million hTERT-specific CTLs could be generated over the course of five sequential stimulations, representing an expansion of approximately 1 x 10(5). Our data show that AAPCs process hTERT antigen and efficiently stimulate hTERT-specific CTLs from human peripheral blood T lymphocytes and suggest that sufficient expansion could be achieved to be clinically useful for adoptive cell therapy.

Paclitaxel and carboplatin in the treatment of advanced or recurrent endometrial cancer: a large retrospective study

The aim of this study was to assess the efficacy and tolerability of paclitaxel and carboplatin (TC) in the treatment of patients with advanced or recurrent endometrial cancer. Patients eligible for this retrospective analysis had endometrial cancer with either advanced or recurrent measurable disease (untreated primary stage III/IV or stage III/IV patients with persistent, measurable disease [≥2 cm] after surgery), Eastern Cooperative Oncology Group (ECOG) performance status ≥3, and received at least one cycle of TC. Response rates were determined using Response Evaluation Criteria in Solid Tumors criteria. Institutional Review Board approval was obtained prior to the initiation of this study. Eighty-five eligible patients, with a median age of 62 years (range 36–80) were identified. Fifty-seven (67%) of patients were treated at the time of recurrence. Prior radiation therapy had been used in the treatment of 36 (42%) patients, while 13 (15%) patients had received prior chemotherapy. Median follow-up time was 11.7 months (range 1.1–96.7 months), and the median number of cycles of therapy received was six (range 1–18). The overall response rate (ORR) was 43%, with a complete response rate of 5% and a partial response rate of 38%. Chemotherapy-naive patients had an ORR of 47%. Only seven (8%) patients had to discontinue therapy due to toxicity. Median progression-free survival was 5.3 months (95% CI, 4.6–7.4), with a median overall survival of 13.2 months (95% CI, 11.7–18.2). We conclude that TC is an active and tolerable regimen in the treatment of patients with advanced or recurrent endometrial cancer

Lysophosphatidic acid acyltransferase-β (LPAAT-β) is highly expressed in advanced ovarian cancer and is associated with aggressive histology and poor survival

Lysophosphatidic acid acyltransferase‐β (LPAAT‐β) tumor expression is an emerging prognostic, diagnostic, and therapeutic target in early epithelial ovarian cancer (EOC). The significance of tumor overexpression of LPAAT‐β was investigated in a large number of advanced‐ and early‐stage EOC patients.

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

SummaryThe purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90xa0min on days 1 and 8 plus BMS-247550 over 3xa0h on day 8, every 21xa0days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2xa0weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900xa0mg/m2 and BMS-247550 20xa0mg/m2. Grade 4 neutropenia lasting ≥7xa0days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900xa0mg/m2 plus BMS-247550 30xa0mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750xa0mg/m2 plus BMS-247550 30xa0mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750xa0mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900xa0mg/m2 over 90xa0min days 1 and 8 plus BMS-247550 20xa0mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

A phase I study of subcutaneously administered aflibercept (VEGF trap) in a new formulation in patients with advanced solid tumors

SummaryTargeting angiogenesis is a valid anti-cancer strategy. Aflibercept is designed to sequester circulating vascular endothelial growth factor (VEGF) by preventing VEGF from binding to its receptors. This phase I study was to evaluate a new formulation of subcutaneously administered aflibercept in patients with advanced solid tumors. Here we report our experience with the toxicity, pharmacokinetic profile and efficacy of the new 100xa0mg/mL subcutaneous (SC) formulation of aflibercept administered at a dose of at 4xa0mg/kg every 2xa0weeks.

Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma.

SummaryPurpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4xa0weeks (Schedule A) or 2 out of 3xa0weeks (Schedule B) with KOS-862 (16–120xa0mg/m2). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100xa0mg/m2. Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120xa0mg/m2. PK data were linear from 16 to 100xa0mg/m2, with proportional increases in mean Cmax and AUCtot as a function of dose. Full PK analysis (meanu2009±u2009SD) at 100xa0mg/m2 revealed the following: half-life (t ½)u2009=u20099.1u2009±u20092.2xa0h; volume of distribution (Vz)u2009=u2009119u2009±u200941xa0L/m2; clearance (CL)u2009=u20099.3u2009±u20093.2xa0L/h/m2. MTBF (nu2009=u20099) was seen in 40% of PBMCs within 1xa0h and in 15% of PBMC at 24-hours post infusion at 100xa0mg/m2. Tumor shrinkage (nu2009=u20092, lymphoma), stable disease >3xa0months (nu2009=u20095, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (nu2009=u20091, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100xa0mg/m2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.