Humoral immune-response to naturally occurring STn in metastatic breast cancer patients (MBC pts) treated with STn-KLH vaccine

Ibrahim, NK; Murray, James L.; Parker, Jennifer J.; L, Finke; Miles, David

doi:10.1200/jco.2004.22.90140.2547

Cited by 5 publications

(3 citation statements)

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“…These observations led the authors to conclude that a hormone-based treatment may collaborate with antigen-specific tumor immunity to produce improved tumor control in patients with breast cancer. Results from the phase III study showed that patients receiving Theratope plus concomitant hormone therapy had a prolonged survival over those patients receiving a control vaccine plus hormone therapy [ 17 ]. Survival in these patients was also positively associated with immunoglobulin G titers to the underglycosylated mucin-associated glycoprotein, an antigen similar to that recognized by AS1402.…”

Section: Discussionmentioning

confidence: 99%

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

et al. 2009

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IntroductionMUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy.MethodsPatients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied.ResultsTwenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 ± 37.1 hours.ConclusionsRepeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer.Trial registrationClinicalTrials.gov Identifier: NCT00096057.

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Section: Discussionmentioning

confidence: 99%

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

et al. 2009

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“…In an exploratory analysis of the survival data patients who received hormonal therapy with the STn-KLH vaccine and had anti-OSM IgG titers higher than the median of 1:320 had a longer median OS compared with the KLH-control group 14. To confirm this observation, we undertook a post hoc analysis of the TTP and OS data of the patients who were concurrently using an antiestrogen, most often a SERM or AI; this subgroup constituted approximately one third of the trial population 13.…”

Section: Introductionmentioning

confidence: 99%

Survival Advantage in Patients with Metastatic Breast Cancer Receiving Endocrine Therapy plus Sialyl Tn-KLH Vaccine: Post Hoc Analysis of a Large Randomized Trial

Ibrahim¹,

Murray²,

Zhou³

et al. 2013

J. Cancer

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Background: A multicenter, double blinded, randomized phase III trial of the therapeutic cancer vaccine sialy1-Tn (STn) conjugated to keyhole-limpet Hemocyanin (KLH) was completed in an international cohort of 1,028 women with metastatic breast cancer who had nonprogressive disease or no evidence of disease after first-line chemotherapy (ClinicalTrials.gov, (NCT00003638). STn-KLH was safe and relatively well tolerated but did not affect time to progression (TTP) or overall survival (OS) duration. The purpose of this post hoc analysis was to explore whether patients who received concurrent endocrine therapy and STn-KLH had a TTP or OS benefit.Methods: A retrospective, blinded review of the data from the phase III trial of STn-KLH was performed to ensure that strata assignments were appropriate. We then studied the effect of concomitant endocrine therapy and STn-KLH or KLH on TTP and OS in the cohort described above. We also assessed the TTP and OS by antibody responses in patients who received endocrine therapy.Results: The women treated with concomitant endocrine therapy, a pre-stratified subset comprising approximately one-third of the original study population, and STn-KLH had longer TTP and OS than the control group of women who received KLH alone. Moreover, of the women who received endocrine therapy, those who had a median or greater antibody response (titer >1:320 toward ovine sub maxillary mucin) to the STn-KLH vaccine had significantly longer median OS than those who had a below-median antibody response.Conclusion: Adding STn-KLH to endocrine therapy may improve clinical outcomes with few adverse effects for women with metastatic breast cancer.

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“…No differences in time to disease progression (TTP) or OS emerged [58]. However, exploratory analyses revealed a trend toward improved TTP and OS in the setting of concomitant hormone therapy [59], and the association of an improvement in median OS specifically in those who developed greater than average median IgG titers for naturally clustered STn antigens [60]. Other Phase III clinical trials are testing peptide-based vaccines specific for the universal tumor antigen telomerase (GV1001) and the melanoma antigen gp100.…”

Section: Peptide/small Epitope Vaccinesmentioning

confidence: 99%

Cancer vaccines: on the threshold of success

Emens

2008

Expert Opinion on Emerging Drugs

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Background-Cancer vaccines are a unique approach to cancer therapy. They exert an antitumor effect by engaging the host immune response, and have great potential for circumventing the intrinsic drug resistance that limits standard cancer management. Additional advantages of cancer vaccines are exquisite specificity, low toxicity, and the potential for a durable treatment effect due to immunologic memory. Objectives-This review aims to consider the promise of cancer vaccines, review the current state of cancer vaccine development, and suggest directions for future research. Methods-The scope of this review was defined peer-reviewed information found on Medline, and information found on the Internet about Phase III clinical trials that are ongoing and not yet published. Results/conclusions-Multiple Phase III clinical trials have demonstrated the promise and challenges posed by therapeutic vaccines, and defined the next steps in their clinical development. Determining the optimal integration of cancer vaccines with chemotherapy, radiation, surgery, and biologically targeted therapies, defining predictive biomarkers of immunologic and clinical response, and combining tumor vaccines with new drugs that effectively modulate the antitumor immune response, will ensure that cancer vaccines become part of standard cancer therapy and prevention.

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Humoral immune-response to naturally occurring STn in metastatic breast cancer patients (MBC pts) treated with STn-KLH vaccine

Cited by 5 publications

References 0 publications

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

Survival Advantage in Patients with Metastatic Breast Cancer Receiving Endocrine Therapy plus Sialyl Tn-KLH Vaccine: Post Hoc Analysis of a Large Randomized Trial

Cancer vaccines: on the threshold of success

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