Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients

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Abstract

DepoVax™ is an innovative and strongly immunogenic vaccine platform. Survivin is highly expressed in many tumor types and has reported prognostic value. To generate tumor-specific immune response, a novel cancer vaccine was formulated in DepoVax platform (DPX-Survivac) using survivin HLA class I peptides. Safety and immune potency of DPX-Survivac was tested in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients. All the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generating significantly higher magnitude responses. Strong T cell responses were associated with differentiation of naïve T cells into central/effector memory (CM/EM) and late differentiated (LD) polyfunctional antigen-specific CD4 ⁺ and CD8 ⁺ T cells. This approach enabled rapid de novo activation/expansion of vaccine antigen-specific CD8 ⁺ T cells and provided a strong rationale for further testing to determine clinical benefits associated with this immune activation. These data represent vaccine-induced T cell activation in a clinical setting to a self-tumor antigen previously described only in animal models.

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Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

Francois Ghiringhelli, Cédric Ménard, Pierre Emmanuel Puig … (2007)

CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

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Small sample inference for fixed effects from restricted maximum likelihood.

M G Kenward, J H Roger (1997)

Restricted maximum likelihood (REML) is now well established as a method for estimating the parameters of the general Gaussian linear model with a structured covariance matrix, in particular for mixed linear models. Conventionally, estimates of precision and inference for fixed effects are based on their asymptotic distribution, which is known to be inadequate for some small-sample problems. In this paper, we present a scaled Wald statistic, together with an F approximation to its sampling distribution, that is shown to perform well in a range of small sample settings. The statistic uses an adjusted estimator of the covariance matrix that has reduced small sample bias. This approach has the advantage that it reproduces both the statistics and F distributions in those settings where the latter is exact, namely for Hotelling T2 type statistics and for analysis of variance F-ratios. The performance of the modified statistics is assessed through simulation studies of four different REML analyses and the methods are illustrated using three examples.

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Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.

Wei-Ting Hwang, Sarah Adams, Emin Tahirovic … (2012)

The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols. Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I(2) statistics. Ten suitable studies comprising 1815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71-2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified. Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Oncoimmunology

Journal ID (iso-abbrev): Oncoimmunology

Journal ID (pmc): KONI

Title: Oncoimmunology

Publisher: Taylor & Francis

ISSN (Print): 2162-4011

ISSN (Electronic): 2162-402X

Publication date (Electronic): 7 May 2015

Publication date Collection: August 2015

Volume: 4

Issue: 8

Electronic Location Identifier: e1026529

Affiliations

[1 ]Sunnybrook Health Sciences Centre ; Toronto, Ontario, Canada

[2 ]Immunovaccine, Inc. ; Halifax, Nova Scotia, Canada

[3 ]Princess Margaret Cancer Center; University Health Network ; Toronto, Ontario, Canada

[4 ]Roswell Park Cancer Institute ; Buffalo, NY USA

[5 ]Winthrop-University Hospital ; Mineola, NY USA

[6 ]Mary Crowley Cancer Research Center ; Dallas, TX USA

[7 ]Duke University Medical Center ; Durham, NC USA

[8 ]Oregon Health & Science University ; Portland, OR USA

[9 ]QEII Health Sciences Center ; Halifax, Nova Scotia, Canada

[10 ]International Drug Development Institute (IDDI) ; Louvain la Neuve, Belgium

Author notes

[* ]Correspondence to: Marc Mansour; Email: mmansour@ 123456imvaccine.com

Article

Publisher ID: 1026529

DOI: 10.1080/2162402X.2015.1026529

PMC ID: 4570133

PubMed ID: 26405584

SO-VID: 308c7d70-abff-46a7-9b47-8d170a9c82df

Copyright © © 2015 The Author(s). Published with license by Taylor & Francis© Neil L Berinstein, Mohan Karkada, Amit M Oza, Kunle Odunsi, Jeannine A Villella, John J Nemunaitis, Michael A Morse, Tanja Pejovic, James Bentley, Marc Buyse, Rita Nigam, Genevieve M Weir, Lisa D MacDonald, Tara Quinton, Rajkannan Rajagopalan, Kendall Sharp, Andrea Penwell, Leeladhar Sammatur, Tomasz Burzykowski, Marianne M Stanford, and Marc Mansour

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

History

Date received : 13 January 2015

Date revision received : 26 February 2015

Date accepted : 27 February 2015

Page count

Figures: 3, Tables: 2, References: 38, Pages: 10

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Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients

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Abstract

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Gamma Delta T cells

Most cited references 28

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

Small sample inference for fixed effects from restricted maximum likelihood.

Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.

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Cited by 39

Most referenced authors 418