Delving into the Latest Updates on IGFBP-2 DNA plasmid vaccine(Fred Hutchinson Cancer Research Center) with Synapse

Overview

Basic Info

Drug Type

DNA vaccine, Therapeutic vaccine

Synonyms

Target

IGFBP2

Mechanism

IGFBP2 modulators(IGF binding protein-2 modulators)

Therapeutic Areas

NeoplasmsEndocrinology and Metabolic DiseaseUrogenital Diseases

Active Indication

Ovarian Cancer

Inactive Indication-

Originator Organization

Fred Hutchinson Cancer Research Center

Active Organization

University of Washington Bothell

Fred Hutchinson Cancer Research Center

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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AbstractPurpose:Cancer vaccines targeting nonmutated proteins elicit limited type I T-cell responses and can generate regulatory and type II T cells. Class II epitopes that selectively elicit type I or type II cytokines can be identified in nonmutated cancer-associated proteins. In mice, a T-helper I (Th1) selective insulin-like growth factor binding protein-2 (IGFBP-2) N-terminus vaccine generated high levels of IFNγ secreting T cells, no regulatory T cells, and significant antitumor activity. We conducted a phase I trial of T-helper 1 selective IGFBP-2 vaccination in patients with advanced ovarian cancer.Patients and Methods:Twenty-five patients were enrolled. The IGFBP-2 N-terminus plasmid-based vaccine was administered monthly for 3 months. Toxicity was graded by NCI criteria and antigen-specific T cells measured by IFNγ/IL10 ELISPOT. T-cell diversity and phenotype were assessed.Results:The vaccine was well tolerated, with 99% of adverse events graded 1 or 2, and generated high levels of IGFBP-2 IFNγ secreting T cells in 50% of patients. Both Tbet+ CD4 (P = 0.04) and CD8 (P = 0.007) T cells were significantly increased in immunized patients. There was no increase in GATA3+ CD4 or CD8, IGFBP-2 IL10 secreting T cells, or regulatory T cells. A significant increase in T-cell clonality occurred in immunized patients (P = 0.03, pre- vs. post-vaccine) and studies showed the majority of patients developed epitope spreading within IGFBP-2 and/or to other antigens. Vaccine nonresponders were more likely to have preexistent IGFBP-2 specific immunity and demonstrated defects in CD4 T cells, upregulation of PD-1, and downregulation of genes associated with T-cell activation, after immunization.Conclusions:IGFBP-2 N-terminus Th1 selective vaccination safely induces type I T cells without evidence of regulatory responses.

01 Jul 2017·SmallQ2 · MATERIALS SCIENCE

Microneedle-Assisted, DC-Targeted Codelivery of pTRP-2 and Adjuvant of Paclitaxel for Transcutaneous Immunotherapy

Q2 · MATERIALS SCIENCE

Article

Author: Huang, Yongzhuo ; Hu, Ying ; Tao, Jin ; Yang, Yunxu ; Xu, Beihua ; Xu, Jiaojiao

This work aims at developing an immunotherapeutic strategy to deliver a cancer DNA vaccine targeting dendritic cells (DCs), to trigger their maturation and antitumor function, and reduce immune escape using a polymeric nanocomplex of paclitaxel (PTX)-encapsulated sulfobutylether-β-cyclodextrin (SBE)/mannosylated N,N,N-trimethylchitosan (mTMC)/DNA. To enhance DC-targeting and revoke immunosuppression is the major challenge for eliciting effective antitumor immunity. This codelivery system is characterized by using low-dose PTX as an adjuvant that is included inside SBE, and the PTX/SBE further serves as an anionic crosslinker to self-assemble with the cationic mTMC/DNA polyplexes. This system is used in combination with a microneedle for transcutaneous vaccination. Once penetrating into the epidermis, the mannosylated nanocomplexes would preferentially deliver the pTRP-2 DNA vaccine inside the DCs. Phenotypic maturation is demonstrated by the increased expression of costimulatory molecules of CD80 and CD86, and the elevated secretion of IL-12p70. The mixed leucocyte reactions reveal that the PTX/SBE-mTMC/DNA nanocomplexes enhance the proliferation of CD4+ and CD8+ T cells, and inhibit the generation of immune-suppressive FoxP3+ T cells. The system shows high antitumor efficacy in vivo. The PTX/SBE-mTMC/DNA nanocomplexes for DC-targeted codelivery of DNA vaccine and adjuvant PTX yield synergistic effects on the DC maturation and its presenting functions, thus increasing immune stimulation and reducing immune escape.

15 May 2014·Cancer ResearchQ1 · MEDICINE

Elimination of IL-10–Inducing T-Helper Epitopes from an IGFBP-2 Vaccine Ensures Potent Antitumor Activity

Q1 · MEDICINE

Article

Author: Higgins, Doreen ; Childs, Jennifer ; Park, Kyong Hwa ; Gad, Ekram ; Disis, Mary L. ; Rastetter, Lauren ; Cecil, Denise L. ; Holt, Gregory E.

AbstractImmunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4+ T-helper (TH1) and CD8+ cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor–binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope–specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes. Cancer Res; 74(10); 2710–8. ©2014 AACR.

100 Deals associated with IGFBP-2 DNA plasmid vaccine(Fred Hutchinson Cancer Research Center)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ovarian Cancer	Phase 2	-	Fred Hutchinson Cancer Research Center	-
Ovarian Cancer	Phase 2	-	University of Washington Bothell	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01322802 (ASCO 12016 \| ASCO 22016) Manual	Phase 1	Ovarian Cancer	25	IGFBP-2 DNA vaccine	(wxprfwjcqf) = Fatigue (12%) and injection site reactions (12%) yktcrooiuq (rjikiwgntr )	Positive	06 Jun 2016