Human Autologous Tumor-Specific T-Cell Responses Induced by Liposomal Delivery of a Lymphoma Antigen

Neelapu, Sattva S.; Baskar, Sivasubramanian; Gause, Barry L.; Kobrin, Carol B.; Watson, Thelma M.; Frye, Andrea Robin; Pennington, Robin; Harvey, Linda K.; Jaffe, Elaine S.; Robb, Richard J.; Popescu, M.; Kwak, Larry W.

doi:10.1158/1078-0432.ccr-04-1071

Cited by 71 publications

(42 citation statements)

References 44 publications

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“…We also detected MAGE-A3-specific CD8 ϩ T cell responses in patients who developed the highest-titered broadly specific antibody responses after vaccination. So far, few trials have been conducted in which recombinant proteins were used as immunogen in cancer vaccines (12)(13)(14)(15)(16), and if T cell responses have been reported, they consisted mainly of CD4 ϩ T cells (17,18). Two reports have shown that vaccination with CT antigen NY-ESO-1 as a recombinant protein, formulated either with saponin-based adjuvant ISCOMATRIX or with cholesterol-bearing hydrophobized pullulan, induced strong antibody as well as CD4 ϩ and CD8 ϩ responses in the majority of patients (19,20).…”

Section: Discussionmentioning

confidence: 99%

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Atanackovic

Altorki

Cao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

142

107

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We previously reported results of a phase II trial in which recombinant MAGE-A3 protein was administered with or without adjuvant AS02B to 18 non-small-cell lung cancer (NSCLC) patients after tumor resection. We found that the presence of adjuvant was essential for the development of humoral and cellular responses against selected MAGE-A3 epitopes. In our current study, 14 patients that still had no evidence of disease up to 3 years after vaccination with MAGE-A3 protein with or without adjuvant received an additional four doses of MAGE-A3 protein with adjuvant AS02B. After just one boost injection, six of seven patients originally vaccinated with MAGE-A3 protein plus adjuvant reached again their peak antibody titers against MAGE-A3 attained during the first vaccination. All seven patients subsequently developed even stronger antibody responses. Furthermore, booster vaccination widened the spectrum of CD4 ϩ and CD8 ؉ T cells against various new and known MAGE-A3 epitopes. In contrast, only two of seven patients originally vaccinated with MAGE-A3 protein alone developed high-titer antibodies to MAGE-A3, and all these patients showed very limited CD4 ؉ and no CD8 ؉ T cell reactivity, despite now receiving antigen in the presence of adjuvant. Our results underscore the importance of appropriate antigen priming using an adjuvant for generating persistent B and T cell memory and allowing typical booster responses with reimmunization. In contrast, absence of adjuvant at priming compromises further immunization attempts. These data provide an immunological rationale for vaccine design in light of recently reported favorable clinical responses in NSCLC patients after vaccination with MAGE-A3 protein plus adjuvant AS02B.antibody ͉ CD4 ϩ T cell ͉ CD8 ϩ T cell ͉ immunization ͉ non-small-cell lung cancer

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Section: Discussionmentioning

confidence: 99%

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Atanackovic

Altorki

Cao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

142

107

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“…Liposome is a delivery consisting of bilayer phospholipid, which is broadly used as various drug delivery systems. Liposome vaccine that carries idiotype protein and adjuvant cytokines for follicular lymphoma was developed (20,21). In a clinical trial using the vaccine combined with interleukin-2, both CD8 + and CD4 + T-cell immunities were induced along with specific antibody production (21).…”

Section: Discussionmentioning

confidence: 99%

HER2-Specific T-Cell Immune Responses in Patients Vaccinated with Truncated HER2 Protein Complexed with Nanogels of Cholesteryl Pullulan

Kitano¹,

Kageyama²,

Nagata

et al. 2006

Clinical Cancer Research

113

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Purpose: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4 + T cells in HLA-A2402-positive patients with therapyrefractory HER2-expressing cancers. Experimental Design: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 Ag of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4 + T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein.Results: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade1transient skin reaction at the sites of vaccination. HER2-specific CD8 + and/or CD4 + T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom bothT-cell responses were detected in these patients. In four patients with CD8 + T-cell responses, two patients reacted to previously identified HER2 63-71 peptide and the other two reacted only to 146HER2 mRNA-transduced cells. Conclusions: CHP-HER2 vaccine was safe and induced HER2-specific CD8 + and/or CD4 + T-cell immune responses.

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“…Idiotype-specific T-cell cytokine responses, IFN-g enzyme-linked immunospot, and anti-idiotype antibody responses were measured as described previously (22,23).…”

Section: Methodsmentioning

confidence: 99%

A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy

O’Mahony¹,

Morris²,

Quinn³

et al. 2007

Clinical Cancer Research

144

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Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8 + T-cell immune responses, and modulation of CD4 + CD25 + FoxP3 + regulatory T-cell (Treg) numbers were secondary end points. Experimental Design: Three patients with colon cancer, four with non^Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specificT-cell responses was observed after therapy. Tregs as detected by expression of CD4+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. Conclusions: Ipilimumab treatment depressedTreg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8 + T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

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Human Autologous Tumor-Specific T-Cell Responses Induced by Liposomal Delivery of a Lymphoma Antigen

Cited by 71 publications

References 44 publications

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

HER2-Specific T-Cell Immune Responses in Patients Vaccinated with Truncated HER2 Protein Complexed with Nanogels of Cholesteryl Pullulan

A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy

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