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A randomized pilot trial evaluating safety and immunogenicity of recMAGE-A3 + AS15 immunotherapeutic administered by intramuscular versus intradermal/subcutaneous routes

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Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P60

https://doi.org/10.1186/2051-1426-2-S3-P60

  • Published:

Keywords

  • Cell Response
  • Injection Site Reaction
  • Resected Stage
  • Intracellular Cytokine Staining
  • Monophosphoryl Lipid

Introduction

The recMAGE-A3 protein has been administered intramuscularly (IM) with immunostimulant AS15 as an experimental immunotherapeutic. AS15 contains 3-O-desacyl-4'-monophosphoryl lipid A (MPL), QS-21, CpG 7909 and liposome. This MAGE-A3/AS15 immunotherapeutic has not been studied for intradermal (ID) or subcutaneous (SC) use. A clinical trial (NCT01425749) was initiated to test the hypotheses that ID/SQ administration is safe and may induce CD4+ and CD8+ T cell responses to MAGE-A3.

Patients and methods

Twenty-five eligible patients with resected stage IIB-IV MAGE-A3+ melanoma were randomized to 2 arms, treated with MAGE-A3/AS15 Immunotherapeutic IM (Arm A, n = 13) or ID/SC (Arm B, n = 12). Adverse events (CTCAE 4) were recorded. Antibody (Ab) responses to MAGE-A3 protein were assessed by ELISA assay. T cell responses were assessed by flow cytometry after intracellular cytokine staining (ICS) for multifunctional CD4+ and CD8+ responses to overlapping MAGE-A3 peptides, assaying lymphocytes from peripheral blood (PBMC) and sentinel immunized node (SIN), after one in vitro stimulation.

Results

In both arms, the recMAGE-A3/AS15 immunotherapeutic was well-tolerated, with only one grade 3 treatment-related adverse event (hyperglycemia, Arm B), and no grade 4 or 5 events. Grade 2 injection site reactions were observed in 10 patients in Arm A and 7 in Arm B (P > 0.3). Ab responses were detected in all patients, most with high titers persisting at least 6 months, without difference between arms. Preliminary T cell data are that multifunctional (IFNg and TNFα) CD4+ T cell responses to MAGE-A3 were detected in 64% of patients (54% A; 75% B; Table 1). Multifunctional CD8+ T cell responses were evident in 20% of patients (8% A, 33% B). CD4+ responses were higher magnitude in SIN than in PBMC.
Table 1

Multifunctional (IFNg and TNFα) T cell responses to MAGE-A3

 

% of CD4+ T cells

% of CD8+ T cells

 

(90% CI)

(90% CI)

 

SIN

PBMC

Either

SIN

PBMC

Either

Arm A

31%

31%

54%

0%

8%

8%

 

(11, 58)

(11, 58)

(29, 78)

(0, 21)

(0, 32)

(0, 32)

Arm B

64%

50%

75%

18%

25%

33%

 

(35, 86)

(25, 75)

(47, 93)

(3, 47)

(7, 53)

(12, 61)

Total

46%

40%

64%

8%

16%

20%

 

(28, 64)

(24, 58)

(46, 80)

(2, 24)

(6, 33)

(8, 38)

Conclusion

Safety profiles were comparable for ID/SC and IM administration of the MAGE-A3/AS15 immunotherapeutic, which induced high-titer Ab, multifunctional CD4+ Th1 responses, and CD8+ responses when administered by either route. Immune responses were more readily detected in the SIN than in PBMC. These pilot data support further investigation of ID/SC immunization with antigen plus AS15 to support Th1 CD4+ responses and CD8+ responses. Production of Th1 cytokines IFNg and TNFα suggests the induced CD4+ responses may support CD8+ T cells. Other forms of antigen (e.g.: long peptides) may further support induction of CD8+ T cell responses in combination with AS15.

Funding source: GlaxoSmithKline Biologicals SA

Authors’ Affiliations

(1)
University of Virginia, Charlottesville, USA
(2)
Glaxo Smith Kline, Belgium

Copyright

© Slingluff et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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