IRX-2 increases the T cell-specific immune response to protein/peptide vaccines.
Therapeutic cancer vaccines are attractive due to the prospect of specificity and their lack of toxicity; however, their clinical development has been hampered by several biologic and clinical challenges. One of the most important biologic challenges is the relative lack of effective cellular immune adjuvants. Effective physiologic immune responses are characterized by the local generation of a complex cytokine environment that activates and regulates multiple immune cell types. IRX-2 is a primary cell-derived biologic with physiological levels of multiple active cytokine components, produced under pharmaceutical standards. The hypothesis that IRX-2 amplifies the T cell response to defined antigens was assessed in mice by measuring the T cell-specific peptide response to a dominant mouse peptide (NFT) derived from human prostate-specific membrane antigen (PSMA). IRX-2 enhances the T cell response to NFT when antigens were delivered either via irradiated cells expressing human PSMA, NFT peptide in Incomplete Freund's adjuvant (IFA) or NFT peptide conjugated to KLH. The T cell-specific activity was measured in spleen or lymph nodes cells by IFN-γ ELISpot and/or IFN-γ secretion over 6 days or in vivo by peptide-specific delayed-type hypersensitivity reaction (DTH). Further more, a single administration of IRX-2 with the antigen was not active as compared to 4 or 9 additional administrations which were sufficient to enhance the T cell response to antigens. The influence of IRX-2 on the B cell response to ovalbumin when it was used as a carrier protein was measured by ELISA. IRX-2 was compared to a commercially available combination adjuvant (MPL+TDM in squalene/Tween 80) which based on the literature is a potent adjuvant in murine systems. In the T cell assay IRX-2 was superior to the commercially available combination adjuvant and while IRX-2 also increased antibody titer, it was not as potent as the combination adjuvant. Mice immunized with IRX-2 and antigen also exhibited delayed tumor progression following challenge with PSMA-expressing tumor cells. These studies demonstrate that IRX-2 is an immunomodulator with adjuvant activity which preferentially enhances the T cell-specific responses to tumor associated antigens. Based on these studies, IRX-2 is a candidate for evaluation as a T cell adjuvant in a variety of preclinical vaccine delivery systems as well as in human clinical trials with cancer vaccine candidates.
Naylor
Paul H
PH
IRX Therapeutics Inc, Farmingdale, NY 11735, USA. pnaylor@irxtherapeutics.com
Hernandez
Karla E
KE
Nixon
April E
AE
Brandwein
Harvey J
HJ
Haas
Gabriel P
GP
Wang
Ching Y
CY
Hadden
John W
JW
D016475:3T3 Cells; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017430:Prostate-Specific Antigen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; C114857:IRX 2; D022223:Vaccines, Subunit; D007371:Interferon-gamma; D017430:Prostate-Specific Antigen