Time-dependent transition of the immunoglobulin G subclass and immunoglobulin E response in cancer patients vaccinated with cholesteryl pullulan-melanoma antigen gene-A4 nanogel

Abstract

A phase I+II clinical trial of vaccination with MAGE-A4 protein complexed with cholesteryl pullulan melanoma antigen gene-A4 nanogel (CHP-MAGE-A4) is currently underway in patients with MAGE-A4-expressing cancer. In the present study, the primary phase I endpoint was to test the safety of the administration of 300 µg CHP-MAGE-A4 with and without OK-432. Another aim of the study was to clarify the details of the specific humoral immune response to vaccination. The 9 patients enrolled for phase I were vaccinated 6 times, once every 2 weeks: 3 patients with 100 µg and 3 patients with 300 µg CHP-MAGE-A4, and 3 patients with 300 µg CHP-MAGE-A4 plus 0.5 clinical units of OK-432. Toxicities were assessed using Common Terminology Criteria for Adverse Events v3.0. Clinical response was evaluated by modified Response Evaluation Criteria in Solid Tumours. Immunological monitoring of anti-MAGE-A4-specific antibodies was performed by ELISA of pre- and post-vaccination patient sera. The 6 vaccinations produced no severe adverse events. Stable disease was assessed in 4/9 patients. Anti-MAGE-A4 total immunoglobulin (Ig)G titers increased in 7/9 patients. Efficacious anti-MAGE-A4 IgG1, 2 and 3 antibody responses were observed in 7/9 patients. Among them, positive conversions to T helper 2 (Th2)-type antibody responses (IgG4 and IgE) were observed after frequent vaccination in 4/7 patients. The Th2 conversion was possibly associated with undesirable clinical observations, including progressive disease and the appearance of a new relapse lesion. The present study suggested that frequent vaccinations activated a Th2-dominant status in the cancer patients. The identification of a time-dependent IgG subclass and IgE antibody production during vaccination protocols may be a useful surrogate marker indicating a potentially undesirable change of the immunological environment for an effective antitumor immune response in cancer patients.

Prognostic value of MAGEA4 in primary lung cancer depends on subcellular localization and p53 status

“…Such staining conditions are already established for widely studied proteins, such as p53, but not for many cancer-related proteins. Therefore, we optimized the staining conditions for MAGEA4 in the present study, with a view toward enabling patient selection for clinical trials of cancer vaccines against MAGEA4 (4,20,21). This was achieved by the analysis of cells transfected with MAGEA genes and of xenografted non-small cell lung cancer cell lines.…”

Specific humoral response in cancer patients treated with a VEGF therapeutic vaccine under a compassionate use program

“…This polyclonal antibody response was characterized by the presence of IgM, IgA and IgG antibodies specific to VEGF, being the latter the predominant immunoglobulin [22]. So far VEGF-specific IgE antibodies have not been detected in any of the studies of CIGB-247, and the presence of this class of immunoglobulin induced by active immunization has been reported in very few studies of therapeutic vaccines based on other antigens combined with other adjuvants [31,32]. Although IgE has been pointed out as important mediator of anti-tumor effect [33,34], probably, the generation of IgE antibodies by active immunization is the result of some adjuvants, vaccination schedules or both.…”

Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program

“…Ovary ADC -Insulin-dependent diabetic patient with oral administration of metformin with other antigens and adjuvants [28,30]. Although IgE has been pointed out as a mediator of anti-tumor effect [31,32], the generation of IgE antibodies by active immunization is probably the result of the specific antigen, adjuvants or schedules, or a combination of these.…”