MAGE-A3/HPV 16 peptide vaccines for head and neck cancer

Abstract

The present invention relates to Trojan antigens, and immunogenic compositions comprising the Trojan antigens. The present invention also relates to methods of generating an immune response in a subject using the Trojan antigens or immunogenic compositions. The present invention further relates to methods of treating squamous cell carcinoma of the head and neck (SCCHN) using the Trojan antigens and immunogenic compositions of the present invention.

Description

[0001] The present application claims benefit of U.S. provisional application No. 60 / 667,060, filed Apr. 1, 2005, incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION [0002] Squamous cell carcinoma of the head and neck (SCCHN) effects 43,000 individuals in the United States annually with an estimated 5-year overall survival of 50% (R. M. Byers, Dr. Martin: How are we doing in 2000? Archives of Otolaryngology-Head and Neck Surgery 127:759-765 (2001)). For some patients who develop local or distant metastases following primary therapy, surgical salvage is a viable therapeutic option. The remainder of individuals is forced to choose between palliative chemotherapy and supportive care. In order to improve both survival and quality of life for patients with unresectable disease, new therapeutic alternatives are mandated. [0003] One treatment option is the use of T cell-specific immunotherapy to stimulate a patient's anti-tumor immune response. Several T cell based...

AI Technical Summary

Benefits of technology

[0029] In other preferred embodiments, the one or more Trojan antigens are co-administered with montanide, in an amount of between about 0.5 and 1.5 mL, and GM-CSF, in an amount of between about 50 and 150 ug/m2.

[0030] The methods treating squamous cell carcinoma of the head and neck (SCCHN) of the present invention comprising administering to a subject in need of such treatment a therapeutically-effective amount of one of the following Trojan antigens: a polypeptide comprising amino acids 1-35 of SEQ ID NO:15, a polypeptide comprising amino acids 1-47 of SEQ ID NO:17, a polypeptide comprising amino acids 1-21 of SEQ ID NO:19, wherein X may be cysteine or aminobutyric acid, and a polypeptide comprising amino acids 1-43 of

Problems solved by technology

However, the majority of trials have failed to demonstrate any therapeutic benefit (Chang et al.

The causes of these failures are multi-factorial, but are likely related to well characterized immunologic defects within the target population, including aberrant antigen processing and presentation, which restrict T cell function.

Additionally, down regulation of either HLA molecules on the tumor surface or tumor antigen expression limits the efficacy of antigen-specific cytotoxic T cells (Seliger et al.

While ex vivo maturation of DC is one method of priming DC, such maturation is expensive and can lack reproducibility.

Additional problems with whole tumor based approaches include the potential for tumor contamination, small cell number, and limited ability to monitor the immune response.

Additionally, the use of single peptides for immunization limits the potential induction of undesired autoimmunity (Nestle et al.

The primary limitations to peptide-based vaccine strategies are haplotype restriction; potential for degradation; the lack of identifiable putative tumor antigens recognized to induce a CTL response; the potential failure of the efferent arm of the immune response if smaller numbers of peptides are employed; and uncertainty regarding which peptides, used alone or in combination, are the most immunogenic (Nair et al.

No protein identified to date satisfies all of these criteria with regard to SCCHN tumors.

The major limitations to clinical application of these peptide epitopes are both their limited prevalence in SCCHN and putative epitopes restricted by HLA types with low population specific frequencies.

Potential pitfalls in the development of peptide-based immunotherapy for SCCHN including: 1) peptide-induced tolerance, 2) synthetic peptide degradation, 3) limited antigenic repertoire, and 4) inadequate tools for evaluating treatment response.

The second potential problem with synthetic peptide-based immunotherapy is the potential for proteolysis.

This factor, inherent to all peptide-based approaches, restricts patient access.

Additionally, because individual peptides only have the potential to induce epitope specific CTL, the vast majority of potential tumor antigens are not targeted.

Recent evidence, however, suggests that this problem of epitope restriction may not be as physiologically important as was previously postulated.

The fourth and final limitation to peptide-based immunotherapy, is the limited number of diagnostic tools available to evaluate clinical response.

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