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Originally published as JCO Early Release 10.1200/JCO.2008.19.4886 on November 17 2008 © 2008 American Society of Clinical Oncology.
"Groovy" Vaccine for Melanoma—But Which Groove?
Wayne State University and Detroit Medical Center, Detroit, MI To the Editor: Populations around the world have realized the benefits offered by vaccination. The success achieved with the first (whole organisms) and second (immunogenic subunits of pathogens) generations of vaccines has been the impetus for developing more powerful and specific vaccines. Today's engineered DNA vaccines (third generation) have offered a glimpse of success in this regard,1 thus theoretically offering a major advance in this area of disease prevention and cure. Although genetic immunization is currently considered experimental, like all new major advances, given time and due diligence, this science will most likely succeed and perhaps surpass our expectations. Paramount to successful immunization is the presentation of an immunogenic peptide to specific T lymphocytes, a process involving antigen-presenting cells that process the peptide for insertion in the peptide groove of the HLA.2,3 This complex of HLA peptide is transported to the cell surface of the antigen-presenting cells, where it is interrogated by T-cell receptors for initiation of an immune response. To accomplish this, the HLA molecule must bind the peptide with sufficient affinity to transport it to the surface for presentation to lymphocytes. The peptide groove is the single parameter determining which peptides can be bound for presentation—a function that depends on its shape and binding energies, which in turn are dictated by the amino acid sequence of the molecule.4 Because failure to present the desired peptide to the immune system would circumvent successful vaccination, every effort must be made to tailor a vaccine to fit the peptide groove of a specific HLA molecule with relatively high binding affinity. HLA alleles are extremely polymorphic and vary along racial and ethnic lines. For example, HLA-A2, the most common antigen in the US population, has been shown to have more than 100 alleles;5 yet, within any one geographic region, the number of polymorphs would be limited to relatively fewer. The North American population is multiracial and multiethnic, and superimposed on this is the admixture of genes derived from interracial reproduction. In the Detroit population alone, we have found nine alleles of HLA-A*02 and two "new" or "wild" alleles that have not yet been defined. Although there is evidence of a few molecular supertypes,6 little is known about their function in the context of vaccines. Additionally, it was shown as early as 1990 that a single peptide can bind in a specific peptide groove in more than one conformation,7 but whether each conformation can result in an appropriate vaccination is not known at this time, and must be extensively explored if the promise of these vaccines is to be realized. A recent publication by Sosman et al8 in this journal reports a study in which the investigators treated HLA-A2-positive melanoma patients with high-dose interleukin-2 (IL-2) and a gp100 peptide (210M) with the expressed purpose of determining "whether more extensive testing of any of the schedules was justified," and concluded that their treatment "does not seem to represent a significant advance." Yet the HLA-typing technology used in their study was limited to defining whether their patients were HLA-A2 positive, without defining the patients’ HLA-A2 allele, and they have not reported with which HLA-A*02 alleles their vaccine (peptide) fits (probably known by the creators of the vaccine). Even if this clinical trial was designed to include only one racial group in hopes of having included the vaccine-specific allele, assumption that the patients express only those HLA-A2 allele(s) that can accommodate the relevant peptide does not indicate recognition that multiple ethnicities are found within this racial group that may encompass several polymorphisms. The authors found that those patients with the HLA-A2/Cw3 haplotype had better outcomes than other subsets. The fact that statistically this subgroup did better shows that perhaps the vaccine is appropriately handled by these two antigens (irrespective of alleles), but the peptide groove(s) potentially of benefit here (for use in future DNA vaccines) are undefined due to the lack of allele typing. Although admittedly there are multiple factors determining the potential for success in this new science, if we are to realize the full potential of vaccine technology expediently and efficiently, we must use sound scientific principles at each and every junction. There is additional cost for high-resolution allele typing beyond that of antigen typing, but does circumventing this burden justify the ethical considerations of vaccinating patients with experimental materials? Also to be considered are the monies expended for data that are perhaps not reflective of potential effectiveness, as well as the effect of negative reports on the advancement of this field. As an example of how this and other studies could have been designed, a study in which the patients were allele typed and given this 210M vaccine with IL-2 may have yielded data falling into at least three groups: IL-2 alone (non-HLA-A2 patients), IL-2 plus 210M in HLA-A*0201 patients, and IL-2 plus 210M in HLA-A*02-positive patients other than A*0201. With such a design, a positive result may have been observed in the HLA-A*0201 group that received IL-2 plus 210M, which may not have been seen in the "allele other than HLA-A*0201" group. With only antigen-level typing and no mention of the 210M peptide fit with some of the most common HLA-A2 alleles in the Sosman et al8 article, it cannot be concluded that the outcome indicates success or failure. Clinical trials involve significant expenditures of funds and precious resources such as investigator time and labor. Furthermore, regardless of how well written or intended are the signed consents used in such clinical investigations, patient expectations for success are always high. We owe it to them and the future of vaccine technology to provide a sound basis for our scientific pursuits. It is hoped that future studies by all investigators in this exciting and promising field will type their patients to the allele level and then match their study patients accordingly.6,9 Toward this end, there have been remarkable advances made in predicting the T-cell epitope in vaccination10,11 and in defining HLA alleles and supermotifs,12 all of which should support and promote successful investigations of vaccines in the future. AUTHOR's DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on November 17, 2008. REFERENCES
1. Stüve O, Eagar TN, Frohman EM, et al: DNA plasmid vaccination for multiple sclerosis. Arch Neurol 64:1385-1386, 2007 2. Bjorkman PJ, Saper MA, Samraoui B, et al: Structure of the HLA class I histocompatibility antigen, HLA-A2. Nature 329:506-512, 1987[CrossRef][Medline] 3. Bjorkman PJ, Saper MA, Samraoui B, et al: The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329:512-518, 1987[CrossRef][Medline] 4. Rammensee HG, Bachmann J, Stevanovic S: MHC Ligands and Peptide Motifs. Austin, TX, Landes Bioscience, 1997 5. Robinson J, Waller MJ, Parham P, et al: IMGT/HLA and IMGT/MHC: Sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31:311-314, 2003 6. Kangueane P, Sakharkar MK: Structural basis for HLA-A2 supertypes. Methods Mol Biol 409:155-162, 2007[CrossRef][Medline] 7. Shimojo N, Anderson RW, Mattson DH, et al: The kinetics of peptide binding to HLA-A2 and the conformation of the peptide-A2 complex can be determined by amino acid side chains on floor of the peptide binding groove. Int Immunol 2:193-200, 1990 8. Sosman JA, Carrillo C, Urba WJ, et al: Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J Clin Oncol 26:2292-2298, 2008 9. Elsner HA, Eiz-Vesper B, Blascyk R, et al: Allele-specific peptide presentation of human leukocyte antigens: Implications for tumor immunotherapy. Anticancer Res 27:2075-2077, 2007 10. Peters B, Bui H-H, Frankild S, et al: A community resource benchmarking predictions of peptide binding to MHC-1 molecules. PloS Comput Biol 2:0574-0584, 2006 11. Tsurui H, Takahashi T: Prediction of T-cell epitope. J Pharmacol Sci 105:299-316, 2007[CrossRef][Medline] 12. Sidney J, Grey HM, Kubo RT, et al: Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today 17:261-266, 1996[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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