Use Of Hsppeptide Complexes As Cancer Vaccines In View Of Existence Of Shared Melanoma Antigens

One of the advantages of hsp-peptide complexes for vaccination against human cancers lies in the possibility that human cancers, like their murine counterparts, are antigenically diverse and individually distinct (see item number 3 in Sec tion II). In that scenario, it would be practically impossible to identify the antigenic epitopes of individual cancer patients. If, however, human tumors are antigenically cross reactive (as outlined in the preceding section), antimelanoma vaccines could be designed simply on the basis of peptide epitopes of known cross reactive melanoma antigens instead of hsp-peptide complexes isolated from individual melanomas. It is the premise of this chapter that hsp-peptide complexes provide a uniquely effective method of vaccination regardless of antigenic individuality or cross reactivity of human tumor antigens. This premise is elaborated as follows.

First, the antigenic cross reactivity among human melanomas suggests that once a number of shared melanoma antigens are identified, patients can be immunized with synthetic peptides corresponding to the relevant epitopes and that the vaccinated patients will elicit a CD8+ CTL response. Vaccination with peptides under suitable conditions has indeed been shown to elicit CD8+ CTLs in a number of systems (37,44). Such conditions usually include the use of incomplete Freund's adjuvant along with large quantities (~ 100 |ig peptide for a 20-gr mouse) of peptide. This is clearly incompatible with human use. Alternative approaches, such as addition of a lipophilic tail to the peptides, have been employed successfully (45) and could be potentially suited for human applications. In this context, vaccination with in vitro reconstituted complexes of human hsps with the relevant antigenic peptides offers an economical and technologically simple method of vaccination. The ability of hsp-peptide complexes, administered in saline and without any adjuvants, to prime naive CD8+ CTLs in vivo has been reported recently (10,20). The use of human hsps and synthetic peptides is also attractive from the point of view of circumventing hazards associated with the vaccination of patients with chimeric molecular constructs of unknown toxicity.

Second, vaccination with a given peptide will be effective only for patients with a given HLA allele. If different epitopes from a single molecule are recognized by different HLA alleles (as appears to be the case in case of tyrosinase; see refs. 23 and 24), a cocktail of peptides will have to be used for vaccination of a general population. Even for a given patient, a cocktail may have to be used, as humans are outbred and possess several restriction elements. A far more effective and simpler alternative will be to isolate hsp-peptide complexes from human cell lines transfected with the relevant gene under the control of a high-expression promoter. The hsp-peptide complexes purified from such trans-fectants will consist of the entire repertoire of antigenic peptides derived from that particular protein. As hsp-peptide binding is proximal to HLA-peptide binding during antigen processing, there is no HLA restriction in the hsp-bound peptides. Peptides capable of binding to all possible HLA alleles will be represented among the hsp-peptide complexes.

Third, the methodology of identification of CTL epitopes of human cancers suggests that these epitopes may represent a significantly biased sample of the antigenic repertoire of human cancers. Generation of cell lines is an essential prerequisite for isolation of CTLs, and only a very small proportion of human cancers (less than 2% for breast cancers to about 30% for melanomas) lend themselves to it. Of the tumors from which cell lines are developed, only a small proportion permit generation of CTLs. Thus, the CTL epitopes being identified may represent an atypical and sparse sampling of the cancer antigenic repertoire. Immunogenicity of cancers represents, in all likelihood, the sum total of immu-nogenicity of a large number of immunogenic epitopes, and effective anticancer vaccines should include this antigenic multiplicity. Hsp-peptide complexes are such a multicomponent, multivalent vaccine. If cancer antigens are shared and not individually indistinct, the use of hsp-peptide complexes isolated from tumors becomes even simpler, such that these complexes need not be isolated from cancers of individual patients. Instead, they could be purified from a mixture of human melanomas and be used to vaccinate allogeneic melanomas. The lack of HLA restriction of hsp-bound peptides (discussed in the preceding section) is a key advantage in this regard. Vaccination with multicomponent, multivalent vaccines rather than single or oligocomponent vaccines is also necessary for protection against antigenic escape or preexisting antigenic heterogeneity of human cancers.

These three major considerations indicate that regardless of the cross-reac-tive or individually distinct nature of human cancer antigens, hsp-peptide complexes offer unique and unprecedented advantages over other existing methods in vaccination against human cancer. In the final section of this chapter, the emerging thesis that human cancer antigens are cross reactive is examined critically.

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