Practical Issues of Peptide Immunization Assessed in Early Human Clinical Trials

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One of the first considerations addressed in initial clinical trials of peptide-based vaccines was the route of administration. The primary routes of administration that have been used are the intramuscular, subcutaneous, and intradermal routes. The dose and volume of the vaccine itself, the choice of adjuvant, and the desired immune response have largely determined immunization route. There have been few human clinical peptide vaccine studies comparing the routes of administration. For example, one reported study used both an intramuscular and subcutaneous route for vaccination but did not have the power to detect a statistically significant difference in immune response (47). Early vaccine studies with peptide and protein subunit vaccines primarily used an intramuscular approach, based on the model of vaccination for infectious diseases (48-50). Most studies demonstrated evidence of antigen-specific antibody production, and one study showed evidence of a concomitant Th response (50). Clinical investigations using infectious-disease vaccines have given an indication of the most effective routes of immunization by comparing the intramuscular and intradermal routes of immunization for the recombinant hepatitis B surface antigen whole-protein vaccine. Investigators found the intradermal route superior with efficient production of antigen-specific Th cells, antibodies, and CTLs. In addition, patients who were not immunized by the intramuscular route of injection could subsequently be effectively immunized by vaccinating via the intradermal route (51). Furthermore, investigations in a rodent model have demonstrated that the intradermal route was preferable to the subcutaneous route in initiating a T-cell response, presumably due to the presence of professional antigen-presenting LCs in the skin (43). Thus, a majority of peptide vaccine trials have predominantly used subcutaneous and intradermal routes of immunization (52-56), the subcutaneous route having been chosen by some based on prior animal studies and choice of adjuvant (52,57) and by others to accommodate larger volumes of administered vaccine (56).

The choice of adjuvant is another consideration studied in peptide vaccine trials, particularly as peptides themselves are typically only weakly immunogenic. Due to recent renewed enthusiasm for peptide-based tumor vaccines coupled with the search for adjuvants that promote cellular as well as antibody responses, the list of adjuvants being studied continues to grow. The choice of adjuvant has largely been determined by preclinical models. Similar to alum, oil-based incomplete Freund's-type adjuvants, such as Montanide ISA-51 (Seppic, Paris, France) and TiterMax (CytRx Corp., Norcross, GA), have been used in human peptide vaccine studies (56,58), with their adjuvant effect likely mediated by a depot effect, increasing the half-life of the peptide antigen at the site of immunization. Other pro-inflammatory biologic adjuvants such as BCG, Detox (mycobacterial cell-wall skeleton plus a lipid moiety) (Corixa Corp., Seattle, WA), and influenza virosomes have been used as adjuvants in peptide- and protein-based human vaccine studies (59-61). One study compared a variety of adjuvants in a rodent model targeting human MUC1 peptide antigens conjugated to keyhole limpet hemocyanin (KLH), and found the saponin adjuvant QS-21 (Aquilla Biopharmaceuticals, Worcester, MA) to be the most effective in promoting an antigen-specific antibody responses (62). Subsequently, QS-21 has been used as an adjuvant in human peptide cancer vaccine trials (57,63), with the hope that the use of a saponin may allow entry of peptides directly into MHC complexes to stimulate a T-cell response (64). Another type of adjuvant that has been studied in animal models is polymer microspheres that encapsulate the peptide antigen, permitting slow release over variable lengths of time (65). Potential advantages to this type of adjuvant include the ability to use an oral route of delivery (66), continuous release of antigen obviating the need for booster immunizations, and the ability to incorporate other biologic adjuvants or cytokines within the polymer (67). Human trials using microsphere adjuvants in the context of peptide-based cancer vaccines are under way. Finally, the discovery of various cytokines participating in the initiation of immune responses has suggested that cytokines themselves may be useful immunologic adjuvants. As an example, soluble GM-CSF is a vaccine adjuvant, and has the ability to induce the differentiation of DCs and act as a chemoattractant for various immune cell effectors (68,69).

The dose of peptide administered is another factor that has been extensively studied in clinical peptide vaccine trials. Over the last several years that peptide vaccines have been in clinical use, there have been multiple-dose escalation studies designed to evaluate the immunogenicity of progressively higher doses of peptide (50,52,56-58,70). It is difficult to draw overall conclusions from these studies, however, because length and/or stability of peptide, routes of administration, choice of adjuvant, dose, and analysis of immunologic response vary greatly from study to study. In addition, patient cohorts were generally too small to draw definitive conclusions regarding dose efficacy. No peptide dose-related toxicities have been observed, even up to doses of 2000 ^g of a 9-mer peptide (56). Toxicities that have been observed were not related to dose of peptide, but rather were a consequence of the adjuvant used (58,70). Regarding immune responses, two studies suggest that doses of <100 ^g administered subcutaneously were less effec tive than higher doses (52,57). Two studies with peptide administered intramuscularly, however, found transient immune responses at even the lowest doses of 10 |g used (50,70). Several studies showed little difference in immune responses to peptide doses >100 |g (50, 56,57). Clinical vaccine trials in multiple sclerosis have shown that immunization with T-cell receptor (TCR) peptides in doses >1000 |g could produce a tolerizing Th2 peptide-specific response with clinical response (71,72). These results suggest that peptide doses of 100-1000 |g may be appropriate for human peptide vaccines targeting cancer-associated antigens. In addition, because peptides themselves have not to date demonstrated considerable toxicity and are unlikely to exert a biologic effect in the same way as pharmacological agents, the paradigm of dose-escalation studies in phase I trials should perhaps be different. Rather than determining the maximal tolerated dose, a better goal may be to establish the minimal dose required to generate an effective immune response.

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