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Development of Novel Immunotherapeutics 169 targeted therapies such as active immunotherapies—to both the preclinical and clinical phases of drug development. The aim of exploration is twofold: first, demonstrating proof of concept and outlining appropriate end points and second, defining the most optimal settings or indications to take an investigational drug in confirmatory studies. One should also not forget that “off target” and even “on target” toxicity may translate into new therapeutic opportunities; thus, toxicology biomarkers should be viewed as potential efficacy biomarkers in select cases, creating an opportunity to build considerable value in molecular targeted approaches. Overall, while biomarker-guided development is quickly becoming a powerful and necessary tool in support of development of innovative molecular targeted therapies, validation of select biomarkers as diagnostics—although still a lengthy and expensive process—may help expand the clinical and commercial opportunity of a novel drug by directing treatment to patient populations that would benefit the most. CASE STUDY: TRANSLATIONAL APPROACH APPLIED TO AN INVESTIGATIONAL CANCER VACCINE Herein, we illustrate the translational concept applied to a new cancer vaccination approach encompassing recombinant DNA vectors (Table 1). The overarching aim, resulting from the prior evidence in animal and man, was to develop a cell-free immunization approach that does not encompass replicating or integrating microbial vectors, yet has a chance to elicit potent antitumor responses. Recombinant DNA vectors in the form of plasmids expressing antigen fragments were an appealing strategy since the potential to elicit a broader range of immune responses encompassing MHC class I–restricted T-cell immunity (6) does not replicate in mammalian cells and does not significantly integrate into the host’s genome (7). There are, however, several pitfalls associated with plasmid vectors when used as vaccines: first and foremost, the low magnitude of immune response achieved particularly in humans but also in the preclinical models (the data in preclinical models were overestimated primarily because of availability of highly sensitive assays and inbred species—not applicable to primate situation). Upon considerable effort in outlining the causes, we know now that the major factors responsible for the limited immunogenicity of plasmid vaccines are (1) the low rate of in vivo transfection of resident cells capable to support crosspriming mechanisms or directly prime the T cells and (2) the rapid silencing of the expressed insert, promoter, and/or regulatory elements by host cells’ methylation apparatus. Overall, within several tens or hundreds of cells at the injection site this resulted in very low antigen expression that lasted only for several days—despite persistence of inert plasmid for weeks if not months (8). Several key studies demonstrated how important was the limited number of antigen-expressing APCs achieved by plasmid injection in determining the modest immune response (9). For example, adoptive transfer of escalating
170 Bot and Obrocea Table 1 A Translational Approach in Support of a Novel, Plasmid-Based Active Immunotherapeutic Strategy (Cancer Vaccine) Steps (in chronological order) Rationale References Naked plasmid for immunization (intramuscular injection) Naked plasmid for intralymphatic immunization Plasmid priming, peptide boost, by intralymphatic administration Multitargeted, plasmid priming, peptide boost approach, using intralymphatic immunization Biomarker-guided clinical exploration of a prime boost, intranodal immunization approach Expanded array of assays in support of clinical exploration of a prime boost, intranodal immunization approach Plasmid induces broad immune responses in preclinical models Limited magnitude of immunity by intramuscular immunization Limited magnitude of immune response by plasmid immunization in man High-quality immune response afforded by plasmid priming High magnitude of immune response afforded by peptide boost Coexpression of several defined tumor-associated antigens within cancer tissue Coexpression of target antigens across several tumor types Evidence that preexisting immunity was associated with improved clinical outcome number of antigen-expressing cells pooled from many animals immunized with plasmid, resulted in greatly magnified immune responses as compared to those achieved in animals immunized with the same plasmid (9). On the basis of such observations and the hypothesis that directly transfected APCs are more potent in inducing immune responses, several preclinical studies showed that direct intrasplenic or lymphatic injection of plasmid has a potential to generate superior responses (10). There was significant excitement generated by the finding that minute amounts of plasmid delivered to the APCrich skin by gene gun immunization, or secondary lymphoid tissue, were able to elicit robust immunity in preclinical models (10,11). A closer look at the data showed that while less plasmid was required to elicit an immune response, the overall dose-effect plateau in terms of achievable immune response was not dramatically changed. Nevertheless, early-phase clinical trials encompassing plasmid infusion into the groin lymph nodes of patients with advanced melanoma were carried out to test the safety and immunogenicity of this approach (12,13). For example, a more recent trial encompassed a plasmid-expressing Melan-A/MART-1 epitopes including the previously characterized HLA- A2-restricted Melan-A26–35 epitope (13). The plasmid was slowly infused into 22 10 12, 13 23 17 18, 19, 24 18, 19, 24 13
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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Factoring in Antigen Processing in
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2 Outlining the Gap Between Preclin
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Preclinical Models and Clinical Sit
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62 Srinivasan (69). In another stud
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104 Luptrawan et al. antigens (84,8
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Oncology and Immunology about the b
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