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422 Part V: Therapeutic Principles Chapter 27: Vaccine Therapy 423

TABLE 27–1. Examples of Candidate Human Tumor IMMUNOSTIMULANTS TO ENHANCE
Antigens for Hematologic Cancers VACCINE EFFICACY
Antigen Reference Traditionally, immunologic adjuvants, described by the late Charles
Minor histocompatibility 1 Janeway as “immunology’s dirty little secret,” such as alum and oil-
antigens (HA-1, HA-2) in-water emulsions (e.g., incomplete Freund adjuvant), provide a physical
depot for slow release of antigen. Adjuvants also serve as general immune
Proteinase-3 2 stimulants by providing a danger signal to activate antigen-presenting
Wilms tumor antigen-1 3 cells. This feature describes classical adjuvant components, such as bacte-
B-cell receptor (immunoglobulin 4 rial cell wall extracts, as well as unmethylated CpG DNA sequences, which
idiotype) deliver maturation signals to dendritic cells through toll-like receptors
(Chap. 20). The incorporation of either recombinant cytokines or their
25
Anaplastic lymphoma kinase 5 genes into vaccine formulations may increase vaccine potency by broadly
Sperm protein 17 6 enhancing the function of either antigen-presenting cells or T cells.
Sperm protein associated with the 7 Consequently, cytokines, such as interferon-γ, IL-2, and IL-15, may be
26
nucleus on X chromosome (SPAN-X) useful as components of vaccines. Such cytokines also can help direct
the type of immune response elicited. For example, IL-12 elicits primar-
CML-66 8
ily T-helper (Th) type 1 cell responses, whereas the inclusion of IL-4
Survivin 9 or IL-10 generally induces predominantly Th2 cell responses (Chap.
HM1.24 10 76). Some cytokines, such as GM-CSF, which can induce dendritic cell
differentiation, can also function as an adjuvant by recruiting antigen-
Immature laminin receptor protein 11
presenting cells to local vaccination sites. 27
BCR-ABL fusion protein 12
Aurora kinase 13
Fibromodulin 14 CLINICAL TRIAL DESIGN
Cancer vaccine trials might not fit into the paradigm developed for
chemotherapeutic agents, which have direct effects on tumor and nor-
mal host cells. For example, studies in heavily pretreated patients with
terminal disease might be inappropriate for vaccines, which generally
VACCINE DELIVERY require an intact host immune system. For this reason, even safety can-
Effective delivery of the target antigen to the immune system is critical not be evaluated completely in patients who cannot make an immune
response, because any toxicity will likely be indirect, resulting from
for the successful induction of immunity. For most tumor antigens, this the immune response elicited. In addition, animal models show that
is a daunting challenge, as most antigens (with the exception of viral the immune system may be more effective at clearing minimal resid-
antigens associated with cancers) are weakly immunogenic, self, or ual disease than at clearing advanced tumor cell burdens. Accord-
tissue-differentiation antigens. ingly, several late-stage clinical trials of cancer vaccines are testing this
Many vaccine-delivery strategies use dendritic cells. These key approach in the setting of clinical remission, after primary surgery or
antigen-presenting cells are principally responsible for initiating a host chemotherapy.
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immune response. The cells, represented in minute quantities, have Although conventional clinical trials generally test one exper-
the powerful capacity to take up antigens, and once activated, to present imental agent at a time, vaccine formulations may contain several
processed peptides to T cells. Accordingly, optimizing the delivery of components. The simultaneous optimization of multiple variables (e.g.,
tumor antigens to specialized antigen-presenting cells is critical. Such vaccine and adjuvant dose and schedule, and routes of administration)
efforts have included isolation of dendritic cells from blood, followed in a single clinical study often requires the application of novel, more
by physical loading with protein or peptide antigens, or introducing the flexible clinical trial design. 28
genes for candidate antigens by transfection with cDNA or messenger
RNA, or by fusion with whole tumor cells. Loaded dendritic cells have
been administered to patients as vaccines. 21
An alternative strategy is to target the delivery of antigens to den- ASSAYS OF VACCINE EFFICACY
dritic cells in vivo. Traditional approaches focused on attempts to make the The development of surrogate measures of vaccine efficacy has potential
antigen look foreign to the host immune system; for example, by chemi- value for answering the scientific question of whether it is even possi-
cal linkage to larger, highly immunogenic proteins (carriers) or incorpo- ble to vaccinate human patients against a candidate antigen. Traditional
ration into liposomes. Rational approaches to increase the efficiency of assays of immune response, including simple lymphoproliferation and
antigen delivery to dendritic cells have included genetic fusion of the gene cytotoxicity assays, requiring prolonged periods of prior stimulation,
encoding the antigen to one encoding biologically active molecules that are being replaced by quantitative assays that can measure effector func-
has the ability to target cell-surface receptors on antigen-presenting cells. tion of T cells directly sampled from blood (e.g., enzyme-linked immu-
29
Such targeting molecules have included cytokines, chemokines, antibody nospot assay) and by sensitive tetramer binding assays (Table 27–2). In
Fc or Fab fragments, transferrin, CD40, and mannose, which serve as lig- some cases, tetramer-binding assays have been combined with intracel-
22
ands for specific receptors on antigen-presenting cells. Such molecular lular cytokine production to provide both quantitative and functional
30
vaccines can be administered as naked DNA or as fusion proteins. Other analyses of antigen-specific T cells. An important aim of clinical trials
promising approaches to target dendritic cells in vivo are represented by is to determine which, if any, of these measures of immune response are
recombinant viral or bacterial vectors or virus-like particles. 23,24 valid surrogates for vaccine efficacy.

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