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Therapeutic vaccines represent a viable option for active immunotherapy of cancers that aim to treat late stage disease by using a patient's own immune system. The promising results from clinical trials recently led to the approval of the first therapeutic cancer vaccine by the U.S. Food and Drug Administration. This major breakthrough not only provides a new treatment modality for cancer management, but also paves the way for rationally designing and optimizing future vaccines with improved anticancer efficacy. Numerous vaccine strategies are currently being evaluated both pre-clinically and clinically. This review discusses therapeutic cancer vaccines of diverse platforms or targets as well as the preclinical and clinical studies employing these therapeutic vaccines. We will also consider tumor-induced immune suppression that hinders the potency of therapeutic vaccines, and potential strategies to counteract these mechanisms for generating more robust and durable antitumor immune responses.

The 110-kDa heat shock protein (hsp110) has long been recognized as one of the primary heat shock proteins in mammalian cells. It belongs to a recently described protein family that is a significantly diverged subgroup of the hsp70 family and has been found in organisms as diverse as yeast and mammals. We describe here the first analysis of the ability of hsp110 to protect cellular and molecular targets from heat damage. It was observed that the overexpression in vivo of hsp110 conferred substantial heat resistance to both Rat-1 and HeLa cells. In vitro heat denaturation and refolding assays demonstrate that hsp110 is highly efficient in selectively recognizing denatured proteins and maintaining them in a soluble, folding-competent state and is significantly more efficient in performing this function than is hsc70. hsp110-bound proteins can then be refolded by the addition of rabbit reticulocyte lysate or hsc70 and Hdj-1, whereas Hdj-1 does not itself function as a co-chaperone in folding with hsp110. hsp110 is one of the principal molecular chaperones of mammalian cells and represents a newly identified component of the primary protection/repair pathway for denatured proteins and thermotolerance expression in vivo.It has been long recognized that the major heat shock proteins (hsps) 1 of mammalian cells are observed at 28, 70, 90, and 110 kDa (1-3) and other hsp families, e.g. hsp60 and hsp40, have been subsequently identified. All of these stress protein groups have been intensively studied, excluding the hsp110 species. The cloning of hsp110 from hamster, mouse, yeast, arabadopsis, and a variety of other species has been recently described (4 -11, 29, 30). Moreover, as is the case with the hsp70 family, multiple members of the hsp110 family have also been found in individual organisms (8 -11). These studies indicate that hsp110 is a significantly enlarged and diverged relative of the hsp70 family of proteins but also includes unique sequence components. The notable constitutive expression and stress inducibility of hsp110 is highly suggestive of a major role in unstressed cells as well as in the heat shock response and the expression of thermotolerance (1, 2). A description of the heat shock response in eucaryotes is not possible without an understanding of the roles played by this major stress protein.We describe here an analysis of the characteristics of hsp110, both in vivo and in vitro. EXPERIMENTAL PROCEDURESPurification of Recombinant His-tagged HSP110 -cDNA for hsp110 was cloned into pRSET vector (Invitrogen), resulting in introduction of a His 6 -(enterokinase recognition sequence)-Arg-Ser tag to the amino terminus of hsp110 (pRSET-hsp110). pRSET-hsp110 was transformed into Escherichia coli strain JM109(DE3) cells. The transformant containing pRSET-hsp110 was grown at 37°C in LB medium with ampicillin until the OD reached 0.6, when the expression of His-hsp110 was induced by the addition of 0.4 mM isopropyl-1-thio-␤-D-galactopyranoside during further incubation at 30°C for 5 h. Cells were lysed in 20 ...

Living organisms are known to react to a heat stress by the selective induction in the synthesis of several polypeptides. In this review we list the major stress proteins of mammalian cells that are induced by heat shock and other environments and categorize these proteins into specific subgroups: the major heat shock proteins, the glucose-regulated proteins, and the low-molecular-weight heat shock proteins. Characteristics of the localization and expression of proteins in each of these subgroups are presented. Specifically, the nuclear/nucleolar locale of certain of the major heat shock proteins is considered with respect to their association with RNA and the recovery of cells after a heat exposure. The induction of these major heat shock proteins and the repression of the glucose-regulated proteins as a result of reoxygenation of anoxic cells or by the addition of glucose to glucose-deprived cultures is described. Changes in the expression of these protein systems during embryogenesis and differentiation in mammalian and nonmammalian systems is summarized, and the protective role that some of these proteins appear to play in protecting the animal against the lethal effects of a severe heat treatment and against teratogenesis is critically examined.

The hypothesis that the expression of heat shock proteins following a preliminary hyperthermic treatment is responsible for subsequent thermotolerance to a second heat treatment is examined. CHO cells were given a 12 min, 45 degrees C pretreatment and then incubated for varying intervals at 37 degrees C. The synthesis of certain intracellular proteins was monitored as a function of time post-incubation by using 35S-methionine incorporation as determined in SDS polyacrylamide gel electrophoresis. Cell survival was concurrently measured by challenging the cells with a second heat treatment (45 degrees C/27 min). Major heat shock proteins were observed at 68 000, 89 000 and 110 000 daltons. The synthesis of these proteins was significantly reduced in the presence of cyclohexamide. The total 35S-methionine incorporation into these proteins correlated well with the induction of survival resistance (thermotolerance). An approximate exponential relationship between survival and the amount of each of these proteins may occur. These and other heat shock proteins were also present, in a significantly reduced degree, in control (non-heat shocked) cells maintained under normal culture conditions at 37 degrees C. It is possible that heat shock proteins are responsible for the phenomenon of thermotolerance.