Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

260 12 Principles and Strategies Employing Heat Shock Proteins for Immunotherapy of Cancers
Tab. 12.3 T cell immunity against defined antigens induced by HSP±peptide fusion proteins
Antigen Fusion partners (HSP) Reference
Human papillomavirus type 16 E7 BCG Hsp65 108
M. tuberculosis HSP70 109
Ovalbumin Mycobacterial HSP65 64
M. tuberculosis HSP70 61, 63
Influenza virus nucleoprotein M. bovis BCG Hsp65 110
HIV-1 p24 M. tuberculosis HSP70 60
tion. However, from a practical standpoint, recombinant HSP±antigen fusion protein
guarantees coupling and can be manufactured with ease in larger quantities.
Moreover, HSP70 fused with a target antigen has also been used successfully in the
format of a DNA vaccine. Therefore, in the case when antigen is defined, HSP±antigen
fusion vaccine is an attractive approach for immunotherapy (Tab. 12.3).
The mechanism governing the ability of HSP±antigen fusion protein to prime adaptive
immunity appears similar to native HSPs. A recombinant mycobacterial HSP65
fused to a polypeptide that contains an octapeptide (SIYRYYGL) can stimulate
C57BL/6 mice, as well as CD4 + T cell-deficient mice, to produce CD8 + CTLs to the
fusion partner's octapeptide [64]. Moreover, this fusion protein itself stimulated DCs
in vitro and in vivo to up-regulate the levels of MHC (class I and II) and co-stimulatory
molecules.
12.2.3
Strategy 3: Whole Cell Vaccine based on the Modulation of the Expression of HSPs
Autologous, or allogeneic, whole tumor cell vaccines continue to be the most common
tumor vaccines tested clinically [65]. In addition to being safe and easy to manufacture,
there are several unique reasons:
(1) Most tumor antigens are not known, therefore specific antigen-based vaccines
are not applicable to a vast majority of patients.
(2) Whole cell vaccines deliver multivalent antigens of both MHC class I and class II
epitopes for the activation of multivalent tumor immunities.
(3) When carefully controlled and titrated, the efficacy of whole cell vaccines have
been consistently demonstrated in pre-clinical models.
Whole cell vaccines have been tried in numerous clinical settings such as in colorectal
cancer, melanoma, sarcoma, renal cell carcinoma, pancreatic cancer, breast cancer
and others. In order to increase the efficiency of whole-cell-based vaccines, efforts
have been in modifying tumor cells genetically to express immunologically important
molecules such as MHC class I and II molecules, co-stimulatory proteins, chemokines
or cytokines. More recently, fusion of autologous tumor cells with DCs has
shown some clinical promise in the treatment of stage IV renal cell carcinoma [66].