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

258 12 Principles and Strategies Employing Heat Shock Proteins for Immunotherapy of Cancers
Tab. 12.1 Immunotherapy of cancers with tumor-derived HSP±peptide complexes
Host Tumor model HSP Reference
Mouse Meth A fibrosarcoma gp96, HSP90, HSP70 93±95
CRT 96
HSP110, GRP170 97
UV-induced sarcoma gp96, HSP70 98
colon cancer gp96, HSP70 99
leukemia HSP70, gp96, HSP90, CRT 100
melanoma gp96, HSP70 99
lung cancer gp96, HSP70 99
Rat prostate cancer gp96 101
hepatoma gp96 102
Xenopus lymphoma gp96, HSP70 103
Human a variety of tumors gp96 57
perienced them again only after the second immunization. In four patients, pain or
fever occurred during the immunization period; however, their onset was unrelated
to the timing of immunization and the events were attributed to tumor progression.
None of these patients mounted significant titer of the following antoantibodies:
anti-nucleoprotein antibody, antibody to double- or single-stranded DNA, antibodies
to mitochondria, thyroglobulin, microsome, perinuclear, or cytoplasmic antigens
after gp96 immunization. One patient died 4 days after the second immunization,
which was determined to be due to the progression of his disease. Thus, there is no
evidence of acute gp96 induced side effects due to self-destructive immune reactions.
The efficacy of gp96 in the treatment of stage III renal cell carcinoma after surgical
resection is now being studied by a phase III randomized, multi-center trial around
the world. The phase I and II data in the treatment of various malignancies by
gp96 have been reviewed recently [57, 58].
12.2.2
Strategy 2: HSPs as Adjuvant
While the peptide-binding property of HSP is predictable in light of the protein
chaperoning function of HSPs in general, the recent discovery of the immunomodulating
properties of HSPs was entirely unexpected. It was found that gp96,
HSP90, HSP60, calreticulin and HSP70 can all bind to the surface of APCs in a receptor-dependent
manner. They share a common receptor CD91 [43, 44]. The interaction
of HSPs with APCs results in two functional consequences: the activation of
APCs to increase the expression of antigen-presenting and co-stimulatory molecules,
and the cross-presentation of HSP-associated peptides to MHC class I for the
priming of CTLs (Fig. 11.1). The modulating function of HSPs is not dependent
on the ability of them to bind to peptides, which suggest that HSPs can also serve
as adjuvants.