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Heat Shock Protein Vaccines Target Tumor Cell’s ‘Antigenic Profile’

Heat Shock Protein Vaccines Target Tumor Cell’s ‘Antigenic Profile’

ABSTRACT: Experts in cancer immunology and vaccine therapies discussed recent progress in cancer vaccine development at a satellite symposium of the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO). More than 300 clinicians and researchers attended the symposium, sponsored by the University of Connecticut School of Medicine under an unrestricted educational grant from Antigenics Inc. This page includes reports from two presentations.

ORLANDO—Heat shock
proteins (HSPs) purified from tumor cells carry the unique "antigenic
fingerprint" of that tumor, and vaccination with tumor-derived HSPs induces
specific tumor immunity, said Pramod K. Srivastava, PhD, professor of
immunology and director of the University of Connecticut Cancer Center,
Farmington.

Speaking at a symposium held in conjunction with the 2002
ASCO annual meeting, Dr. Srivastava explained that each tumor has a unique
antigenic profile related to the accumulation of random mutations. With each
division of a tumor cell, an estimated 6 to 60 random mutational changes occur,
and because tumor cells are continually dividing, a vast number of mutations
eventually accumulate. This results in a tumor cell population in which each
cell has a unique antigenic profile.

Therefore, although several well-described specific tumor
antigens exist, the complete characterization of the antigens associated with
an individual tumor is not "practically knowable," he said, owing to the
randomness of their generation. However, by isolating the HSPs from individual
tumors, it is possible to capture the antigenic fingerprint of that specific
tumor.

Heat shock proteins are present in every living cell and
have been conserved throughout evolution, from bacteria through humans, Dr.
Srivastava said. Collectively, HSPs constitute approximately 10% of the total
intracellular protein content. Although the expression of HSPs is increased in
response to heat shock, glucose deprivation, or other stresses, HSPs are
present in abundant levels even under normal conditions.

Each HSP molecule serves as a chaperone for an individual
peptide, and together the HSPs collect a heterogeneous assortment of peptides
representative of the antigenic profile of each cell. An extraordinarily useful
property of the HSPs, Dr. Srivastava said, is that although a given HSP may
purify into a single band, there is actually a vast heterogeneity of chaperoned
peptide sequences within this single band. "If, for example, you purify HSPs
from a mouse leukemia, you will find leukemia antigens associated with the HSPs.
In human melanomas, you’ll find antigenic peptides derived from the melanoma
cells. So essentially, when you purify HSPs, you have an antigenic
fingerprint," he said.

The HSPs also have immunogenic functions. They can chaperone
peptides to antigen-presenting cells (APCs) in the lymph nodes. The APCs bind
the HSPs and then re-present the HSP-chaperoned peptides on their MHC class I
and II molecules. Interaction with HSPs also stimulates APCs to release
cytokines.

Vaccines derived from HSPs can provide specific immunity
against individual tumors, Dr. Srivastava said. He described an animal study in
which, following surgery to remove pre-existing tumors, mice were vaccinated
with HSPs derived from their individual tumors. The majority of vaccinated
animals had long-term disease-free survival, whereas nonvaccinated mice died
within a short time after surgery due to the persistence of micrometastatic
disease.

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