Heat shock protein preclinical studies

Using cancer to vaccinate against cancer

Since the 1940s, it has been shown that mice can be vaccinated against cancer by immunization with attenuated (weakened) tumor cells. After being confirmed over many decades in different strains of mice and in other species, it has become a central principle of cancer immunology. It holds true for cancers arising in a large variety of tissues (such as in the skin, colon, breast, liver, kidney and brain), for tumors caused by carcinogens, and for cancers of spontaneous origin.

When first performed in the 1940s, these studies provided the first hint of the enormous diversity of cancers. They also indicated that all cancers are individually distinct, which means that individual cancers can be used to vaccinate against themselves, but not against other kinds of cancer. For example, cells from tumor X can only vaccinate against tumor X, and vaccination with cells from tumor X does not prevent the development of tumor Y. Even two cancers arising from the same type of tissue, such as two skin cancers, are individually distinct. This principle was studied in 1970 and the results are shown below.

Tumor used for challenge

Tumor
used for vaccination

	A	B	C	D	E
A	+	-	-	-	-
B	-	+	-	-	-
C	-	-	+	-	-
D	-	-	-	+	-
E	-	-	-	-	+

+ Tumor rejected

- Tumor grows

Animal models of HSP cancer vaccines

Consistent with earlier studies using whole tumor cells, researchers showed that tumor-derived heat shock proteins (HSPs) could also trigger immunity that is tumor-specific. This phenomenon has now been demonstrated repeatedly in more than a dozen cancer models, including several models of cancer vaccine treatment.

Models of HSP Cancer Vaccines*
Cancer Type	References
Fibrosarcoma • Meth A • CMS5 • CMS13 • MKSA	Srivastava et al., 1986; Wang et al., 2001 Palladino et al., 1987 Udono & Srivastava, 1994, 1995 Udono et al., 1994; Feldweg & Srivastava, 1995
Hepatoma • Zajdela	Srivastava & Das, 1984
Squamous cell carcinoma • UV6138 • UV6139	Janetzki et al., 1998 Janetzki et al., 1998
Colon carcinoma • CT-26	Tamura et al., 1997; Wang et al., 2000
Melanoma • B16	Tamura et al., 1997; Nicchitta, 1998
Lung carcinoma • D122	Tamura et al., 1997
Lymphoma • A20	Sato et al., 2001 Graner et al., 2000
Prostate cancer • Dunning G	Yedavelli et al., 1999
* Partial list

Experimental HSP products

Type of HSP Product	Example of product in clinical testing	Example of product tested in animal models	References
HSPs purified from cancer cells	Oncophage^® (vitespen; formerly HSPPC-96) for several cancers; AG-858 for CML	Oncophage Calreticulin HSP70 HSP90 HSP110 GRP170	See references section
HSPs complexed with synthetic antigens	AG-707 and AG-702 for genital herpes	AG-701 in genital herpes HSP70 in VSV HSP70 in LCMV HSP70 in SV40 gp96 in bovine herpes HSP110 for cancer	Kumaraguru et al., 2002 Navaratnam et al., 2001 Ciupitu et al., 1998 Blachere et al., 1997 Manjili et al., 2000
HSPs purified from cells that have been induced to make antigens of viruses, bacteria or other pathogens	Not in clinic	gp96 in bovine herpes gp96 in influenza	Navaratnam et al., 2001 Blachere et al., 1993
HSPs purified from cells infected with virus, bacteria or other pathogens	Not in clinic	gp96 in tuberculosis gp96 in hepatitis B gp96 in listeria gp96 in bovine herpes	Zugel et al., 2001 Meng et al., 2001 Navaratnam et al., 2001
HSP: heat shock protein; CML: chronic myelogenous leukemia; VSV: vesicular stomatitis virus; LCMV: lymphocytic choriomeningitis virus; SV40: simian virus 40

Other applications of the HSP technologies described above include HIV, human papilloma virus, hepatitis C and malaria.