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 • MC57 • F1αFR	Srivastava et al., 1986; Peng et al., 1997; Wang et al., 2001; Kovalchin et al., 2001; Tamura et al., 1997; Basu and Srivastava, 1999; Chandawarkar et al., 1999 Palladino et al., 1987; Peng et al., 1997 Palladino et al., 1987 Ciupitu et al., 2002 Massa et al., 2004
Hepatoma • Zajdela	Srivastava and Das, 1984
Squamous cell carcinoma • UV6138 • UV6139	Janetzki et al., 1998 Janetzki et al., 1998; Tamura et al., 1997
Colon carcinoma • CT-26 • MCA38	Tamura et al., 1997; Wang et al., 2000 Massa et al., 2004
Melanoma • B16	Tamura et al., 1997; Nicchitta, 1998; Wang et al., 2003; Geng et al., 2006
Lung carcinoma • D122	Tamura et al., 1997; Kovalchin et al., 2001; Yamazaki et al., 1999
Lymphoma • A20	Sato et al., 2001; Graner et al., 2000; Robert et al., 2001
Prostate cancer • Dunning G • TRAMP-C2	Yedavelli et al., 1999 Wang et al., 2004
Breast cancer • 4T1	Liu et al., 2005
* 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; also 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 gp96 in hepatitis HSP110 for cancer	Kumaraguru et al., 2002, 2004 Pack et al., 2005 Navaratnam et al., 2001 Ciupitu et al., 1998 Blachere et al., 1997 Manjili et al., 2002 Wang et al., 2003 Manjili et al., 2003 Kim et al., 2007 Li et al., 2005
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.