Heat shock protein preclinical studies
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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.
|