Biomedical Engineering Reference
In-Depth Information
sunitinib were established in SCID mouse models with
human tumors representing colon carcinomas, NSCLC,
and RCC (Figure 24.7). The results indicate that multicycle
TTS monotherapy is beneficial as compared to one cycle
treatment; the combinations of TTS with bevacizumab,
docetaxel, or sunitinib should provide clinical benefits as
compared to the monotherapies.
The advantages as documented in the vast series of
preclinical experiments with TTS fusion proteins in combi-
nation with different anticancer and immunomodulatory
drugs are very promising. Two of the combination schedules
have so far also been tested in patients, naptumomab esta-
fenatox in combination with docetaxel for treatment of
NSCLC (concluded Phase I) and in combination with
IFN- a for treatment of RCC (ongoing Phase II/III).
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staphylococcal enterotoxin A to accessory cells is a require-
ment for its ability to activate human T cells. J. Immunol.
140, 2484-2488.
5. Fischer H, Dohlsten M, Lindvall M, Sjogren HO, Carlsson R.
(1989) Binding of staphylococcal enterotoxin A to HLA-DR
on B cell lines. J. Immunol. 142, 3151-3157.
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staphylococcal enterotoxin A binds to human MHC class II
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Boylston A, et al. (1989) V beta-specific stimulation of human
T cells by staphylococcal toxins. Science 244, 811-813.
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prepared leukemia cells. Cell Immunol. 129, 426-434.
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Superantigen-based tumor therapy: in vivo activation of cyto-
toxic T cells. Cancer Immunol. Immunother. 36, 89-93.
13. Dohlsten M, Lando PA, Hedlund G, Trowsdale J, Kalland T.
(1990) Targeting of human cytotoxic T lymphocytes to MHC
class II-expressing cells by staphylococcal enterotoxins.
Immunology 71, 96-100.
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enterotoxin-dependent cell-mediated cytotoxicity. Immunol.
Today 12, 147-150.
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Hedlund G, et al. (1993) Preparation and characterization of
conjugates of monoclonal antibodies and staphylococcal enter-
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Hedlund G, et al. (1993) Monoclonal antibodies and super-
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24.7 CONCLUSIONS
TTS fusion proteins have shown proof of principle in
preclinical immune pharmacology and antitumor models
as well as in clinical trials. Selective immune activation
and targeting of T lymphocytes to tumors by TTS thera-
peutics have been documented. Immune mediated inhibition
of tumor growth in the mouse and in patients has been
recorded with different TTS entities including the optimized
TTS naptumomab estafenatox. Clinical Phase I and Phase
IIa data showpromising resultswithRCCandNSCLCpatients
compatible with present frontline treatments [75-78]. Naptu-
momab estafenatox has shown a favorable safety profile as
compared to many other anticancer drugs and can therefore, in
addition to monotherapy, be used in combination with other
anticancer treatments. To further increase the therapeutic
efficiency of the TTS fusion proteins, treatment combinations
to inhibit anti-SAg antibody production with, for example,
docetaxel and modulation of immune suppressive activity by
anti-CTLA-4 antibody treatment, for instance, have been
successfully evaluated. Naptumomab estafenatox is presently
in pivotal Phase II/III clinical trials add-on to IFN- a for
treatment of RCC.
REFERENCES
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(1995) Antibody-targeted superantigens are potent inducers
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