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In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids.

Galili U, Albertini MR, Sondel PM, Wigglesworth K, Sullivan M, Whalen GF - Cancers (Basel) (2010)

Bottom Line: Most require effective uptake by antigen presenting cells (APC).Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC.The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

ABSTRACT
Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

No MeSH data available.


Related in: MedlinePlus

Melanocytes activation following subcutaneous injection of 1.0 mg α-gal glycolipids into the KO mouse. A. The epidermis displays 4–5 layers of cells 7 days post injection in the black spot area. The apical region under the keratinous layer (stained in red) is filled with many melanin granules. B. The injected skin four weeks post injection. The epidermis displays normal structure of ~2 layers of epidermal cells, the amount of melanin granules is residual and the overall color of the skin returns to normal pink (x400).
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cancers-02-00773-f006: Melanocytes activation following subcutaneous injection of 1.0 mg α-gal glycolipids into the KO mouse. A. The epidermis displays 4–5 layers of cells 7 days post injection in the black spot area. The apical region under the keratinous layer (stained in red) is filled with many melanin granules. B. The injected skin four weeks post injection. The epidermis displays normal structure of ~2 layers of epidermal cells, the amount of melanin granules is residual and the overall color of the skin returns to normal pink (x400).

Mentions: Injection of α-gal glycolipids into B16 melanoma lesions resulted in stopping tumor growth in 65% of the treated KO mice, whereas in the remaining 35%, tumors continued to grow at a rate that was significantly slower than that of PBS injected tumors [52]. It should be stressed that B16 melanoma is a very aggressive tumor that usually doubles its size in KO mice (following subcutaneous implantation) every 4–8 days. In 20% of the tumors injected with α-gal glycolipids, the destruction of the tumor cells resulted in regression of the tumor. An example of tumor regression is shown in Figure 4 where the melanoma lesion and the adjacent normal skin were injected with α-gal glycolipids (1 mg in 0.1 mL). Injection of α-gal glycolipids into normal skin tissue resulted in a local inflammatory response due to anti-Gal/α-gal epitope interaction which induced temporary activation of melanocytes. This is seen as the dark spot appearing at the injection site by the treated lesion (Figure 4). As discussed in the safety section below, this activation of melanocytes in mice is transient and it always disappears within 3–4 weeks post injection (Figure 6).


In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids.

Galili U, Albertini MR, Sondel PM, Wigglesworth K, Sullivan M, Whalen GF - Cancers (Basel) (2010)

Melanocytes activation following subcutaneous injection of 1.0 mg α-gal glycolipids into the KO mouse. A. The epidermis displays 4–5 layers of cells 7 days post injection in the black spot area. The apical region under the keratinous layer (stained in red) is filled with many melanin granules. B. The injected skin four weeks post injection. The epidermis displays normal structure of ~2 layers of epidermal cells, the amount of melanin granules is residual and the overall color of the skin returns to normal pink (x400).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475649&req=5

cancers-02-00773-f006: Melanocytes activation following subcutaneous injection of 1.0 mg α-gal glycolipids into the KO mouse. A. The epidermis displays 4–5 layers of cells 7 days post injection in the black spot area. The apical region under the keratinous layer (stained in red) is filled with many melanin granules. B. The injected skin four weeks post injection. The epidermis displays normal structure of ~2 layers of epidermal cells, the amount of melanin granules is residual and the overall color of the skin returns to normal pink (x400).
Mentions: Injection of α-gal glycolipids into B16 melanoma lesions resulted in stopping tumor growth in 65% of the treated KO mice, whereas in the remaining 35%, tumors continued to grow at a rate that was significantly slower than that of PBS injected tumors [52]. It should be stressed that B16 melanoma is a very aggressive tumor that usually doubles its size in KO mice (following subcutaneous implantation) every 4–8 days. In 20% of the tumors injected with α-gal glycolipids, the destruction of the tumor cells resulted in regression of the tumor. An example of tumor regression is shown in Figure 4 where the melanoma lesion and the adjacent normal skin were injected with α-gal glycolipids (1 mg in 0.1 mL). Injection of α-gal glycolipids into normal skin tissue resulted in a local inflammatory response due to anti-Gal/α-gal epitope interaction which induced temporary activation of melanocytes. This is seen as the dark spot appearing at the injection site by the treated lesion (Figure 4). As discussed in the safety section below, this activation of melanocytes in mice is transient and it always disappears within 3–4 weeks post injection (Figure 6).

Bottom Line: Most require effective uptake by antigen presenting cells (APC).Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC.The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

ABSTRACT
Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

No MeSH data available.


Related in: MedlinePlus