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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

In vivo effect of injection of the α-gal glycolipids into B16 melanoma. Lesions reaching subcutaneous size of ~5 mm received one injection of α-gal glycolipids and were resected at different time points for histological analysis. (A) On day 2 post injection, mononuclear cells migrating from blood vessels (BV) are detected already; (B) On day 7 post injection, the infiltration is more extensive as indicated by the number of mononuclear cells migrating from blood vessels into the tumor; and (C) On day 7 post PBS injection, control tumors displayed no infiltration of mononuclear cells (×200).
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cancers-02-00773-f003: In vivo effect of injection of the α-gal glycolipids into B16 melanoma. Lesions reaching subcutaneous size of ~5 mm received one injection of α-gal glycolipids and were resected at different time points for histological analysis. (A) On day 2 post injection, mononuclear cells migrating from blood vessels (BV) are detected already; (B) On day 7 post injection, the infiltration is more extensive as indicated by the number of mononuclear cells migrating from blood vessels into the tumor; and (C) On day 7 post PBS injection, control tumors displayed no infiltration of mononuclear cells (×200).

Mentions: Anti-Gal IgM and IgG molecules are released to the injection site from capillaries ruptured by the injecting needle. These anti-Gal molecules interact with α-gal epitopes on α-gal glycolipid micelles and rapidly induce a local complement cascade within the treated lesion. Complement cleavage chemotactic factors C5a and C3a, generated by this activation process, direct migration of APC such as monocytes/macrophages and dendritic cells into the injected tumor and induce intratumoral inflammation [52]. This could be demonstrated in B16 melanoma lesions (~5 mm in diameter) developing in KO mice within 5-6 days post subcutaneous inoculation of 1 × 106 B16 cells. Such B16 melanoma lesions were injected with 1 mg α-gal glycolipids in 0.1 mL solution (~2 × 1016 α-gal epitopes/mg). Recruitment of APC is evident within two days post injection (Figure 3A). At that time point, multiple mononuclear cells are found in areas surrounding the blood vessels. Immunostaining and flow cytometry analysis of surface markers of the infiltrating cells indicated that a large proportion of these cells are macrophages and dendritic cells [52]. The infiltration of mononuclear cells increases by Day 7 post injection (Figure 3B). In melanoma lesions injected with PBS, no recruitment of APC is observed (Figure 3C), indicating that the migration of APC into lesions is directly associated with the presence of α-gal glycolipids within the injected tumors, rather than with the tissue damage caused by the injection needle.


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)

In vivo effect of injection of the α-gal glycolipids into B16 melanoma. Lesions reaching subcutaneous size of ~5 mm received one injection of α-gal glycolipids and were resected at different time points for histological analysis. (A) On day 2 post injection, mononuclear cells migrating from blood vessels (BV) are detected already; (B) On day 7 post injection, the infiltration is more extensive as indicated by the number of mononuclear cells migrating from blood vessels into the tumor; and (C) On day 7 post PBS injection, control tumors displayed no infiltration of mononuclear cells (×200).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

cancers-02-00773-f003: In vivo effect of injection of the α-gal glycolipids into B16 melanoma. Lesions reaching subcutaneous size of ~5 mm received one injection of α-gal glycolipids and were resected at different time points for histological analysis. (A) On day 2 post injection, mononuclear cells migrating from blood vessels (BV) are detected already; (B) On day 7 post injection, the infiltration is more extensive as indicated by the number of mononuclear cells migrating from blood vessels into the tumor; and (C) On day 7 post PBS injection, control tumors displayed no infiltration of mononuclear cells (×200).
Mentions: Anti-Gal IgM and IgG molecules are released to the injection site from capillaries ruptured by the injecting needle. These anti-Gal molecules interact with α-gal epitopes on α-gal glycolipid micelles and rapidly induce a local complement cascade within the treated lesion. Complement cleavage chemotactic factors C5a and C3a, generated by this activation process, direct migration of APC such as monocytes/macrophages and dendritic cells into the injected tumor and induce intratumoral inflammation [52]. This could be demonstrated in B16 melanoma lesions (~5 mm in diameter) developing in KO mice within 5-6 days post subcutaneous inoculation of 1 × 106 B16 cells. Such B16 melanoma lesions were injected with 1 mg α-gal glycolipids in 0.1 mL solution (~2 × 1016 α-gal epitopes/mg). Recruitment of APC is evident within two days post injection (Figure 3A). At that time point, multiple mononuclear cells are found in areas surrounding the blood vessels. Immunostaining and flow cytometry analysis of surface markers of the infiltrating cells indicated that a large proportion of these cells are macrophages and dendritic cells [52]. The infiltration of mononuclear cells increases by Day 7 post injection (Figure 3B). In melanoma lesions injected with PBS, no recruitment of APC is observed (Figure 3C), indicating that the migration of APC into lesions is directly associated with the presence of α-gal glycolipids within the injected tumors, rather than with the tissue damage caused by the injection needle.

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