6 Aptamers for Targeted Therapy
153
of 4-1BB ligands may be a useful way to enhance the protective immunity of cancer
patients [185]. However, there may also be a risk of immune abnormalities, especially polyclonal activation of CD8+T cells and cytokine storms. In addition, 4-1BB
is an internalized receptor on the cell surface, and the ligands targeting 4-1BB need
to be kept on the cell surface to bind to T tumor infiltrating cells, so it is necessary to prevent internalization during ligand binding. Gilboa et al. [186] coupled
excitatory aptamers with aptamers targeting VEGF to form VEGF-4-1BB aptamers.
Among them, VEGF is a product secreted into the tumor matrix, and VEGF-4-1BB
can co-stimulate tumor infiltrating T cells without being internalized by tumor cells.
The results showed that the 4-1BB aptamer ligand targeted by VEGF showed a
superior therapeutic index at least 10 times higher than that of 4-1BB antibody, and
there was no CD8+T cell proliferation and multiple organ inflammatory response.
It is suggested that tumor stroma and agonistic bifunctional aptamer polymer is a
clinically feasible method to enhance tumor immunity, which avoids the defects of
non-targeted monoclonal antibodies used at present.
Benaduce et al. [187] compared the therapeutic effects of 4-1BB aptamer and
4-1BB monoclonal antibody in a mouse breast cancer and melanoma model. It was
found that 4-1BB monoclonal antibody had synergistic effect with radiotherapy,
while the inhibitory effect of 4-1BB aptamer on tumor was equivalent to that of 41BB mAb, and did not cause CD8+ proliferation in liver and spleen. It is suggested
that the co-stimulation based on 4-1BB aptamers provides an equivalent and less
toxic strategy for enhancing RT-mediated tumor inhibition. Glioblastoma multiforme (GBM) is one of the most malignant cancers with a 5-year survival rate of
5%. It is characterized by low T cell infiltration but strong macrophage infiltration.
Osteopontin (OPN) is a powerful macrophage chemokine, and the blocking of OPN
significantly weakens the ability of glioma cells to recruit macrophages. In addition,
OPN deficiency makes glioma cells to have a direct killing effect on CD8+T cells.
Heimberger et al. [188] constructed bispecific aptamers, which have high specificity
to immune cells and tumor cells in GBM tumor microenvironment, and can enhance
naturally occurring anti-tumor immunity through tumor targeting. After systemic
injection of 4-1BB-OPN bispecific aptamer into GL261 glioma model mice, it was
found that the median survival time was prolonged by 68% (P < 0.05), indicating that
4-1BB-OPN bispecific aptamer is a promising treatment strategy for GBM patients
with mesenchymal subtypes. In the 4T1 breast cancer model with poor immunogenicity, Rajagopalan et al. [189] constructed the conjugate of 4-1BB aptamer-CD25
siRNA and 4-1BB-Axin-1 siRNA. Among them, siRNA targeting CD25 (IL-2R α)
blocks the negative response of IL-2 to the activation of CD8+T cells. Treatment with
4-1BB aptamer-CD25 siRNA conjugate enhanced the anti-tumor response of cell
vaccine or local radiotherapy. 4-1BB aptamer targeted delivery of Axin-1siRNA (the
rate-limiting component of β-catenin destruction complex) enhanced the memory
development and antitumor activity of CD8+T cells. It is suggested that 4-1BB
aptamer-targeted siRNA therapy can regulate the function of circulating CD8+T
cells and make them develop into long-term memory CD8+T cells, thus enhancing
anti-tumor immunity. Gilboa E et al. constructed the conjugate of 4-1BB and transforming growth factor β siRNA (Smad4) to target vaccine-activated mouse CD8+T
153
of 4-1BB ligands may be a useful way to enhance the protective immunity of cancer
patients [185]. However, there may also be a risk of immune abnormalities, especially polyclonal activation of CD8+T cells and cytokine storms. In addition, 4-1BB
is an internalized receptor on the cell surface, and the ligands targeting 4-1BB need
to be kept on the cell surface to bind to T tumor infiltrating cells, so it is necessary to prevent internalization during ligand binding. Gilboa et al. [186] coupled
excitatory aptamers with aptamers targeting VEGF to form VEGF-4-1BB aptamers.
Among them, VEGF is a product secreted into the tumor matrix, and VEGF-4-1BB
can co-stimulate tumor infiltrating T cells without being internalized by tumor cells.
The results showed that the 4-1BB aptamer ligand targeted by VEGF showed a
superior therapeutic index at least 10 times higher than that of 4-1BB antibody, and
there was no CD8+T cell proliferation and multiple organ inflammatory response.
It is suggested that tumor stroma and agonistic bifunctional aptamer polymer is a
clinically feasible method to enhance tumor immunity, which avoids the defects of
non-targeted monoclonal antibodies used at present.
Benaduce et al. [187] compared the therapeutic effects of 4-1BB aptamer and
4-1BB monoclonal antibody in a mouse breast cancer and melanoma model. It was
found that 4-1BB monoclonal antibody had synergistic effect with radiotherapy,
while the inhibitory effect of 4-1BB aptamer on tumor was equivalent to that of 41BB mAb, and did not cause CD8+ proliferation in liver and spleen. It is suggested
that the co-stimulation based on 4-1BB aptamers provides an equivalent and less
toxic strategy for enhancing RT-mediated tumor inhibition. Glioblastoma multiforme (GBM) is one of the most malignant cancers with a 5-year survival rate of
5%. It is characterized by low T cell infiltration but strong macrophage infiltration.
Osteopontin (OPN) is a powerful macrophage chemokine, and the blocking of OPN
significantly weakens the ability of glioma cells to recruit macrophages. In addition,
OPN deficiency makes glioma cells to have a direct killing effect on CD8+T cells.
Heimberger et al. [188] constructed bispecific aptamers, which have high specificity
to immune cells and tumor cells in GBM tumor microenvironment, and can enhance
naturally occurring anti-tumor immunity through tumor targeting. After systemic
injection of 4-1BB-OPN bispecific aptamer into GL261 glioma model mice, it was
found that the median survival time was prolonged by 68% (P < 0.05), indicating that
4-1BB-OPN bispecific aptamer is a promising treatment strategy for GBM patients
with mesenchymal subtypes. In the 4T1 breast cancer model with poor immunogenicity, Rajagopalan et al. [189] constructed the conjugate of 4-1BB aptamer-CD25
siRNA and 4-1BB-Axin-1 siRNA. Among them, siRNA targeting CD25 (IL-2R α)
blocks the negative response of IL-2 to the activation of CD8+T cells. Treatment with
4-1BB aptamer-CD25 siRNA conjugate enhanced the anti-tumor response of cell
vaccine or local radiotherapy. 4-1BB aptamer targeted delivery of Axin-1siRNA (the
rate-limiting component of β-catenin destruction complex) enhanced the memory
development and antitumor activity of CD8+T cells. It is suggested that 4-1BB
aptamer-targeted siRNA therapy can regulate the function of circulating CD8+T
cells and make them develop into long-term memory CD8+T cells, thus enhancing
anti-tumor immunity. Gilboa E et al. constructed the conjugate of 4-1BB and transforming growth factor β siRNA (Smad4) to target vaccine-activated mouse CD8+T