Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery

Abstract

An anti-glucocorticoid induced TNF receptor (GITR) agonistic antibody (Ab) induces an antitumor immunity with both stimulation of effector T cells and inhibition of regulatory T cell activity. To enhance GITR Ab-mediated tumor immunity, we focused on the intratumoral route, since a tumor-localized high concentration of Ab would confer activation of only tumor-infiltrating T cells. First, in a murine colon cancer model, we showed that the intratumoral delivery of Ab significantly increased the number of effector T cells infiltrated into tumors, and suppressed tumor growth more effectively than the intraperitoneal and intravenous injections did. Then, we found that the injection of Ab into the peritumoral area induced a systemic antitumor immunity at a similar level to the intratumoral injection. Therefore, we hypothesized that the transfer of locally administrated Ab into tumor-draining lymph nodes (TDLNs) plays an important role in inducing an effective immunity. In fact, intratumorally or peritumorally injected Ab was detected in TDLNs, and resection of Ab-injected TDLNs significantly reduced GITR Ab-mediated systemic tumor immunity. Intratumoral injection showed less number of auto-reactive T cells in the spleen than the intraperitoneal injection did. Intratumoral delivery of GITR Ab is a promising approach to induce an effective immunity compared to the systemic delivery.

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

“…These molecules suppress the function of Treg and activate the effector T cells. In mice, treatment with agonist antibodies to OX-40 and GITR result in a decrease of Treg and reinforced anti-tumor immune responses in the presence of various cancers [161,162]. In humans, the anti-tumor immune responses of OX-40 against malignant melanoma and renal cell carcinoma have already been confirmed in a phase I study [163].…”

Combinatorial Immunotherapies for Metastatic Colorectal Cancer

“…Several antibodies have been designed to promote CTL activity ( Figure 1 ). Agonistic targeting of the co-stimulatory receptors OX40 (CD134), 4-1BB (CD137), and glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) can increase infiltration and activity of effector T cells while decreasing infiltration of regulatory immune cells in preclinical CRC models [ 138 , 139 , 140 , 141 , 142 ]. These antibodies have entered clinical investigation ( Table 1 ).…”

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

“…In addition to non-targeted GITR agonists, efforts are being made to develop tumor-targeted GITRL fusion proteins 11,16 , since there is evidence that the local delivery of GITR agonists can improve the therapeutic activity of GITR agonists 17 . Our group has worked for the last two decades on the antibody-based delivery of cytokine payloads to tumors and has characterized more than 100 fusion proteins until now 18 , but had never worked before with GITRL payloads.…”