Targeting the tumor microenvironment to enhance antitumor immune responses

Abstract

The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients.

Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells

“…Tumor length and width were measured using a caliper, and volumes were calculated using the formula for a prolate ellipsoid. Mice were killed when tumors exceeded 1,500 mm 3 .…”

“…It has been proposed that adjuvants like Toll-like receptor (TLR) ligands and agonistic antibodies to CD40 can restore the function of TiDCs (3)(4)(5). However, adjuvants are not TiDC-specific and could therefore evoke adverse effects when administered in an untargeted fashion.…”

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…The delivery of targeted therapies specifically into a tumor has proven efficacious for several immunebased agents and can significantly reduce toxicity that is observed with systemic treatment [98].…”

Antitumor activity of a novel small molecule TLR7 agonist via immune response induction and tumor microenvironment modulation

“…The anticancer therapies given directly into tumors may be more effective than given systemically, because local therapies could overcome natural suppressive factors in the tumor microenvironment, and induce systemic antitumor immunity (39). For solid tumors, especially breast cancer, direct intratumoral injection is safe and effective (40). In the 4T1 mouse model of breast cancer, intratumoral administration of SZU101 generated systemic antitumor immunity and suppressed both injected and distant tumors.…”