Immunotherapeutic Agents for Intratumoral Immunotherapy

Abstract

Immunotherapy using systemic immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cells has revolutionized cancer treatment, but it only benefits a subset of patients. Systemic immunotherapies cause severe autoimmune toxicities and cytokine storms. Immune-related adverse events (irAEs) plus the immunosuppressive tumor microenvironment (TME) have been linked to the inefficacy of systemic immunotherapy. Intratumoral immunotherapy that increases immunotherapeutic agent bioavailability inside tumors could enhance the efficacy of immunotherapies and reduce systemic toxicities. In preclinical and clinical studies, intratumoral administration of immunostimulatory agents from small molecules to xenogeneic cells has demonstrated antitumor effects not only on the injected tumors but also against noninjected lesions. Herein, we review and discuss the results of these approaches in preclinical models and clinical trials to build the landscape of intratumoral immunotherapeutic agents and we describe how they stimulate the body's immune system to trigger antitumor immunity as well as the challenges in clinical practice. Systemic and intratumoral combination immunotherapy would make the best use of the body's immune system to treat cancers. Combining precision medicine and immunotherapy in cancer treatment would treat both the mutated targets in tumors and the weakened body's immune system simultaneously, exerting maximum effects of the medical intervention.

Keywords: antitumor immunity; body; immunotherapeutic; intratumoral; neoantigen; xenoantigen.

Figure 1

The classes of immunotherapeutic agents for intratumoral immunotherapy. Classification of the different types of immunotherapeutic agents from small molecules to cells used for intratumoral immunotherapy that induce the immune responses in the body to revive and direct antitumor immunity for the eradication of tumor cells.

Figure 2

Intratumoral immunotherapy involves direct injection of immunotherapeutic agents into tumors. The immunosuppressive tumor microenvironment of an injected tumor is stimulated to turn the immunosuppressive state into an immunostimulatory state by using the injected agents, involving innate and adaptive immunity depending on the class of agents. The immune-active tumor microenvironment promotes recruitment of NK and DC cells as well as recognition of tumor antigens by DCs. The tumor antigen-loaded DCs present tumor antigens to T cells, triggering the generation of polyclonal effector and memory T cells. Then, the primed T cells circulate systemically to infiltrate into injected tumors and noninjected tumors to achieve durable and global antitumor immune responses to eliminate and contain tumor cells.