Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer

With the establishment of the immune surveillance mechanism since the 1950s,attempts have been made to activate the immune system for cancer treatment through the discovery of various cytokines or the development of antibodies up to now.The fruits of these efforts have contributed to the recognition of the 3rd generation of anticancer immunotherapy as the mainstream of cancer treatment.However,the limitations of cancer immunotherapy are also being recognized through the conceptual establishment of cold tumors recently,and colorectal cancer(CRC)has become a major issue from this therapeutic point of view.Here,it is emphasized that non-clinical strategies to overcome the immunosuppressive environment and clinical trials based on these basic investigations are being made on the journey to achieve better treatment outcomes for the treatment of cold CRC.

Th1 cytokine-based immunotherapy for cancer

Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited.Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment.In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings.Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

Cytokines that target immune killer cells against tumors

T-cell-stimulating cytokines have shown promise as monotherapies or in combination with other therapeutic modalities for immunotherapy of cancer.However,their efficacy is limited due to their short half-life,pleiotropic roles,and induction of severe toxicity even at therapeutic doses.To overcome these major therapeutic barriers,cytokine-based products are being further developed to improve their therapeutic index.These approaches include manipulating their activity to preferentially bind to effector immune cells rather than immune-suppressive cells,prolonging their half-life in vivo and modifying them to target tumors.This review focuses on IL-2,IL-15,and IL-10,which have potent effects on immune cells that mediate effective antitumor responses.We will summarize the recent progress of these cytokines in both preclinical studies and selective clinical applications and will discuss our perspectives on the development of new strategies to potentiate cytokine-based immunotherapy.

A concise review of immunotherapy for glioblastoma

Glioblastoma(GB)is the most common and aggressive form of primary brain tumors in adults with a universally poor prognosis despite multimodal management including surgery,chemotherapy and radiation therapy.Among the novel therapeutic strategies,immunotherapy deserves particular attention with its potential to evoke biologic response and harness the host immune system.Considerable success achieved for other tumors has elicited great enthusiasm and prompted research on immunotherapy for GB.While the central nervous system has traditionally been thought of as an immune-privileged site,our understanding is being refined with emerging evidence.Several studies have been conducted and more are under way to establish the role of immunotherapy in management of GB.Immunotherapy of GB has yet resulted in mixed success with conflicting research findings,emphasizing the need for extensive study before its integration into routine clinical practice.Although there is a lot of room for improvement,immunotherapy for GB may be feasible and serve as a viable management strategy broadening and strengthening the therapeutic armamentarium to combat this deadly disease.Herein,we present a concise review of immunotherapy for GB.