Abstract
The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics.
Highlights
Traditional therapy of disseminated cancer is usually based on systemic treatment with several types of chemotherapy, including molecularly targeted small molecules
Another issue related to the adaptation of cancer cells is checkpoint inhibition by amplification of other negative checkpoint molecules in order to keep the exhausted phenotype of tumor-infiltrating lymphocytes (TILs)
Due to several limitations that appear in therapies based on the use of the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), PD-1, or PD-L1 monoclonal antibodies, both as monotherapy or in combination regimens, the additional co-inhibitory pathways are intensively investigated as novel pharmacological targets
Summary
Traditional therapy of disseminated cancer is usually based on systemic treatment with several types of chemotherapy, including molecularly targeted small molecules. In standard systemic anticancer treatment, the intratumor diversity of cancer cell phenotypes can be a major cause for tumor resistance to the chemotherapeutic agent(s), as some phenotypes can be much more resistant than others to a given therapy. It is exactly the opposite in case of active immunotherapy targeting immune checkpoint molecules with monoclonal antibodies, as the more different the cancer cell is from the host, the stronger immunogenicity it presents. This review aims to present the comprehensive look at the current clinical status of both types of therapeutic approaches, and to describe the most promising recent developments in the field
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