Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

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.

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…When talking about the immune microenvironment in clinical cancer research, the hot topic concerns the development of immunotherapeutic tools to enable an immune response against tumors [36]. Indeed, therapies targeting immune-checkpoint molecules (e.g., programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)) are currently used in clinical practice for the treatment of several cancers [37]. In the case of CRC, immunotherapy is approved for the treatment of mismatch repair (MMR) deficient metastatic tumors refractory to other lines of treatment, representing only~2-4% of all CRC patients [38].…”

“…While MMR proficient patients do not benefit from anti-PD-L1 therapies, MMR deficient ones yield a better, though not complete, overall response rate, and impressive improvements of progression-free survival rates [38,39]. In NSCLC, the use of anti-PD-L1/PD-1 therapy is clinically approved [37], where PD-L1 positive patients have been showing great responses. Nevertheless, studies involving therapies targeting other immune checkpoint molecules in NSCLC, such as anti-CTLA-4 antibodies, have shown more disappointing results [40].…”

Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high‑dimensional single‑cell analysis

“…These immune regulatory checkpoints play critical roles in the maintenance of self-tolerance and immune homeostasis under normal physiological conditions; however, cancer cells co-opt these checkpoints to escape immune attack (19,20). Nevertheless, blocking inhibitory receptors can enlist and strengthen the immune system to attack tumors and has achieved clinical success in treating many tumor types, even metastatic and chemo-resistant cancer (21)(22)(23)(24). Targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the interaction between programmed cell death 1 (PD-1) and PD ligand 1 (PD-L1) are the most prominent immune checkpoint blockade strategies in the clinic (25)(26)(27)(28).…”

Adjuvant Effect of Toll-Like Receptor 9 Activation on Cancer Immunotherapy Using Checkpoint Blockade

“…Studies of T-cell activation and suppression mechanisms have led to the discovery of key checkpoints for immune suppression, including the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (13)(14)(15), programmed cell death protein 1 (PD-1), and the PD-1 ligands programmed death-ligand (PD-L)1 and PD-L2 (16)(17)(18)(19). The use of antibody (Yervoy, ipilimumab) for immune checkpoint blockade to increase the anti-cancer effect of T-cells was first approved by the FDA in 2011, and several additional checkpoint blockage drugs were subsequently approved (20)(21)(22). These immunotherapies have effectively improved the survival and life quality of cancer patients, resulting in their acceptance as the fourth standard treatment for cancers after surgery, chemotherapy, and radiation therapy.…”