The blockade of immune checkpoints in cancer

immunotherapy Unleashing the immune

system to combat cancer

Bui Dac Chi,MDMedic Center

• Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand–receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T‑lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

• Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand–receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T‑lymphocyte-associated antigen 4 (CTLA4) antibodies .and blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), enhance antitumour immunity with the potential to produce durable clinical responses.

What’s New in Cancer Immunotherapy?

• A surge of advances began in 2011, when ipilimumab, the first “checkpoint inhibitor” drug was approved by the Food and Drug Administration (FDA) to treat advanced melanoma. By mid-2016 the FDA had approved four checkpoint inhibitors as therapy for six forms of cancer. And these drugs, alone and in combination with a wide variety of other agents, are in clinical trials in more than 20 cancer types.

• “The future is combination therapy,” Such therapies could hit cancer with two or more checkpoint blocking drugs along with drugs that stimulate the immune system, or teamed with agents that directly attack cancer cells. “We’re enthusiastic about checkpoint blockade plus targeted kinase inhibitors.”

• Roche has received market approval for atezolizumab to treat a common type of bladder cancer. It’s the 3rd checkpoint inhibitor on the market, and the first to target PD-L1

• "The Earthquake of Immunotherapy in Lung Cancer."

• all patients with newly diagnosed NSCLC should have biopsy samples tested for mutations and PD-L1 expression status, and "this testing should be done reflexively, as these patients cannot wait." Patients with tumors showing mutations (about 20% of all NSCLC cases) should be treated first line with targeted agents, and those with high PD-L1 expression (about 30% of the remaining 80%), with immunotherapy with pembrolizumab,

Multiple co-stimulatory and inhibitory interactions regulate T cell responses

• Immune checkpoint inhibitors have transformed the treatment of several cancers by releasing restrained antitumor immune responses.Ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, and nivolumab, an anti–programmed death-1 (PD-1) antibody, have individually improved survival in patients with melanoma, and early results suggest that their combination further enhances antitumor activity and survival.

• Tasuku Honjo

Tasuku Honjo

The field of cancer immunotherapy

looks brighter than ever