Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy

Abstract

The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first-line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC.

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

“…PD-1 blockade can reverse tumor-induced T cell dysfunction and lead to heightened antitumor immunity and cancer regression (La-Beck et al, 2015). We thus wanted to determine whether PD-1 blockade might rescue loss of mitochondrial function in tumorinfiltrating T cells.…”

“…Recent advances in cancer immunotherapy have revealed that the T cell response to cancer can be reinvigorated in a variety of ways, resulting in durable and effective benefit in a wide array of cancer types (La-Beck et al, 2015;Mahoney et al, 2015;Ribas, 2015). These include engineering chimeric antigen receptors redirect T cells to tumors, personalized antigen vaccines to persistent neoepitopes, and, probably most prominently, antibodymediated blockade of co-inhibitory "checkpoint" molecules, like programmed death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and mucin-containing gene 3 (Tim-3), among others (LaBeck et al, 2015).…”

“…Thus for improving the treatment of cancer, chronic viral infections, and other diseases, it is critical to understand the mechanisms behind the dysfunction in chronically activated T cells . This is especially important considering that, while checkpoint blockade has had remarkable success in the clinic, the majority of patients still do not respond to these therapies (La-Beck et al, 2015).…”

Unerwünschte Wirkungen der Immuntherapie

“…Sie blockieren kostimulatorische Signale der Immunaktivierung und führen zu einer T-Zell-Anergie und Immunsuppression. In der Tumortherapie bietet die Blockade dieses Signalwegs (Immuncheckpointinhibition) mit dem Ziel der Steigerung der T-Zell-vermittelten Immunantwort gegen Tumorzellen neue Behandlungsoptionen für eine Reihe von Krebsarten wie das metastasierte Melanom, nichtkleinzellige Lungenkarzinom und das Nierenzellkarzinom [21].…”

Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

“…[12][13][14][15][16][17] A major limitation of the approach is its unspecific nature of T cell targeting, resulting in severe side effects. [18][19][20] Strategies allowing for a more directed and specific therapeutic use of T cells may have advantages in terms of specificity and efficacy. …”