- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Cancer Biology and Therapeutics: High-Impact Cancer Research Program, Harvard Medical School, Boston, MA 02115, USA
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Science, Lebanese University, Beirut, Lebanon
Correspondence Address:
Jawad Fares, Youssef Fares
Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Science, Lebanese University, Beirut, Lebanon
DOI:10.4103/sni.sni_366_18
Copyright: © 2019 Surgical Neurology International This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.How to cite this article: Jawad Fares, Mohamad Y. Fares, Youssef Fares. Immune checkpoint inhibitors: Advances and impact in neuro-oncology. 25-Jan-2019;10:9
How to cite this URL: Jawad Fares, Mohamad Y. Fares, Youssef Fares. Immune checkpoint inhibitors: Advances and impact in neuro-oncology. 25-Jan-2019;10:9. Available from: http://surgicalneurologyint.com/surgicalint-articles/9169/
Keywords: Immune checkpoint inhibitors, immunotherapy, T-cells, Nobel prize, James P. Allison, Tasuko Honjo, neuro-oncology
INTRODUCTION
The Nobel Assembly, consisting of 50 professors at the Karolinska Institutet, in Sweden, awarded the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation.[
Dr. James Allison is an American immunologist who holds the position of professor and chair of immunology at the University of Texas M.D. Anderson Cancer Center. Dr. Tasuku Honjo is a Japanese immunologist who is a professor of immunology at Kyoto University.[
Figure 1
Upper half: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint protein functions as a brake on T-cells that inhibits T-cell activation. CTLA-4 inhibitors block the function of the brake leading to activation of T-cells and attack on cancer cells. Lower half: programmed cell death protein 1 (PD-1) is another checkpoint protein that functions as a brake that inhibits T-cell activation. PD-1 blockade inhibits the function of the brake leading to activation of T-cells and highly efficient attack on cancer cells
Clinical studies exploring the effects of CTLA-4 and PD-1 blockades have been dramatic. The treatment agents that are referred to as “immune checkpoint inhibitors,” have completely altered the outcome for certain groups of patients with advanced cancer. In tumors of the central nervous system (CNS) though, their effects remain to be seen. In this paper, we explore the impact of immune checkpoint inhibitors on CNS-related neoplasms and discuss the latest advances targeting CTLA-4 and PD-1 in neuro-oncology.
CTLA-4 TARGETTED IMMUNOTHERAPY
In 1996, James Allison, lead investigator in his laboratory at University of California, Berkeley, published in Science his observation that CTLA-4, a protein known as a target in the treatment of autoimmune diseases, is a negative regulator of T-cell activation.[
DISCOVERY OF PD-1
In 1992, 4 years before Allison's observations on CTLA-4 were published, Tasuko Honjo discovered PD-1 as a novel member of the immunoglobulin gene superfamily. His new observation published in The EMBO Journal suggested that the PD-1 protein may be involved in the classical type of programmed cell death.[
IMPACT IN NEURO-ONCOLOGY
The development of immune checkpoint inhibitors targeting CTLA-4 and PD-1 has significantly improved the treatment of a variety of cancers, such as metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma. Nevertheless, little has been said about the effect of these inhibitors on CNS-related neoplasms.
Glioblastoma multiforme
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor (46%), as well as the deadliest.[
Preclinical studies corroborate that CTLA-4 blockade has shown positive results in animal models of GBM. After blockade of CTLA-4, there was an increase in number of CD4 T cells with improved function.[
PD-1 is highly expressed in GBM[
Metastatic brain tumors
Brain metastases outnumber primary malignant brain tumors with a ratio of 10 to 1.[
Studies have shown that immune checkpoint inhibitors are effective in the treatment of brain metastases from malignant melanoma and non-small cell lung cancer.[
Immune-related adverse events
Despite the effective antitumor immune response induced by these inhibitors, immune checkpoint blockade can result in inflammation of any organ. Inflammatory adverse effects that result from the treatment are known as immune-related adverse events. In general, PD-1 inhibitors have a lower incidence of immune-related adverse events compared with those that block CTLA-4. In addition, combination of nivolumab and ipilimumab has a higher rate of immune-related adverse events than either approach as monotherapy.[
Cost of therapy
Therapies with immune checkpoint inhibitors are quite expensive. The average annual cost of treatment with each drug can surpass $100,000. Managing the immune-related adverse events will also add to the tally. This makes it much harder to make decisions on the sequence of treatments and the dosing schedule. Policymakers must be informed about the value of these treatments to develop cost-effective strategies for therapy. For example, Kohn et al.[
CONCLUSION
The discovery and evolution of immune checkpoint inhibitors is one of the most exciting advances in cancer immunotherapy. Non-CNS tumors, specifically, have experienced impressive responses with long-lasting survival benefits. Early preclinical work has demonstrated that immunotherapy may potentially hold similar promise for GBM and metastatic brain cancers; however, more studies on the patient level are required to validate its true efficacy. As CNS tumors can develop multiple mechanisms for immune-resistance, combinations using multiple checkpoint inhibitors targeting both CTLA-4 and PD-1, with or without other immune-based strategies may be the most effective means in generating an antitumor immune response. In addition, discovering new checkpoint proteins and targeting the immune active microenvironment of CNS tumors can be vital to overcome potential resistance mechanisms. Awareness and multidisciplinary management of immune-related adverse events and developing cost-effective strategies for treatment are also necessary to ensure the optimal clinical benefit from these therapeutic agents.
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