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| EDITORIAL |
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| Year : 2019 | Volume
: 2
| Issue : 1 | Page : 3-4 |
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Unleashing the immune system to conquer cancer
Abdulrahman Alsultan
Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| Date of Web Publication | 7-Jan-2019 |
Correspondence Address:
Abdulrahman Alsultan
Department of Pediatrics, College of Medicine, King Saud University, P.O. Box 261182, Riyadh 11342
Saudi Arabia
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/JNSM.JNSM_84_18
How to cite this article:
Alsultan A. Unleashing the immune system to conquer cancer. J Nat Sci Med 2019;2:3-4 |
Programmed cell death receptor 1 (PD-1) naturally inhibits T-cell immune response when it interacts with programmed cell death ligand 1 (PD-L1). Similarly, cytotoxic T-lymphocyte antigen 4 (CTLA-4) is another negative regulator of T-cell response by interacting with its ligands CD80/CD86. Both PD-1/PD-L1 and CTLA-4 create a checkpoint on the immune system to maintain self-tolerance and prevent autoimmune disorders.[1],[2] The expression of PD-L1 by tumor cells is a mechanism that is present in various types of cancer to evade the immune system.[3],[4] Thus, blockade of PD-1/PD-L1 interaction or CTLA-4 was proposed to be a potential strategy for cancer immunotherapy.[2],[3] This led to the development of immune checkpoint inhibitors that target CTLA-4, PD-1, or PD-L1 in cancer.[5],[6],[7] The Nobel Prize in Physiology or Medicine 2018 was awarded to both James P. Allison from the United States and Tasuku Honjo from Japan “for their discovery of cancer therapy by the inhibition of negative immune regulation” which is related to their work on PD-1 and CTLA-4.[8]
Ipilimumab, an anti-CTLA-4 antibody, and six PD-1/PD-L1 inhibitors were approved by the Food and Drug Administration (FDA) for the treatment of advanced cancer since 2011. Pembrolizumab, nivolumab, and cemiplimab-rwlc are PD-1 inhibitors, whereas atezolizumab, durvalumab, and avelumab are PD-L1 inhibitors. [Table 1] summarizes FDA-approved indications for checkpoint inhibitors. The overall response rate (ORR) to PD-1/PD-L1 inhibitors whether used alone or in combination with other therapy ranges between 26% and 61% in advanced melanoma, 28% and 55% in advanced non-small cell lung cancer, 65% and 70% in relapsed/refractory Hodgkin lymphoma, and 17% and 28% in advanced urothelial carcinoma.[9] The presence of microsatellite instability (MSI) or mismatch repair deficiency (dMMR) in solid tumors such as colon cancer is associated with a high number of somatic mutations and increased sensitivity to PD-1 inhibitors, with ORR of about 50%.[10] Combination of two checkpoint inhibitors such as ipilimumab and nivolumab showed encouraging results in advanced melanoma, renal cell carcinoma, and MSI/dMMR metastatic colon cancer.[11],[12],[13] The optimal treatment duration of checkpoint inhibitors still needs to be determined.[14] There are limited reports about the use of checkpoint inhibitors in children with refractory solid tumor, and several clinical trials are ongoing to address the safety and efficacy of checkpoint inhibitors in advanced childhood malignancies.[15] | Table 1: FDA approved indications for checkpoint inhibitors as of December 2018
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Checkpoint inhibitors disrupt the self-tolerance in the immune system and could potentially cause autoimmune disorders in different tissues and organs. Rash, colitis, hepatitis, thyroid dysfunction, pneumonitis, anemia, neutropenia, thrombocytopenia, encephalitis, myocarditis, and nephritis are examples of reported complications. Nevertheless, a recent meta-analysis showed that PD-1/PD-L1 inhibitors are associated with lower high-grade adverse events (AEs) and are better tolerated compared to chemotherapy.[16] The American Society of Clinical Oncology recently published clinical practice guideline on the management of immune-related AEs in patients treated with checkpoint inhibitors.[17] For Grade 2 immune-related AEs, checkpoint inhibitors should be stopped and should not be resumed until AEs become of Grade 1 or less. For Grade 3 toxicity, corticosteroids should be initiated and checkpoint inhibitors should be interrupted. Checkpoint inhibitors should be permanently discontinued in Grade 4 immune-related AEs except in endocrinopathies if managed with hormonal replacement. Long-term toxicities of checkpoint inhibitors need to be defined given the short follow-up duration for most of the treated patients.
The field of cancer immunotherapy is evolving rapidly with promising results in refractory malignancies. The use of chimeric antigen receptor (CAR) T-cell therapy, monoclonal antibodies, and cancer vaccines is another example of cancer immunotherapy. CD19 CAR T-cell therapy was approved by the FDA recently for refractory/relapsed B-cell acute lymphoblastic leukemia and large B-cell lymphoma in adults and children.[18] Combining checkpoint inhibitor with CAR T-cell therapy may augment the response rate.[19] Future studies will examine whether checkpoint inhibitors will provide a survival advantage when used upfront in newly diagnosed cancer patients. This might modify our conventional treatment approach to cancer in the near future. However, checkpoint inhibitors are expensive and their use will escalate the health-care costs.[20] Thus, it is essential to incorporate cost-effectiveness studies into future evidence-based treatment decisions with the use of checkpoint inhibitors.
| References | |  |
| 1. | Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999;11:141-51.  |
| 2. | Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-6. |
| 3. | Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99:12293-7. |
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| 7. | Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. |
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| 9. | Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J Immunother Cancer 2018;6:8. |
| 10. | Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13. |
| 11. | Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34. |
| 12. | Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90. |
| 13. | Overman MJ, Lonardi S, Wong KY, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-9. |
| 14. | Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, et al. Nivolumab for patients with advanced melanoma treated beyond progression: Analysis of 2 phase 3 clinical trials. JAMA Oncol 2017;3:1511-9. |
| 15. | Lucchesi M, Sardi I, Puppo G, Chella A, Favre C. The dawn of “immune-revolution” in children: Early experiences with checkpoint inhibitors in childhood malignancies. Cancer Chemother Pharmacol 2017;80:1047-53. |
| 16. | Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: A meta-analysis. Oncologist 2017;22:470-9. |
| 17. | Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36:1714-68. |
| 18. | Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-48. |
| 19. | Li AM, Hucks GE, Dinofia AM, Seif AE, Teachey DT, Baniewicz D, et al. Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia. ASH 2018 Annual Meeting; 2018. |
| 20. | Verma V, Sprave T, Haque W, Simone CB 2 nd, Chang JY, Welsh JW, et al. A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer 2018;6:128. |
[Table 1]
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