AccScience Publishing / EJMO / Volume 6 / Issue 4 / DOI: 10.14744/ejmo.2022.50386
REVIEW

Immunotherapy in Elderly Patients: A Review

Alfredo Colombo1 Concetta Maria Porretto1
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1 Department of Oncology, Casa di Cura Macchiarella, Palermo, Italy
EJMO 2022, 6(4), 271–281; https://doi.org/10.14744/ejmo.2022.50386
Submitted: 19 October 2022 | Revised: 17 November 2022 | Accepted: 23 November 2022 | Published: 30 December 2022
© 2022 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Immunotherapy is a recently developed treatment against most forms of cancer. Although since the early 1990s, many advances have been made with the finding of new drugs as chemotherapy and molecular targeted therapies, the latest drugs approved for cancer treatment are mostly immunotherapy.
These immunotherapies, including drugs directed against immune checkpoint Programmed cell death protein 1 (PD1), Programmed cell death protein 1 ligand (PD-L) 1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have become a consolidated treatment strategy regarding various kinds of tumors, with an effective response, and good tolerability towards patients. Patients over 65 years old constitute a large portion of the neoplastic population, and are increasingly represented in medical oncology clinics. Unfortunately, however, these patients are underrepresented in randomized clinical trials. We also know that with aging, the microenvironment and immune cells undergo marked changes that are defined by the term immunosenescence. In this review, we will consider the various studies on immunotherapy in elderly patients, while evaluating the subgroup analyses to better clarify the efficacy and safety that immunotherapy shows in this frail population in which the treatment strategy must be carefully selected.

Keywords
Aging
anti PD-L1
cancers
immunotherapy
safety
Conflict of interest
None declared.
References

1. Fowler H, Belot A, Ellis L, Maringe C, Luque-Fernandez MA, Njagi EN, et al. Comorbidity prevalence among cancer patients: a population-based cohort study of four cancers. BMC Cancer 2020;20:2. [CrossRef]
2. Kendal WS. Dying with cancer: the influence of age, comorbidity, and cancer site. Cancer 2008;112:1354–62. [CrossRef]
3. European Medicines Agency. YERVOY. Annex I summary of product characteristics. Available at: http://www.ema.europa.
eu/docs/en_GB/document_library/EPARproduct_Information/human/002213/WC500109299.pdf. Accessed Jun 19, 2015.
4. European Medicines Agency. OPDIVO. Annex I summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ human/003985/WC500189765.pdf. Accessed Jun 19,
2015.
5. European Medicines Agency: EMEA/H/C/003820 —pembrolizumab product information. Keytruda. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003820/WC500190990.pdf. Accessed Jul 17, 2015.
6. FDA. Yervoy FDA label. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed Dec 15, 2022.
7. FDA. Opdivo FDA label. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.pdf. Accessed Dec 15, 2022.
8. FDA. Keytruda FDA label. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s00lbl.pdfdrugsatfda_docs/label/2015/125514s005lbl.pdf. Accessed Dec 15,
2022.
9. Antonia SJ, Bendell JC, Taylor MH. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO 2015. J Clin Oncol 2015;33:abstract 7503. [CrossRef]
10. Plimack ER, Bellmunt J, Gupta S. Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and biomarker analysis from KEYNOTE-012. ASCO 2015. J Clin Oncol 2015;33:abstract 4502. [CrossRef]
11. Seiwert TY, Haddad RI, Gupta S. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): preliminary results from KEYNOTE-012 expansion cohort. ASCO 2015. J Clin Oncol 2015;33:abstract LBA6008. [CrossRef]
12. Segal NH, Ou AI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer Jr, et al. Safety and efficacy of MEDI4736, an anti-PDL1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. ASCO 2015. J Clin Oncol 2015;33:abstract 3011. [CrossRef]
13. Bang Y, Chung H, Shankaran V, Geva R, Catenacci DVT, Gupta S, et al. Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK3475) in KEYNOTE-012. ASCO 2015. J Clin Oncol 2015;33:abstract 4001. [CrossRef]
14. A El-Khoueiry AB, Melero I, Crocenzi TS, Welling TH, Yau TC, Yeo W, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. ASCO 2015. J Clin Oncol 2015;33:abstract LBA101.
15. Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Matsumara N, et al. Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. ASCO 2015. J Clin Oncol 2015;33:abstract 5570. [CrossRef]
16. Varga A, Piha-Paul A, Ott PA, Mehnert JM, Berton-Rigaud D, Johnson EA, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: interim results from a phase Ib study. ASCO 2015. J Clin Oncol 2015;33:abstract 5510. [CrossRef] 
17. Emens LA, Braiteh FS, Cassier P. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18–22. Philadelphia, PA: American Association for Cancer Research; 2015. p. Abstract 6317.
18. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. [CrossRef]
19. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015;372:311–9. 
20. Moskowitz CH, Ribrag V, Michot JM. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Blood 2014;124:abstract 290. [CrossRef]
21. NIH. Surveillance, epidemiology and end results program. Available at: http://seer.cancer.gov. Accessed Dec 15, 2022.
22. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–64. [CrossRef]
23. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33:1889–94.
24. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13:227–42.
25. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012;18:6580–7.
26. Crane CA, Panner A, Murray JC, Wilson SP, Xu H, Chen L, et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 2009;28:306– 12. [CrossRef]
27. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7- H1 expression and immunoresistance in glioma. Nat Med 2007;13:84–8. [CrossRef]
28. Hayflıck L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585–621.
29. Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, et al. Aging of the immune system: Focus on inflammation and vaccination. Eur J Immunol 2016;46:2286–301.
30. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6:2853–68. [CrossRef]
31. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007;128:92–105. [CrossRef]
32. Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 1993;23:2375– 8. [CrossRef]
33. Tu W, Rao S. Mechanisms Underlying T Cell Immunosenes-cence: Aging and Cytomegalovirus Infection. Front Microbiol 2016;7:2111. [CrossRef] 
34. Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immun Ageing 2008;5:11. [CrossRef] 35. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 2005;102:9194–9.
36. Berent-Maoz B, Montecino-Rodriguez E, Dorshkind K. Genetic regulation of thymocyte progenitor aging. Semin Immunol 2012;24:303–8. [CrossRef]
37. Wang J, Geiger H, Rudolph KL. Immunoaging induced by hematopoietic stem cell aging. Curr Opin Immunol 2011;23:532– 6. [CrossRef]
38. Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A 2011;108:20012–7.
39. Lin J, Zhu Z, Xiao H, Wakefield MR, Ding VA, Bai Q, et al. The role of IL-7 in Immunity and Cancer. Anticancer Res 2017;37:963–7.
40. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007;447:725–9. [CrossRef]
41. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009;22:1041–50. [CrossRef]
42. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1–10. 
43. Fang M, Roscoe F, Sigal LJ. Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med 2010;207:2369–81. [CrossRef]
44. Metcalf TU, Cubas RA, Ghneim K, Cartwright MJ, Grevenynghe JV, Richner JM, et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 2015;14:421–32.
45. Manser AR, Uhrberg M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother 2016;65:417–26.
46. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA. NK cell and DC interactions. Trends Immunol 2004;25:47–52.
47. White MJ, Nielsen CM, McGregor RH, Riley EH, Goodier MR. Differential activation of CD57-defined natural killer cell subsets during recall responses to vaccine antigens. Immunology 2014;142:140–50. [CrossRef]
48. Hazeldine J, Hampson P, Lord JM. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 2012;11:751–9. [CrossRef]
49. Hearps AC, Martin GE, Angelovich TA, Cheng WJ, Maisa A, Landay AL, et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 2012;11:867–75. [CrossRef]
50. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013;13:875–87. [CrossRef]
51. Fülöp T, Fóris G, Wórum I, Leövey A. Age-dependent changes of the Fc gamma-receptor-mediated functions of human monocytes. Int Arch Allergy Appl Immunol 1984;74:76–9.
52. Nyugen J, Agrawal S, Gollapudi S, Gupta S. Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 2010;30:806–13. [CrossRef]
53. Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 2015;21:938–45.
54. Plowden J, Renshaw-Hoelscher M, Gangappa S, Engleman C, Katz JM, Sambhara S. Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function. Cell Immunol1 2004;229:86–92. [CrossRef]
55. Herrero C, Marqués L, Lloberas J, Celada A. IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest 2001;107:485–93.
56. Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res 2008;68:6341–9. [CrossRef]
57. Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naive T cell maintenance and function in human aging. J Immunol 2015;194:4073–80. [CrossRef]
58. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 2007;211:144–56. 
59. Hirokawa K, Utsuyama M. Combined grafting of bone marrow and thymus, and sequential multiple thymus graftings in various strains of mice. The effect on immune functions and life span. Mech Ageing Dev 1989;49:49–60.
60. Yanes RE, Gustafson CE, Weyand CM, Goronzy JJ. Lymphocyte generation and population homeostasis throughout life. Semin Hematol 2017;54:33–8. [CrossRef]
61. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, et al. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 2000;95:2860–8.
62. Richner JM, Gmyrek GB, Govero J, Tu Y, van der Windt GJ, Metcalf TU, et al. Age-dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of west nile virus infection. PLoS Pathog 2015;11:e1005027.
63. Agrawal A, Agrawal S, Gupta S. Dendritic cells in human aging. Exp Gerontol 2007;42:421–6. [CrossRef]
64. Li G, Smithey MJ, Rudd BD, Nikolich-Žugich J. Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium. Aging Cell 2012;11:968–77. [CrossRef]
65. Sridharan A, Esposo M, Kaushal K, Tay J, Osann K, Agrawal S, et al. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr) 2011;33:363–76.
66. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell 2004;3:161–7.
67. Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis 2011;2:382–97.
68. Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol 2014;192:2689–98. [CrossRef]
69. Whisler RL, Chen M, Liu B, Newhouse YG. Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59fyn/ p56lck in human T cells. Mech Ageing Dev 1999;111:49–66.
70. Wikby A, Johansson B, Olsson J, Löfgren S, Nilsson BO, Ferguson F. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 2002;37:445–53. [CrossRef]
71. Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev 1998;102:187–98. [CrossRef]
72. Farber DL, Yudanin NA, Restifo NP. Human memory T cells: Generation, compartmentalization and homeostasis. Nat Rev Immunol 2014;14:24–35. [CrossRef]
73. Po JL, Gardner EM, Anaraki F, Katsikis PD, Murasko DM. Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev 2002;123:1167–81. [CrossRef]
74. Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol 2009;30:306–12.
75. Verschoor CP, Johnstone J, Millar J, Dorrington MG, Habibagahi M, Lelic A, et al. Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 2013;93:633–7. [CrossRef]
76. Pawelec G. Immunosenescence and cancer. Biogerontology 2017;18:717–21. [CrossRef]
77. Grizzle WE, Xu X, Zhang S, Stockard CR, Liu C, Yu S, et al. Agerelated increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice. Mech Ageing Dev 2007;128:672–80. [CrossRef]
78. Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 2009;124:2621–33. [CrossRef]
79. Tsukamoto H, Senju S, Matsumura K, Swain SL, Nishimura Y. IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat Commun 2015;6:6702.
80. Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, et al. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 2008;181:1835–48. [CrossRef]
81. Foster AD, Sivarapatna A, Gress RE. The aging immune system and its relationship with cancer. Aging health 2011;7:707–18.
82. Funakoshi T, Muss H, Moschus S. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a meta-analysis of randomized controlled trials. [abstract]. Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16–19, 2015; New York, NY. Cancer Immunol Res Philadelphia (PA): AACR, 2016, [Abstract no A159]. [CrossRef]
83. Huang XZ, Gao P, Song YX, Sun JX, Chen XW, Zhao JH, et al. Efficacy of immune checkpoint inhibitors and age in cancer patients. Immunotherapy 2020;12:587–603. [CrossRef]
84. Galli G, De Toma A, Pagani F, Randon G, Trevisan B, Prelaj A, et al. Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer. Lung Cancer 2019;137:38–42. 
85. Xin Yu J, Hodge JP, Oliva C, Neftelinov ST, Hubbard-Lucey VM, Tang J. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Discov 2020;19:163–4. [CrossRef]
86. Granier C, De Guillebon E, Blanc C, Roussel H, Badoual C, Colin E, et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open 2017;2:e000213.
87. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–27. [CrossRef]
88. Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE-001 study. J Clin Oncol 2019;37:2518–27.
89. De Guillebon E, Dardenne A, Saldmann A, Séguier S, Tran T, Paolini L, et al. Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination. Int J Cancer 2020;147:1509–18. [CrossRef]
90. Granier C, Dariane C, Combe P, Verkarre V, Urien S, Badoual C, et al. Tim-3 expression on tumor-infiltrating PD-1+CD8+ T cells correlates with poor clinical outcome in renal cell carcinoma. Cancer Res 2017;77:1075–82. [CrossRef] 
91. Nizard M, Roussel H, Diniz MO, Karaki S, Tran T, Voron T, et al. Induction of resident memory T cells enhances the efficacy of cancer vaccine. Nat Commun 2017;8:15221.
92. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin 2020;70:86–104. 
93. Urwyler P, Earnshaw I, Bermudez M, Perucha E, Wu W, Ryan S, et al. Mechanisms of checkpoint inhibition-induced adverse events. Clin Exp Immunol 2020;200:141–54. [CrossRef]
94. Canouï-Poitrine F, Lièvre A, Dayde F, Lopez-Trabada-Ataz D, Baumgaertner I, Dubreuil O, et al. Inclusion of older patients with cancer in clinical trials: The SAGE prospective multicenter cohort survey. Oncologist 2019;24:1351–9. [CrossRef]
95. Hamaker ME, Vos AG, Smorenburg CH, de Rooij SE, van Munster BC. The value of geriatric assessments in predicting treatment tolerance and all-cause mortality in older patients with cancer. Oncologist 2012;17:1439–49. [CrossRef]
96. Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014;32:2595–603.
97. Pamoukdjian F, Liuu E, Caillet P, Herbaud S, Gisselbrecht M, Poisson J, et al. How to optimize cancer treatment in older patients: an overview of available geriatric tools. Am J Clin Oncol 2019;42:109–16. [CrossRef]
98. Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and metaanalysis. Cancer Treat Rev 2016;45:30–7.
99. Daste A, Domblides C, Gross-Goupil M, Chakiba C, Quivy A, Cochin V, et al. Immune checkpoint inhibitors and elderly people: A review. Eur J Cancer 2017;82:155–66. [CrossRef]
100. Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer 2018;6:26.
101. Ferrara R, Mezquita L, Auclin E, Chaput N, Besse B. Immunosenescence and immunecheckpoint inhibitors in nonsmall cell lung cancer patients: Does age really matter? Cancer Treat Rev 2017;60:60–8. [CrossRef]
102. 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. [CrossRef]
103. Herin H, Aspeslagh S, Castanon E, Dyevre V, Marabelle A, Varga A, et al. Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours. Eur J Cancer 2018;95:68–74. [CrossRef]
104. Elkrief A, Richard C, Malo J, Cvetkovic L, Florescu M, Blais N, et al. Efficacy of immune checkpoint inhibitors in older patients with non-small cell lung cancer: Real-world data from multicentric cohorts in Canada and France. J Geriatr Oncol 2020;11:802–6.
105. Landre T, Taleb C, Nicolas P, Des Guetz G. Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour?. J Clin Oncol 2016;34:1123– 35. [CrossRef] 
106. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627–39.
107. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123–35. [CrossRef]
108. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.
109. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856– 67. [CrossRef]
110. Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016;34:2980–7. [CrossRef]
111. Spigel DR, McCleod M, Jotte RM, Einhorn L, Horn L, Waterhouse DM, et al. Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153). J Thorac Oncol 2019;14:1628–39.
112. Grossi F, Crinò L, Logroscino A, Canova S, Delmonte A, Melotti B, et al. Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme. Eur J Cancer 2018;100:126–34. [CrossRef]
113. Betof AS, Nipp RD, Giobbie-Hurder A, Johnpulle RAN, Rubin K, Rubinstein SM, et al. Impact of age on outcomes with immunotherapy for patients with Melanoma. Oncologist 2017;22:963–71.
114. Rai R, McQuade J, Wang D, Park J, Nahar K, Sosman J. Safety and efficacy of anti-PD-1 antibodies in elderly patients with metastatic melanoma. Ann Oncol 2016;27:379–400.
115. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320–30. [CrossRef] 
116. Chiarion Sileni V, Pigozzo J, Ascierto PA, Grimaldi AM, Maio M, Di Guardo L, et al. Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme. J Exp Clin Cancer Res 2014;33:30. [CrossRef]
117. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18:1483–92.
118. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al; KEYNOTE-045 Investigators. Pembrolizumab as secondline therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–26. [CrossRef]
119. Johnpulle RA, Conry RM, Sosman JA, Puzanov I, Johnson DB. Responses to immune checkpoint inhibitors in nonagenarians. Oncoimmunology 2016;5:e1234572.
120. Kugel CH 3rd, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-Cell populations. Clin Cancer Res 2018;24:5347–56.
121. Ibrahim T, Mateus C, Baz M, Robert C. Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study. Cancer Immunol Immunother 2018;67:1571–8.
122. Pasquini M, Locke F, Herrera A, Siddiqi T, Ghobadi A, Komanduri K. Post-marketing use Outcomes of an anti- CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (Axi-Cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US). Blood 2019;134:764– 78. [CrossRef]
123. Bouchlaka MN, Murphy WJ. Impact of aging in cancer immunotherapy: The importance of using accurate preclinical models. Oncoimmunology 2013;2:e27186. [CrossRef] 
124. Impact of age on the toxicity of immune checkpoint inhibition. A. Samani ,S. Zhang, S. Merrick, J Immunother Cancer 2020;8:e000871.
125. Spigel D, Schwartzberg L, Waterhouse D, Chandler J, Hussein M, Jotte R. Is ivolumabsafe and effective in elderly and PS3 patients with non-small cell lung cancer (NSCLC)? Results of CheckMate 153. J Thorac Oncol 2017;12:1023–35. 
126. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: Immune aging & checkpoint inhibitors. J Geriatr Oncol 2017;8:229–35. [CrossRef]
127. Friedman C, Horvat T, Minehart J, Panageas KS, Callahan M, Chapman P. Efficacy and safety of checkpoint blockade for treatment of advanced melanoma (mel) in patients (pts) age 80 and older (80þ). 2016 ASCO Annual Meeting I. J Clin Oncol 2016;34:1001–20. [CrossRef]
128. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/ PD-L1. Clin Cancer Res 2017;23:1920–8.
129. Ratner L, Waldmann TA, Janakiram M, Brammer JE. Rapid progression of adult T-Cell leukemia-lymphoma after PD-1 inhibitor therapy. N Engl J Med 2018;378:1947–8.
130. van Holstein Y, Kapiteijn E, Bastiaannet E, van den Bos F, Portielje J, de Glas NA. Efficacy and adverse events of immunotherapy with checkpoint inhibitors in older patients with cancer. Drugs Aging 2019;36:927–38. [CrossRef]

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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing