Immunotherapy in older patients with cancer

Abstract

Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated CD4 and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.

Getting older implies several changes. Particularly, ageing is accompanied by biological senescence. The process of cellular senescence was first described on fibroblasts by L. Hayflick in the early 1960s. Indeed, he reported a maximum proliferative lifespan of in vitro primary human fibroblasts [1]. This process characterizes the replicative senescence. One of the processes leading to replicative senescence is the telomere shortening when the cell enters in division. Telomeres are repeated hexameric DNA sequences located at the end of the chromosomes that are unable to replicate. This results in the telomere shortening from 11 kb at birth to 4 kb in the old age [2,3].

The senescence mechanism implies tissue ageing, but is useful to avoid malignant transformation of cells. Senescent cells can be cleared by the immune system; however, senescent cells accumulate with age. The immune system itself undergoes senescence. The overall process of immune and non-immune senescence is thought to induce several pathologies linked with ageing.

The cancer incidence increases with age [4]. Chemotherapies are used cautiously in the elderly, because of high risk of side effects in patients with several criteria of frailty. Immunotherapies targeting immune checkpoints, as PD-1 and PD-L1, have emerged recently as a new therapeutic class in the field of cancer with a good response rate and less side effects in average compared to chemotherapies. Immunotherapies constitute an excellent alternative option in the elderly. Focusing in the elderly population treated by this immunotherapy is necessary in our world with increasing lifespan.

Immunity, ageing and cancer

Variation of immune parameters with age

During life, the immune system is shaped by several environmental factors, sex and age.

The naïve T cells are released by the bone marrow and mature into the thymus from birth. They protect against all the encountered pathogens during the childhood. The progressive thymus involution and loss of T cell repertoire occurs during ageing and are well characterized in older people. In the thymus, the epithelial space that nurtures developing thymocytes is reduced with age, benefiting to the perivascular space that contain adipocytes. In the thymus microenvironment, the stromal cell functions are diverted as well. This leads to decrease in IL-7 secretion that plays an important role for T cell ontogenesis into the thymus [5,6].

Hematopoietic stem cells loss progressively their repopulation capacities and homing abilities [7]. The hematopoiesis is reoriented toward myeloid versus lymphoid lineage. Increase of IL-6 during ageing could play a role in this differentiation bias as shown in murine models. Myeloid phagocytic cells have higher capacities to secrete pro-inflammatory cytokines but are less able to exert their activity against pathogens [8].

The whole cytokine network progresses with a ‘secretory associated senescence phenotype’ or SASP. Proinflammatory cytokines (IL-6, TNFα, IL-8, TGFβ, IL-10) are one of the SASP components involved in the chronic progressive increase in the proinflammatory status [9]. This basal inflammatory state could be involved in inflammatory disease development that occurs during ageing [10]. This phenomenon, theorized and named inflamm-aging is provoked by a continuous antigenic load and stress and is accompanied by slightly higher levels of CRP in older people [5,11].

The basal level of cytokines production by monocytes and dendritic cells (DC) is sometimes increased in the elderly. However, in many contexts, the monocyte and DC functionality after Toll-like receptor (TLR) stimulation were found to be altered. This suggests that the TLR-mediated immunity is impaired. Interestingly, the increasing oxidative stress during ageing could be responsible for the subsequent impaired type I IFN response. Plasmacytoid DC, involved in the antiviral rapid response via IFN type I secretion, has reduce capacity to secrete type I IFN in response to TLR or CMV and herpes virus stimulation, probably preventing herpes virus clearance [[12], [13], [14]].

The proportion of individuals seropositive for CMV increases with age. It was suggested that the CMV repertoire takes more and more space in the whole repertoire during ageing. Even if the CMV serological status has been reported to affect various aspects of the immune response, the idea of its implication in the reduction of T cell repertoire has been recently challenged. Highly differentiated CMV specific T cells accumulate and resist to apoptosis [15].

Immune and lympho-senescence

Independently of their specificity, highly differentiated T cells accumulate during ageing. At the cellular level, during T cell differentiation into memory phenotype CD28 and CD27 expressions progressively decrease. At the individual level, the proportion of CD28⁺/CD27⁺ in the whole CD4 and CD8 subsets decreases during ageing. The naïve pool of T cells (CD28⁺ CD27⁺) has been estimated to reduce of 3% per year. In parallel, specific memory T cells accumulate.

CD45RA is lost during the naïve to effector transition and can be reacquired at the very late stages of T cell differentiation. The CD28-/CD45RA⁺ subset called EMRA is the more differentiated. These cells also lack CCR7 homing markers that is lost when the T cell becomes an effector.

CD57 expression frequently accompanied T cell differentiation.

The proliferation capacity of EMRA had been shown to decrease and EMRA T cells harbor shorter telomere length, which are characteristics of cellular senescence [16,17].

Physiologically, the cell proliferation is induced by mitogenic stimuli (growth factors, hormones, nutrients and cytokines) that activate MAPK and mTOR signaling. These pathways induce cyclin D1 and the cell cycle. This drives cell growth that is balanced by cell division. When the cell cycle is arrested by p21 or p16 cell cycle inhibitors, the MAPK and mTOR growth promoting pathway are activated in turn to overcome this block. This induces cell growth in size and without cell division, leading to hypertrophy and hypersecretory phenotype. When the mitogenic stimuli are strong, the geroconversion happens and the senescence becomes irreversible.

A cell that senesces is characterized by a cell cycle arrest with an upstream activation of mitogenic stimulation. Thus, MAP-Kinases increase in T cells during ageing. Particularly, in highly differentiated T cells a complex of Erk, Jnk and p38 accumulates. This complex is coupled together with stress sensing proteins named sestrins. The sMAC (sestrin MAP-Kinase complex) is another intracytoplasmic marker of senescence that has been well characterized in CD4⁺ T cells [18].

During cell differentiation, the metabolism is reoriented. The mitochondria and their functions decline in the EMRA-T cells compare to early differentiation stages. In EMRAs, anaerobic glycolysis becomes predominant and fatty acid oxidation is altered leading to glucose dependence and lipid accumulation [16].

Finally, it seems like late differentiated T cells acquire an NK-like behavior. They recognize cells via non-MHC mediated interaction, harbor narrow TCRβ gene expression and express KIR (that regulate the cell in case of non-self MHC recognition). Highly differentiated T cell can express other NK receptors KLRG1, NKG2D and NKG2A [19,20].

T cell senescence and exhaustion are two different processes to distinguish. Highly differentiated T cells loss proliferative capacities (Ki-67, CFSE), but conserve their functional capacities. They secrete perforin/granzyme cytotoxic granules and cytokines. Even if it is clear that EMRA express more granzyme B and perforin in pheripheral blood, they are less prone to secrete two or three cytokines at the same time (IL-2 and TNFα ± IFNγ) [16,21]. When compared between young and old people, T cell polyfunctionality after a superantigen stimulation is the same (effector memory or effector) or sometimes increase (for naïve T cell subset) for both CD4 and CD8 T cells. This suggests that the immune system adapts from the loss of the T cell pool regeneration and loss of naïve T cells. It has been shown that such CD4⁺ T cells were significantly more functional and cytotoxic in people over 110 years of age in a Japanese cohort [22].These results were observed independently of any TCR specificity. One study reports that melanoma specific T cells secrete less granzyme B in older people so it might be possible that the effect of ageing could impact T cells when they are specific [23].

Conversely, highly dysfunctional T cells named ‘exhausted’ T cells loss their functionality. Multiple inhibitory receptor (PD-1, TIM-3, LAG-3 and CTLA-4) expression occurs in chronic antigen exposure leading to a chronic stimulation and progressively to exhaustion. In many studies, people use these markers to identify exhausted T cells. But these are indirect markers: they are expressed also just after T cell stimulation (to progressively turn off the T cell activation) and can in this case reflect activation [24]. An exhaustive characterization of functional testing (abolition of cytotoxicity/cytokine secretion/death receptor apoptosis induction) should be the best way to identify them [25]. Exhausted T cells are thought to be involved in chronic antigen persistence in certain situations (cancer, HIV, HCV) in which senescence is not involved so far.

Infection and vaccination in the elderly

A couple of studies reported an immune risk profile in patients suffering of healthcare-associated infections. Their rate of naïve subset among CD8 T cells was decreased compared to the patients without healthcare-associated infection. Their CD4/CD8 ratio was lower. In addition, they harbor a higher count of more differentiated and memory CD28⁻ CD8⁺ T cells [26].

Globally viral and bacterial infections have different clinical manifestations and certain are more severe in older compared to younger people. The higher prevalence of infections in the elderly varies according to the pathogen and strain involved. Fever is infrequent in the older patients. Hospitalization rate and institutionalization favor respectively nosocomial and community infections. Pneumonia and urinary tract infections seem to be the more prevalent. Influenza and shingles (VZV reactivation) are of major concern in the elderly as their clinical manifestations are more frequent and/or severe.

The majority of the seasonal influenza related mortality occurs in individual over age 65. However, the majority of the deaths linked with the H1N1 pandemic influenza virus in 2009 touch age 20–49 people. This suggests the presence of antibodies generated after H1N1 strain exposure in the 1950s that could induce cross-protection in the elderly [27]. In anti-influenza immunity, CD8-T cell functionality (IFNg secretion and cytotoxicity) as well as T cell expansion decreases with age [28].

Vaccination represents the main tool today to protect people from flu epidemy, but its efficacy can be limited. In particular, vaccination is thought to be less effective generally in the elderly. This loss of efficacy against flu vaccine in older people was accompanied with lower levels of vaccine-specific antibodies [29]. Clinical data reported that older people vaccinated for the flu can undergo more severe complications compared to younger people. For the H3N2 but not for the H1N1pdm09 strain, the vaccination efficacy is lower in the older population [30].

A link between telomere shortening of immune cells and vaccine decreased efficacy had been suggested. Najarro et al. reported that not only antibodies titer, but also specific CD8-T cell expansion in vitro were higher in influenza vaccinated older people with increased B-lymphocytes count and CD8 telomere length [31]. This reflects the impact of cellular senescence on B and T cellular specific responses with potential clinical consequences.

The frequency and severity of VZV increase with age. This increase seems to correlate with the age decline of VZV-specific cell mediated immunity, while specific antibodies remain stable with aging [32]. In another hand, VZV reactivation occurs in patients with a cellular immune deficiency. These arguments support the role of lymphocyte immunity in the control of VZV reactivation. CD4-T cells seem to be particularly involved, as after VZV challenge with live attenuated antigens, functional and specific CD4-T cell responses significantly decrease with age. This was correlated with a lower clinical score in older people [33]. Among VZV vaccinated people, after 70 years old the efficacy tumble (half efficacy compared to under 70 years) [34]. This loss of vaccine response to live attenuated vaccine seems not to be observed with recombinant VZV vaccine (at least 90% of efficacy against zona in all age groups) [35].

The efficacy depends also on the viral strain, the adjuvant composition or the vaccine formulation.

Immune age defects and pathology

Considering epidemiological data in the elderly leads to the suggestion that an abolished immunity in the elderly favors cardiovascular disease and cancer. Scientific proofs are scarce in the literature.

Cardiovascular morbidities had been correlated with the leukocyte telomere length. The shorter leukocyte telomere length was related with cardiovascular disease events [36,37].

During lifespan, the immune system is less able to differentiate the self from the non-self, leading to increased auto-immunity. Increased risk of auto-immune disease arises during ageing particularly for thyroiditis and arthritis [38,39]. This occurs in parallel with senescent T cells accumulation. These two observations could be linked [40]. Because highly differentiated T cells adopt a non-specific way to recognize their target, it could be that they are becoming sensitive toward self-antigen positive cells. Regarding the fact that immunotherapy targeting PD-1 and PD-L1 awakes auto-immunity with possible severe adverse effects, these considerations are meaningful.

The increase in cancer incidence with age could be an indirect suggestion that the immunosurveillance is weakened by senescence but it does not constitute a scientific proof. CD4 regulatory T cells (T-REG) as well as other immunosuppressive cells like MDSC levels are found to be higher in the elderly [8,41]. A report had shown that less naïve (CD28⁺) and more differentiated (CD28− CD57⁺) percentages among CD8-T cells in PBMCs of lung cancer patients versus controls. Surprisingly some CD57⁺ CD8-T cells were found to express CD28 [42]. In line with the importance of CD28 expression by T cells in the cancer treatment, after anti-PD-1/PD-L1 treatment of lung cancer patients, CD28+ CD8-T cells were found to be highly proliferative (Ki67+). They also expressed less frequently the TIM-3 inhibitory receptor compared with CD28− cells [43].

Biology: senescent cell elimination by the immune system

Cellular senescence is characterized by a cell cycle arrest, which is an advantageous mechanism to avoid the tumor cell transformation. However, during ageing senescent cells accumulate in tissue, responsible for tissue ageing. They are metabolically active and secrete inflammatory mediators that constitute together the SASP (cytokines (see upper)), chemokines, metalloproteases, growth factors and also the reactive oxygen species. The fate of the senescent cell is to undergo apoptosis or to be recognized and eliminated by the immune system. This should at the end protect from cancer development.

Senescent cells can be recognized by NK cells via the MICA/MICB expression and ligation to NKG2D [44].

An in vitro, irradiation-induced senescence on primary fibroblasts leads to non-classical MHC class I MICA/MICB and HLA-E expression. HLA-E can engage NKG2A leading to NK inhibition. In addition, highly differentiated T cells, that are overrepresented in older people, can express NKG2A as well. Therefore the HLA-E expression by senescent cells allows the immune-escape from not only NK but also CD8⁺ T cell mediated cytolysis. HLA-E expression was (i) induced by the IL-6 and other SASP components and (ii) regulated by p38 MAPK that accumulates in the highly differentiated cells. Interestingly in vivo exploration shows that in the old compared to young skins HLA-E was overexpressed in senescent fibroblasts. Finally, HLA-E overexpression in melanocytic nevi may explain their persistence for decades in the tissues despite the CD8⁺ T cell infiltrate [45].

Tumor cell develops more easily in an immunosuppressive microenvironment. In a mouse model it has been proven that the senescent stromal cells drive immunosuppressive myeloid cell accumulation via interleukin-6. In humans, this cytokine is overexpressed in invasive forms of cervical carcinomas [46] and the implication of the intratumor IL-6 in tumorigenesis, aggressiveness and drug resistance was demonstrated. IL-6 and CRP levels (that are both increasing with age) correlated with IL-2 resistance and prognosis in melanoma treated patients [47].

Globally the chronical inflammation, commonly designated as inflamm-aging, could initiate under certain conditions a favorable niche for tumor cell induction.

T cell dysfunction and cancer

The antitumor immunity is also abolished by inhibitory molecules expression on intratumor T cells. Inhibitory receptors are physiologically expressed by T cells after T cell activation in order to stop T cell activation and proliferation. Under certain circumstances with chronic antigen exposure like cancer and chronic infection, these inhibitory receptors can accumulate on T cells. They counteract intracellular TCR kinases signaling. This effect is exerted by dephosphorylation of the TCR-CD3 directly or via CD28, a costimulatory molecule essential for T cells to be activated [48]. CTLA-4 and PD-1 are the two mainly described inhibitory receptors. CTLA-4 appears rapidly after T cell activation and PD-1 accumulates mainly in peripheral T cells after activation. In cancer patients, PD-1 and other inhibitory receptors (TIM-3, LAG-3) are overexpressed by lymphocytes within the tumor compared to peripheral blood [49]. PD-1 is the most famous one, as monoclonal antibodies targeting PD-1 and its ligand PD-L1 are successful in many indications of cancer treatment.

Cancer immunotherapy and cancer management in the elderly

Cancer immunotherapy: a brief overview

Since the first demonstrations of the clinical efficacy of the PD-1/PD-L1 and CTLA-4/CD80-CD86 axis inhibitors, the success of these treatments has continued to be confirmed and expanded. Objective clinical responses to these treatments have been observed in more than 20 types of cancer and marketing approval has been granted for 19 clinical indications (melanoma, NSCLC, renal cell carcinoma, bladder cancer, breast cancer, Hodgkin lymphoma, Merckel carcinoma, MSI-H or dMMR cancer, gastric cancer, hepatocellular carcinoma, cervical cancer, PMBCL, SCLC, cutaneous squamous cell carcinoma, endometrial carcinoma esophagus cancer, colorectal cancer) by the FDA. Anti-PD-1 and anti-PD-L1 represent the immunomodulatory antibodies with the most clinical indications and whose development remains the most important with 2975 clinical trials evaluating these molecules alone or in combination with other treatments at the end of 2019. Seven anti-PD-1 antibodies (Pembrolizumab, nivolumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab) and three anti-PD-L1 antibodies (durvalumab, Atezolizumab, avelumab) are currently available worldwide. The 2nd generation of immunotherapy is based on the combination of several immunomodulators (i.e. anti-PD-(L)1 and anti-CTLA-4) or the association of anti-PD(L)-1 with conventional treatments (chemotherapy, radiotherapy, anti-angiogenic, targeted therapies). These treatments, initially given as 2nd or 3rd line therapy, are currently being evaluated as 1st line therapy or as neoadjuvant therapy and have already obtained FDA approval in patients without prior treatment [[50], [51], [52], [53]].

Recent data obtained with more than 3–4 years of follow-up show that many patients treated with these immunotherapies remain long responders in patients with melanomas, non-small cell lung cancer or clear cell kidney cancer. The overall survival of these patients has significantly increased over the last 5 years with these treatments and some of them could be considered as cured [54]. The expression of PD-L1 or the microsatellite instability status allow in some indications to select patients for these treatments, but these biomarkers remain imperfect and the identification of novel one remains an important medical challenge [55]. Many biomarkers are currently being evaluated (mutational load, IFN signature, expression of checkpoint inhibitors in the tumor microenvironment, microbiota, infiltration by CD8⁺ T cells, etc.) [52,56,57]. Regarding the toxicity of these products, it is now established that PD-1-PD-L1 axis inhibitors as monotherapy are globally well tolerated with grade 3 and 4 side effects less frequent than chemotherapy. Anti-CTLA-4 antibodies alone or in combination appear more toxic [58,59]. This therapeutic revolution led to the awarding of the Nobel Prize to two researchers, Tasuku Honjo and JP Allison, who identified and/or validated the PD-1, PD-L1 and CTLA-4 targets.

Chemotherapy risk/benefit in the elderly

The median age of cancer diagnostic is mainly around 65 according to the National cancer statistic institute: 70 for lung cancer, 63 for melanoma and 64 for kidney [83]. Despite the rapid growth of the older patients with cancer in the real-life setting, they are underrepresented in the clinical trials that set the standards of care in oncology [60]. As a result, there is a lack of evidence on the risk/benefit ratio of cancer treatments in older patients. Comorbidities, organ-specific physiologic changes, disabilities and geriatric syndromes become increasingly prevalent with advancing age and are associated with treatment-related side effects and poorer outcomes [61]. Thus, a major issue for oncologists is determination of the intensity of cancer treatment best suited to each older patient. There is considerable heterogeneity among older patients of the same age, so that chronologic age alone provides little information regarding an individual's tolerance to cancer treatments.

Identifying comorbid conditions and geriatric health domains that increase the risk of toxicities may allow oncologists to better assess the risk/benefit ratio in individual patients, to develop customized treatment adjustments, and to implement interventions designed to decrease the risk of toxicity [61]. Scientific societies recommend a comprehensive geriatric assessment (CGA) to detect multi-domain health problems potentially associated with adverse outcomes, to guide decision making about cancer treatments [62].The assessment is based on validated tools to systematically assess functional, nutritional, cognitive, emotional, and social status as well as comorbidities. Geriatric assessment can help oncologists identify older patients with cancer who could benefit from optimal anticancer treatment and those likely to benefit from adapted treatment [63]. Moreover, CGA allows for organizing early medico-psycho-social follow-up and supportive care, before and during the anticancer treatment, to improve treatment safety and to maintain the quality of life of older patients.

Clinical response to immunotherapy in elderly

Because of the immunosenescence and the data in the literature showing a poorer vaccine response in the elderly, it was expected that the elderly would have a poorer clinical response to treatment with molecules that block the interaction of checkpoint inhibitors with their ligands (anti-PD-1/PD-L1, anti-CTLA-4) [52].

In fact, in the majority of published studies and meta-analyses, people with different types of cancer (non-small cell lung cancer, clear cell renal cancer, melanoma, head and neck cancer), aged between 65 and 75 years, respond as well as the subjects under 65 years. This conclusion was true whatever the response criteria (overall survival, recurrence-free survival, RECIST response) and regardless the location of the cancer. Results from these analysis included both molecules inhibiting the PD-1-PD-L1 axis and anti-CTLA-4 antibodies [[64], [65], [66], [67], [68], [69], [70]].

However, in patients over 75 years of age, some controversies still exist. Indeed, resistance to anti-PD-1/PD-L1 therapy has been observed, particularly in Phase 3 pivotal clinical trials in patients with squamous cell carcinoma or adenocarcinoma of the lung, metastatic clear cell renal cancer and squamous cell carcinoma of the upper aerodigestive tract [[71], [72], [73], [74], [75]]. Nevertheless, in NSCLC, other studies show a benefit of anti-PD-1 treatment in patients over 70 or 75 years of age [[76], [77], [78]].

On the contrary, in patients with metastatic melanoma or advanced bladder cancer, no age limit for response to these treatments has been recorded. In both cancer types, clinical responses in subjects over 70 or 75 years of age have been observed in a comparable manner to younger subjects [[79], [80], [81], [82], [83], [84]]. Anecdotally, in patients with metastatic melanoma, clinical responses have been reported after treatment with anti-PD-1 or a combination of anti-PD-1 and anti-CTLA-4 in patients over 90 years of age [85]. These results and publications are summarized in Table 1.

Table 1.

Outcomes in cancer patients treated by immunotherapy: studies including age group comparisons.

Publication (author, journal, year and study type)	Reference number	Immunotherapy (ies) used	Tumor localisation(s)	Immunotherapy arm	Elderly population		ORR	Overall survival (patients receiving immunotherapy)		Progression free or recurrence free survival		Toxicity (grade 3-4 adverse events unless specified any grades)		Statistical effect on clinical outcome	Conclusion
				n=	Age groups	n=		Median or HR	Statistical difference	Median or HR	Statistical difference	Median or HR	Statistical difference
Elkrief A, J Geriatr Oncol, 2020, retrospective, real life and multicentric cohort	70	Anti-PD-1 and anti-PD-L1 nivolumab, pembrolizum and others	NSCLC	381	<70	257		13,7 months	p = 0,23	3,2 months	p = 0,92	6%		no age interaction with the clinical outcome	No difference according to age groups
					≥70	124		11,6 months		4,3 months		5%
Borghaei H, NEJM, 2015, clical trial versus docetaxel, subgroup analysis	72	Nivolumab	NSCLC	582	<65	339		HR = 0,81							OS comparable in the 65-75 but less better in the ≥ 75 years old group
					65–75	200		HR = 0,63
					≥75	43		HR = 0,9
Brahmer J, NEJM, 2015, clical trial versus docetaxel, subgroup analysis	73	Nivolumab	NSCLC	135	<65	79		HR = 0,52							OS worse in the ≥75 years old group
					65–75	45		HR = 0,56
					>75	11		HR = 1,85
Gettinger SN, JCO, 2015, phase 1	76	Nivolumab	NSCLC	129	<70	90	16.7%								Similar ORR in age groups
					≥70	39	17.9%
Spigel D, J Thor oncol, 2019, phase 3–4b	77	Nivolumab	NSCLC	1426	<70	870		10,3 months		60%		12%	p = ns	ECOG PS = 2 had shorter OS	No difference according to age groups
					≥70	556						14%
					whole	1426		9,1 months		62%					ECOG geriatric score impacts OS
Grossi F, Eur J Cancer 2018, multicentric real-world study	78	Nivolumab	NSCLC	371	<65	126	18%	8,6 months		4 months	ns	3%			No difference in <65 and 65–75 years of age
					65–75	175	18%	8 months		4,5 months		9%
					≥75	70	19%	5,8 months		3,2 months		3%
					whole	371	18%	7,9 months		4,2 months		6%			OS/PFS worse in the ≥ 75 years old group
Landre T, JCO, 2016, sub-group analysis of pooled published randomized control trials versus standard therapy	71	Nivolumab	NSCLC & RCC	687	65–75	541		HR = 0.6	p < 0.0001	HR = 0.78	p = 0.06			age effect depending on the age group	Immunotherapy better than standard therapy in 67–75 but not if ≥ 75 years old
					≥75	146		HR = 1.22	p = 0.36	HR = 1.24	p = 0.43
Motzer RJ, NEJM, 2015, phase 3 versus everolimus	74	Nivolumab	RCC	410	<65	257		HR = 0,78							OS comparable in the 65–75 but worse in the ≥75 years old group
					65–75	119		HR = 0,64
					≥75	34		HR = 1,23
Motzer RJ, NEJM, 2018, phase 3 versus sunitinib	74	Nivolumab + ipilimumab	RCC	425	<65	265		HR = 0,53							OS better in the 65–75 but worse in the ≥ 75 years old group compare to sunitinib
					65–75	125		HR = 0,86
					≥75	35		HR = 0,97
Ferris RL, NEJM, 2007, phase 3 versus standard chemotherapy	75	Nivolumab	Head and neck	228	<65	172		HR = 0,64							OS worse in the 65–75 years old group
					65–75	56		HR = 0,93
Balar AV, lancet oncol, 2017, multicentre phase 2, subgroup analysis	83	Pembrolizumab	Bladder	370	<65	57	30%							in PD-L1>10%, worse ORR in elderly	Similar ORR in age grops
					≥65	25	26%
Bellmunt J, NEJM, 2017, phase 3 versus chemotherapy, subgroup analysis	84	Pembrolizumab	Bladder	270	<65	105		HR = 0,75							Similar ORR in age grops
					≥65	165		HR = 0,76
Betof AS, the oncologist, 2017, retrospective, 2 centers	79	Anti-PD-1 and anti-PD-L1	Melanoma	254	<50	57		22,9 months	ns HR = 0,93	4,1 months	ns HR = 0,98	any 38,6%			No difference according to age groups
					50–64	85		25,3 months	ns HR = 0,88	6,5 months	ns HR = 0,82	43.50%
					65–74	65		22 months	ns HR = 0,83	5,4 months	ns HR = 0,85	49.20%
					>75	47	1	24,3 months	HR = 1	7,9 months	HR = 1	40.40%
Rai R, annal oncol, 2016, retrospective and multicentric analysis	80	Pembrolizumab and nivolumab	Melanoma	283	≤75	256	34%	48,1 months	p = ns	4,6 months	p = ns	any 37%	p = ns		No difference according to age groups
					>75	35	48%	33,5 months		8,7 months		40%
Robert C, NEJM, 2015, phase 3 versus dacarbazine, subgroup analysis	81	Nivolumab	Melanoma	210	<65	106		HR = 0,52							OS similar in the 65–75 and better in the ≥75 years old group compare to sunitinib
					65–75	77		HR = 0,44
					>75	27		HR = 0,25
Chiarion Sileni V, J Exp Clin Cancer Res, 2014, multicentric pooled analysis	82	Ipilimumab	Melanoma	833	≤70	645		3,7 months	p = 0,17	7 months	p = 0,33	any 36%	p = ns		No difference according to age groups
					>70	188		4 months		8,9 months		any 33%
Kugel CH, clin cancer research, 2018, restrospective multicentric + preclinical model	88	Pembrolizumab	Melanoma	538	<62	238				progression 48%	p = 0,02				Probability of progression significantly decreases with age
					≥62	300				37%

Abbreviations: HR: hazard ratio; ns: non significant; NSCLC: non small cell lung cancer; OS: overall survival; ORR: overall response rate; RCC: renal cell carcinoma.

It therefore appears that there may be a difference in sensitivity to immunotherapy in people over 75 years of age depending on the location of the tumour, although these results deserve to be validated on larger series of patients. In addition, older adults are often underrepresented in clinical trials because of selective inclusion criteria, such as a good performance status, normal hepatic and renal function, and no autoimmune disease.

More recent studies in patients with metastatic melanoma suggest that anti-PD-1 treatments may be more effective in elderly patients with a threshold of 60–80 years of age to define this group of patients [86,87]. In order to explain this paradoxical effect, the authors showed in both elderly mice and melanoma patients treated with anti-PD-1, an increased ratio of the number of CD8⁺ T cells to regulatory T cells [86]. Another hypothesis to explain this better response of elderly subjects to immunotherapy would be that the tumour of these patients would present more mutations or neoantigens because of a longer exposure to environmental carcinogens. It is interesting to note that in another form of immunotherapy based on the administration of T cell with a receptor composed of antibodies fragment (scFv) directed against the CD19 molecule (CAR T cells) in patients with large cell lymphomas, the elderly have the same response rate as younger subjects, but more complete clinical responses (62% vs. 46%) [88].

Immunotherapy toxicity

Due to preclinical data in mice showing that immunotherapy resulted in often rapid and sometimes lethal toxicity in older mice compared to younger mice [89], the follow-up of side effects in patients treated with immunotherapy was particularly well analysed. Overall, no more general or severe (particularely for grade 3 or 4) adverse events were observed in elderly patients treated with immunotherapy compared to the general population or younger patients [Table 1]. This lack of increase in adverse events was reported for both anti-PD-1/PD-L1 or anti-CTLA-4 monotherapies and anti-PD-1 and anti-CTLA-4 combination therapies [69,78,82,90,91]. Although the thresholds varied from one study to an other to define the elderly, these cohorts included patients between 70 and 80 years of age, which seems to rule out a threshold effect.

A few studies have reported a slight increase in toxicity with anti-PD(L)-1 and anti-CTLA-4 combination therapies in people over 80 years of age [92,93].

Different studies have reported a risk of hyperprogression under anti-PD-1/PD-L1 immunotherapies with variable frequency depending on the authors and the tumour location [94,95]. Although the studies reported conflicting results, it should be mentioned that in one publication, age has been associated with a risk of hyperprogression under immunotherapy [94].

Although the frequency of side effects of immunotherapy does not appear to be significantly higher in the elderly, the impact of these effects may be more pronounced in the elderly due to co-morbidity and lack of functional reserve.

Finally, there is clear evidence that immunotherapy by blocking the PD-1-PD-L1 axis is less toxic than chemotherapy in the elderly [96].

Recommendations and concluding remarks

Initial studies are quite reassuring about the use of immunotherapy in the elderly. The risk of toxicity does not seem to increase significantly and reproducibly with the age of the patients. Clinical efficacy in patients under 75 is well demonstrated. Beyond 75 years of age, the studies are more contradictory. Differences in response depending on tumor location may exist in the elderly. Nevertheless, the limitations and potential biases of these studies must be considered. Indeed, in the majority of cases, the influence of age is sought from retrospective studies, where the number of elderly patients is not very large. The threshold for defining an elderly person is variable across studies (between 65 and 75 years of age) often making meta-analyses difficult. In the protocols, elderly patients are selected on the basis of fairly strict criteria (performance status: 0–1), which probably eliminates patients with significant comorbidities. No in-depth Geriatric Evaluation (functional status and mobility, number of drugs, comorbidities, mood and cognitive disorders, nutritional status …) has been performed during these different protocols. A global assessment of frailty could improve the future studies.

Perspective in immunotherapy management in older patients

The immune system is challenged from the birth and during lifelong. As all the cells in our body, it undergoes several changes, more or less characterized so far. Its remodeling induced by ageing varies among people according to their environment, sex and age leading to immunosenescence. There are several studies linking telomere length with several pathologies. The telomere length attrition had been linked with many comorbidities factors in the elderly, while it seems to be improved by favorable social context and sport activity [97]. It might be therefore possible that some immunosenescence patterns are linked with frailty degree of the older patients. The elderly whom health support is delicate rightly because of their weakness would benefit form a scoring of these criteria. The geriatric assessment already includes an evaluation of the frailty with scoring like GCA. Immunosenescence markers are known, but does not benefit to the clinical practice so far. In cancer patients, few studies exist. Anti-melanoma T cells are less functional in the old versus young people [23]. However, at the basal level, the functionality of the ageing T cells, but also DC, NK cells and monocytes is preserved if not enhanced. B and T cells senescence seem to also impair vaccination against VZV and influenza that induce severe infections in the elderly. In another hand, in the HIV-infected individuals, persistent replication of HIV leads to antigen specific and non-specific differentiation and proliferation of T cell subsets and ultimately, to accumulation of highly differentiated immunosenescent cells characterized by a lack of CD28 expression, an increase in the expression of CD57 and a decrease in leucocyte telomere length compared to HIV negative people [98]. These are arguments to reinforce the studies of the immune system differentiation in the contexts like cancer. Finding the contexts in which the immune-age is more important for the treatment strategy than the chronological age is challenging. In the future, it will be ideal to find a way to score or stratify immunosenescence. This score could be used to monitor anti-cancer immunotherapy and vaccination in the elderly.

Concerning the use of immunotherapies in the elderly, the subgroup or pooled analysis are reassuring regarding the safety and the clinical response. But the criteria to fit inclusion in industrial trials are often drastic leading to potential risk of inclusion bias in favor to the healthier older people that could be over-represented in these studies. Real-life clinical data are thereby very informative. A retrospective study in lung cancer patients treated by immunotherapy in real-life practice suggests that patients over 70 years old may have a shorter overall survival than younger. This is regarding the fact that in the whole population the elderly also have shorter survival. The progression free survival was shorter as well, but at a lesser extend (p = 0.012). Finally, the toxicity was identical between the 2 sub-groups [99]. Furthermore, the age comparison results of immunotherapies could be organ and molecule-dependent. A geriatric evaluation of the frailty criteria is lacking in the existing studies. Whatever the case, even if these data has to be confirmed, the practitioners should be aware. Other larger studies conducted in a geriatric population with an evaluation of their frailty are needed to draw a more precise conclusion.

Conflicts of interest

The authors have no conflict of interest to declare.