P-ISSN 2587-2400 | E-ISSN 2587-196X
EJMO. 2022; 6(4): 271-281 | DOI: 10.14744/ejmo.2022.50386

Immunotherapy in Elderly Patients: A Review

Alfredo Colombo1, Concetta Maria Porretto1
1Department of Oncology, Casa di Cura Macchiarella, Palermo, Italy,

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, including drugs directed against immune checkpoint PD-1, PD-L1 and CTLA-4, have become a consolidated treatment strategy regarding various kinds of tumours, with an effective response, and good tolerability towards patients. Older patients, aged over 65 years, constitute a large portion of neoplastic population, and are increasingly represented in medical oncology clinics. Unfortunately, however, these patients are underrepresented in randomized clinical trials, and we also know that with aging the microenvironment and immune cells undergo marked changes that are defined with the term of immunosenescence. In this review we will consider the various studies on immunotherapy in elder patients, 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. Key words: Immunotherapy, aging, cancers, anti PD-L1, safety

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Colombo A, Porretto C. Immunotherapy in Elderly Patients: A Review. EJMO. 2022; 6(4): 271-281

Corresponding Author: Alfredo Colombo

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Introduction Age is a major cancer risk factor, and it is associated with poor prognosis [1-2]. The exciting revolution of development of Immune Checkpoint Inhibitors (ICIs) in Oncology raises high expectations for our elder patients. Indeed, ICIs have been approved for melanoma, non-small cell lung cancer, renal cell cancer and others type of malignancy [3-8]. Immunotherapy has encountered great results in the treatment of cancer, as in lung cancer where an ORR of 15% [9] was obtained, in urothelial tumors (ORR 25%) [10], in HNCs (ORR 20%) [11,12], gastric cancer (ORR 20%) [13], hepatocellular carcinoma (ORR 20%) [14], ovarian cancer (15 %) [15,16], triple negative breast cancer (ORR 20%) [17], mismatch deficient repair colon cancer (ORR 60%) [18], and Hodgkin lymphoma (ORR 65-80%) [19,20], with new indications in progress in different districts. Moreover, ICIs monotherapy obtained an excellent toxicity profile. Half of the patients diagnosed with neoplasia have an average age above 65 years and thanks to the good toxicity profile of immunotherapy this becomes a good option in curing elderly patients [21]. But the full efficacy and toxicity of these drugs are still widely unknown and unfortunately in randomized clinical trials, the percentage of elderly patients included is very low. Furthermore, comorbiditiy and the aging of the immune system can affect the efficacy and tolerability of these drugs. In this review, we will consider the efficacy of ICIs in the elderly population and evaluate toxicities and its management. Metods We have carried out a careful search of the full papers on PubMed (www.ncbi.nlm.nih.gov/pubmed/, accessed on 30 June 2022) starting from 2017, inserting as keywords "Immunotherapy, aging, anti PD-L1" The full articles found have been reviewed in detail. In addition, all abstracts from international congresses from 2020 to June 2022 were reviewed. How targeting immune checkpoints works. Immune checkpoints are a class of receptor-ligand that modulate the immune response. In fact, after the recognition of the antigen by the T cell receptor (TCR), the T-cell response is regulated by suppressor or stimulatory mechanisms influenced by immune checkpoint inhibitors (ICIs). Their function is to maintain self-tolerance, limiting the immune response over time [22]. Unfortunately, cancer cells do acquire the ability to divert the immune system by blocking it with the insertion on the cell surface of immune checkpoints capable of inhibiting the cells of the immune system from recognizing and destroying neoplastic cells. Immune checkpoint inhibitors can restore the immune system, activating, and prolonging the immune system's response against neoplastic cells [23]. To date, many immune check points have been identified, but only few have found therapeutic use in clinical practice such as anti CTLA-4, anti PD-1 and PD-L1. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) CTLA-4 is one of the best-known immune check point (ICs). It interacts with TCR, CD 28. CD 28 and CTLA-4 also share the same ligand: CD 80 (also known B7.1) and CD 86 (also known B7.2). CTLA-4 has a high affinity whit ligands. It is expressed on surface of CD 4 +, CD 8+ T cell and regulatory T cells (Tregs). The hyperactivity of CTLA-4 increases the suppressor function of Tregs, while reducing the production of IL-2 with less expression of the IL-2 receptor. By blocking this Immune checkpoint, the T cell cytotoxicity is amplified with simultaneous inhibition of Tregs, stimulating and reactivating the anti-neoplastic function of the immune system. PD1/ PDl-1 pathway PD 1 is another immune check point that is expressed by T lymphocyte cells in peripheral tissues. It recognizes two ligands: PDL-1 and PDL-2, both expressed on antigen presenting and tumor cells [22,23,24,25]. This is an immune evasion mechanism, which puts the cancer cell in place to slow down the immune system. This process can be intrinsic through constitutive oncogenic signalling, or secondary to a hyper production of IFN gamma [26,27]. Thus, by inhibiting these Immune checkpoints with ICIs, a prolonged response from the immune system can be achieved with a long control of tumor growth. Immunosenescence and tumorogenesis. As we age, all organs undergo a slow and gradual process of deterioration. In non-malignant cells, there is a reduction in duplication velocity after a reduced number of passages [28]. Cellular aging is associated with changes in chromatin structure, with excessive accumulation of DNA damage, mitochondrial dysfunction, and reactivation of oncogenes [29]. Unlike dormancy cells, senescent cells still maintain the ability to secrete soluble factors in the surrounding environment, controlling processes that affect inflammation and tumorigenesis [30]. Furthermore, the cellular aging process induces a state of chronic inflammation caused by the secretion of pro-inflammatory cytokines such as interleukin 1? (IL-1?), interleukin 18 (IL-18) and tumor necrosis factor– ? (TNF-?) [31]. Inflammation also causes some age-related diseases such as cardiovascular disease, degenerative brain disease and cancer. This process is called inflammageing Fig. 1 [32]. The mechanism that causes inflammation is not well known. Immunosenescence determines a continuous remodelling of the immune system with its reduced functioning, even if there are no objective parameters to evaluate this process, even if the low levels of chronic antigenic stimulation, together with Cytomegalovisrus (CMV) infections, suggest this [33]. The aging of the immune system determines a reduced immunosurveillance and therefore an increase in the onset of infections and cancer. Haematopoietic stem cell (HSC) aging Changes occurring in the HSC are due to impaired immunosurveillance and tumorigenesis. Furthermore, there is also an imbalance in the production of blood elements with a reduction in the lymphocyte share at the expense of the myeloid series [34,35,36,38]. This imbalance is caused by the reduction in production of IL 7, produced by stromal cells, an important cytokine that intervenes in the maturation of lymphoid cells [39]. This shift towards the myeloid series, associated with the accumulation of reactive oxygen species (ROS), could also explain the increased occurrence of myeloid leukaemia in the elderly population [40]. The aging of the bone marrow, with an increase in the adipose component, also intervenes in the process of reduced production of the cellular component [41]. Immunosenescence and tumor antigen release. Cancer cells, over time accumulate genetic and epigenetic alterations with an increase in the expression of neo - antigens [42]. With the aging process, a reduced capacity for expression of neoantigens has been seen with consequent declined immune response, explained by the impaired response of immune cells to cytokines (IL-2 and IL-12) [43]. The changes observed also in the ratios between cells of the myeloid compartment, may favour the activation of cells with an inflammatory phenotype instead of a cytotoxic phenotype [44]. NK cells are another group of immune cells that malfunction during aging. Specifically, a variable NK activity was observed in elderly subjects [45,46]. Furthermore, reduced cytotoxicity of CD 56/CD 16 cells was noted in elderly patients, because of a lower expression of activating receptors such as NKG2A [47]. We observed furthermore monocytes/macrophages malfunction with aging with reduced superoxide production [40-50] and decreased antibody dependent cell mediated cytotoxicity activity [51]. In addition, an increase in danger associated molecular patterns DAMPs [52] and a reduction in lymphocytes ?? were observed [53]. Tumor antigens are processed by cells presented antigens (APCs) whih together MHC class I present it to T lymphocytes. Ageing is characterized by a reduction in the number of APCs and a consequent reduction in the adaptive immune response [54-56]. A reduced production of T cells has been demonstrated in the thymus in the elderly 57. This occurs because the normal stroma of the thymus is replaced by adipose tissue [58,59] with consequent production of pro-inflammatory cytokines [60]. Furthermore, the CD4 / CD8 ratio is altered due to an increase in CD8 [61] After being produced in the thymus, the T cells migrate to the lymph nodes, where they mature. This trafficking has been found to be reduced in older mice [62]. Furthermore, with aging, an increase in the number of memory cells has been observed, with loss of CD 28 expression and consequent loss of proliferation arrest with increased apoptosis [67]. In addition, the reduction of naive T-cells is associated with a decrease in the repertoire of the T cell receptor (TCR) [68]. On the other hand, no structural changes were observed in the TCR but downstream signalling events were described [69]. T cell, with ageing, are characterised by a decline in control to kill tumour cells because of they are the principal effector of antitumor response. The immunonosenescnece of these cells are being associated with a poor outcome [70-71]. T cells undergo notable changes during aging even after 65 years [72]; a reduction in activity of CD 8+ and CD 4+ has been shown after an infectious stimulus in elderly patients [73, with reduced production of perforins and granzyme [74]. Furthermore, myeloid-derived suppressor cells (MDSCs) also undergo changes with the process of aging [75], secondary to the increase in pro-inflammatory cytokines [76], with an immunosuppressive activity [77-78-79], consequent to the increase in Treg [80]. Furthermore, during aging, CD 4+ cells differentiate towards a regulatory phenotype [81]. Efficacy data of ICIs in elderly patients In clinical practice some molecules have been approved by EMA/FDA, such as anti CTLA-4 (Ipilimumab) and anti PD-1/ PDL-1 (Nivolumab/ Pembrolizumab). We have a meta-analysis published in 2015 where has been studied ICIs efficacy in older patients compared with younger [82]. This analysis included 5265 patients treated in nine clinical trials phase III and II, with 5 trials in patients with melanoma, 1 with prostate cancer, 2 with lung cancer and 1 with renal cell carcinoma. Five trials had as cut- off age 65 years, and one had 70 years as limit between old and young patients [Table 1]. In 2078 young patients the pooled HR for overall survival had a significance difference respect to control (HR, 0.73; 95% CI, 0.66–0.81; p < 0.001). In older patients, 1244, at the same way, the pooled Hazard ratio for overall survival of ICIs treatment reached a significance difference regarding the control (HR, 0.72; 95%CI, 0.58–0.90; p = 0.004). Moreover, in this meta-analysis we didn’t have differences statistically significant for HR overall survival between old and young patient (p=0.93). Another large meta?analysis of 34 randomized studies including a total of 20511 patients, Huang et al. reported that patients aged >65 years derived similar overall survival (OS) (HR 0.79 vs. 0.76) and progression?free survival (PFS) (HR 0.77 vs. 0.69) benefits compared to those of their younger counterparts from immunotherapeutic agents [83]. Patients aged 75 years or more did not derive a definite PFS or OS benefit with ICIs; however, these results may have been confounded by the small number of patients in this age group. Finally, Galli et all. reviewed 290 cases, with a median age of 67 (range: 29–89). Patients aged <70, 70–79 and ?80 year-old were 180, 94 and 16, respectively. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class [84]. Response Rate (RR) was similar across age groups (p 0.9470). Median Progression Free Survival (PFS) and Overall Survival (OS) did not differ according to age (p 0.2020 and 0.9144, respectively). Toxicity was comparable across subgroups (p 0.6493). The only variables influencing outcome were performance status (PS) (p < 0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and ICIs line (p < 0.0001 for both PFS and OS). Cancer immunotherapy and cancer management in the elderly Since the first results of preclinical studies of drugs blocking the PD-1/ PDL-1 and CTLA- 4/CD80 axis have been obtained, there has been a rapid and ever-increasing application in clinical practice such that today the FDA approved indications are in nearly over 20 different types of cancers. Anti PD-1 and anti PDL-1 represent the class of drugs with the greatest use in clinical practice, with nearly 3000 clinical trials both in single agent and in combination with other treatments. Today we have seven anti PD-1 drugs (Pembrolizumab, Nivolumab, Cemiplimab, Sintilimab, Carmelizumab, Toripalimab, Tislelizumab) and three anti PDL-1 antibodies (Atezolizumab, Durvalumab, Avelumab). Furthermore, combinations of two immunotherapeutic agents or the association of an immunotherapy with chemotherapy, radiotherapy or anti-angiogenic drugs were studied. Studies have tested them in the second or later lines, but now we also have encouraging results in the first line or in the neo adjuvant setting [83,86]. Having the follow-up data at more than 5 years, we have seen that treatment with immunotherapy prolongs life and, in some cases, we can consider them to be long-survival [87]. The research of PDL-1 levels and microsatellite instability (MSI), allows to better select the patients who respond to immunotherapy, but given the recent results, new response drivers are always sought to better select the patient responders. For this reason, new biomarkers are being evaluated (tumour mutational burden, Interferon signature, lymphocyte infiltrate, microbiome [85,89,90]. Regarding toxicity, anti PD-1 and anti PDL-1 are more tolerated than chemotherapy, with a few G3-G4 toxicity. Instead, drugs that act on the CTLA-4/CD 80 axis, are more toxic [91,92]. Elderly and treatment From the data of the national cancer statistic institute, the average age of onset of tumours is 65 years; 70 years for lung cancer, 63 years for melanoma and 64 years for kidney cancer, 71 for colon cancer. [93]. Despite the lengthening of the average life span of the population, the elders are still underrepresented in randomized clinical trials [94,95]. So, we don't have the risk / benefit results in this population. In geriatric patients, comorbidities, organ dysfunction and geriatric syndrome heavily influence treatment outcomes and toxicity. Therefore, there is less scientific evidence in this patient setting, leaving open issues for oncologists, who must deal with oncological disease in patients where chronological age often does not coincide with clinical conditions. It is very important to use tools that can give us clear information on the real clinical conditions of the elderly in order to intensify or reduce the oncological treatment [96]. For this reason, scientific societies recommend the comprehensive geriatric assessment (CGA) to evaluate multi domain health problems capable of influencing treatment outcomes [97]. These tools evaluate together the social, nutritional, cognitive, behavioural status, together with comorbidities. From the obtained results, the oncologist can treat the elderly patients with standard treatment or with a dose reduction, adapting therapy to the clinical condition, or referring them only to best supportive care (BSC) [98]. Elderly and response to immunotherapy In the elderly, where the immune system lost its functions, with a response in which type B cells, Natural killer (NK) and dendritic cells (DC) are involved, considering that they respond less to vaccination, it could think that they respond consequently less to drugs that block the PD-1/PDL-1 or CTLA-4/CD80 axis [99]. However, there are still doubts about the efficacy of immunotherapy in patients over 75 years of age, especially regarding the response compared to the organ under consideration. In pivotal phase III trials, we have immunotherapy patients not responders over 75 aged, in non-small cell lung cancer, metastatic renal cancers and in tumors of the upper GI [98-109] However, other studies carried out in non-small cell lung cancers have shown an advantage in immunotherapy even in patients over 70-75 years old [110-112]. In metastatic bladder cancers and metastatic melanomas, no differences were observed between elderly and younger patients [113-118]. Specifically, anecdotal responses have been observed in 90-year-old patients with metastatic melanoma, associating anti PD-1 with anti CTLA-4 [119]. But in some studies of metastatic melanomas in the elderly aged 60-80 years, a better response to immunotherapy was observed [66,67] with a greater number of CD 8+ cells respect to regulatory T cells (Treg) [120]. A possible explanation for this paradoxical result is that elderly patients have a greater burden of antigenic mutations, linked to the long period of exposure to carcinogenic agents. Immunotherapy and toxicity in elderly Since in animal models, immunotherapy treatment showed a high rate of toxicity in elderly mice, this aspect was carefully controlled in randomized clinical trials, where an equal level of G3 toxicity was observed in elderly and young patients [123]. This was noted both in monotherapy with anti PD-1, PDL-1, and anti CTLA-4 and in anti PD-1 and anti CTLA-4 combination, even if in various studies considered the threshold age for defining an elderly patient between 70 and 80 years, demonstrating that there is no threshold value [93,122,126,124,125]. However, a limited number of trials have shown greater toxicity in patients over 80 years of age treated with anti PD-1 in combination with anti CTLA-4. (126,127) Furthermore, in many works, a phenomenon called hyper progression, has been highlighted during treatment with immunotherapy, with variable frequency depending on the authors and the tumour location [128,129]. Although there are different results, in one of them, older age correlated with a higher frequency of hyper progression during treatment with immunotherapy [128] Even if the percentage of side effects in elderly patients has been the same as that of younger, the different impact in the elderly population has to be still considered, given the reduced functional reserve of the various organs of this vulnerable population. However, there is great evidence that immunotherapy is less toxic than chemotherapy in the elderly [130]. Conclusion All studies to date, have shown that immunotherapy is safe and effective in patients under 75 years old. On the other hand, contradictory data are present in the elderly population over 75 years old because of a very small number of this population represented in randomized clinical trials. Furthermore, in these patients the response also depends on the tumor location. Consideration should be given to the high bias caused by the small number of patients and the retrospective nature of many studies. Furthermore, the threshold for defining elderly patients varies from study to study with values ranging between 70 and 75 years, making the meta-analysed data not very homogeneous and difficult to understand. Furthermore, in the clinical trials, the conditions of the patients were only evaluated with the Performance Status (PS), without performing any multidimensional evaluation tests. However, the subgroup data of pooled analysis comfort us in the use of immunotherapy in elderly patients, where the efficacy has been found to be comparable respect to younger population. The toxicities also seem to be the same between the elderly and young population, although in subjects over 80, the combination of anti PD-1 / PDL-1 with anti CTLA-4 showed greater toxicity. 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