Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?

Abstract

Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients.

Family History of Cancer as Surrogate Predictor for Immunotherapy with Anti-Pd1/Pd-L1 Agents: Preliminary Report of the Fami-L1 Study

“…A possible explanation could be represented by the higher incidence, among young patients, of very aggressive forms of cancers (such as renal carcinoma with Xp11.2 translocation). Our result of a statistically significant benefit in OS for patients with non-EO of cancer compared with whom with EO of cancer meets halfway the opposite evidences of immunosenescence and residual immunocompetence in elderly patients [42,43]. The statistically significant correlation between sex and median OS at multivariate analysis, in favor of female patients, remains partly unexplained, and needs further confirmations.…”

Immune Checkpoint Inhibitors in Real‐World Treatment of Older Adults with Non–Small Cell Lung Cancer

“…Whether the efficacy and toxicity profile of ICIs in older patients differs from that in younger patients remains unclear . Concerns have been raised about diminished efficacy of immunotherapy in the older patient population, perhaps secondary to immunosenescence, involving a complex physiologic interplay between both the aging innate and adaptive immune systems . In addition, it is unclear if the efficacy and toxicity profile of ICIs differs by PS.…”

“…18 Concerns have been raised about diminished efficacy of immunotherapy in the older patient population, perhaps secondary to immunosenescence, involving a complex physiologic interplay between both the aging innate and adaptive immune systems. [18][19][20][21] In addition, it is unclear if the efficacy and toxicity profile of ICIs differs by PS. To address these knowledge gaps, we conducted this study to evaluate the efficacy and toxicity of ICIs in older patients with advanced NSCLC seen in routine clinical practice.…”

Durvalumab in frail and elderly patients with stage four non-small cell lung cancer: Study protocol of the randomized phase II DURATION trial

“…In addition, it remains an unresolved question whether efficacy of checkpoint inhibitors in older patients is affected by a still poorly characterized phenomenon referred to as immunosenescence, i.e., the global and progressive remodeling of immune functions with aging [14,15,18,19]. Age-related alterations such as impaired T-cell activation, reduced T-cell receptor diversity, altered antigen-uptake and -presenting functions, or the increased generation of immune suppressive cells may impair the antitumor response and thus could be one of the reasons for a higher incidence and prevalence of most cancers in older people.…”