You are viewing the site in preview mode

Skip to main content

Advertisement

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Abstract

Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.

While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.

The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.

Introduction and rationale

Small-cell lung cancer (SCLC) globally accounts for 13–15% of all lung malignancies. It is a highly aggressive neuroendocrine tumor, characterized by rapid growth and early tendency to widespread metastasis; stage IV disease represents over 70% of new diagnoses. Clinical onset is often associated with heavy symptomatic burden and rapid decline of overall health [1].

Chemo- and radiotherapy still represent the mainstay of treatment and an initial high responsiveness to such treatments is often observed [2, 3]. Recurrence, however, occurs very early in most cases, leading to a very dismal prognosis and a 5-year overall survival (OS) of 14.7–27.3% and 2.8% for early-stage (LD) and extended disease (ED), respectively [1, 4, 5].

Unfortunately, during the last three decades, life expectancy for SCLC patients has not improved, resulting in SCLC being defined as a recalcitrant cancer [6, 7].

In this disappointing scenario, there is a strong rationale for testing immune checkpoint inhibitors (ICIs), drugs that have changed the paradigm of treatment of non-small cell lung cancer (NSCLC) and other solid tumors in the latest years [8] (Table 1).

Table 1 Summary of immune-modulating drugs and their targets

Epidemiological, biological and clinical features of SCLC suggest a potential efficacy of ICIs.

First of all, SCLC has a strong association with smoking status and exposure to cigarette smoking is a predictive factor for responsiveness to ICIs in NSCLC [9].

SCLC also harbors a high load of non-synonymous somatic mutations, so called Tumor Mutational Burden (TMB) [10]. This feature potentially results in the release of tumor neoantigens able to elicit an adaptive immune response against the tumor cells [11].

The capacity of SCLC to elicit immune response is also suggested by the presence of auto-immune paraneoplastic syndromes in about 20 to 40% of cases [12]. Tumor-enhanced immunity and neurologic paraneoplastic syndromes have been associated with better prognosis. In particular, in a recent study, median OS of SCLC patients without paraneoplastic syndromes was 9.5 months, versus 18 months for the patients with Lambert-Eaton syndrome [13, 14]. Even when a clinically overt paraneoplastic syndrome is not diagnosed, the mere presence of auto-antibodies is related to better outcome, reflecting the ability to elicit a humoral immune response [15].

On the other hand, there are specific clinical features of SCLC that may potentially limit the usefulness and the benefit of ICIs. First of all, SCLC is a rapidly progressive disease, requiring rapid tumor shrinkage with chemotherapy. Moreover, the majority of SCLC patients are symptomatic and require steroids and this is particularly true in case of superior vena cava syndrome and brain metastases [16, 17]. Chronic steroids are a known limitation for ICIs treatment [18].

For all these reasons, up to now, clinical data on the efficacy of monotherapy with ICIs in this disease are not so promising, in spite of a sound biological background. The antibodies used as immunotherapeutic agents belong to different IgG isotypes (Table 1). This may result in different activities since IgG1 are known to have stronger binding affinity to Fcϒ receptors compared to IgG2-3-4, thus able to mediate more effective antibody dependent cell-mediated cytotoxicity (ADCC). Despite pharmacological rationale, there are no demonstrated clinical differences among different isotypes; a reason can be found in the mechanism of action in relation to the immune target, since the action of anti-PD-1 antibodies can be independent from Fcϒ receptors [19].

Increasing evidence is available about molecular characterization and key pathways explaining specific features of immune-related microenvironment and key pathways responsible for the development of chemo-resistance.

In the manuscript we review molecular rationale for immunotherapy treatment, for synergism with chemotherapy and for other potential combination treatment including immunotherapy. We also summarize clinical evidence available and provide future potential perspectives.

Molecular basis of chemo-resistance and synergism with immunotherapy

Cytotoxic drugs can induce an immunogenic cell death, leading to the generation of molecular signals that promote the uptake of dying cancer cells’ debris by antigen presenting cells (APC), and the cross-presentation of tumor antigens to T cells. Multiple molecular mechanisms induced by cancer cells, such as downregulation of major histocompatibility complex antigen expression, induction of an immunosuppressive milieu and negative regulation of cytotoxic T-cells via checkpoint inhibition, can inhibit this response. Combining ICIs with chemotherapy may disrupt these escape pathways and efficiently restore the anti-tumor activity of the immune system [20, 21]. In SCLC, however, the level of evidence in this field is still scarce and incomplete; a more comprehensive knowledge of the molecular basis of the mechanisms of resistance to chemotherapy and immunotherapy and of the expected activity of different chemo-immunotherapy combinations is needed.

SCLC cells are characterized by ubiquitous loss of tumor protein p53 (TP53) and Retinoblastoma 1 (Rb1), the main gatekeepers of G1-S transition [11]. This results into tumor cells arrest upon DNA damage at G2-M checkpoint with subsequent imbalance in expression and interaction of many DNA-damage response (DDR) proteins (Fig. 1) [22].

Fig. 1
figure1

Molecular landscape of SCLC. SCLC cells are characterized by ubiquitous loss of TP53 and Rb1 (dotted lines), the main G1-S cellular cycle checkpoints. SCLC cells depend on G2-M cell cycle checkpoint, that may be influenced by Aurora kinase A over-expression, characterizing the Myc-driven “variant” subtype of SCLC) and by Chk1-WEE1 axis. Chk1 is activated by Ataxia telangiectasia Mutated (ATM)/Ataxia telangiectasia and Rad-3 related protein (ATR) pathway upon chemo-induced DNA double strand break. After its activation, Chk1 can induce G2 cell cycle arrest through the phosphorylation of WEE1. Activated Chk1 can also up-regulate PD-L1 expression through the activation of the Signal Transducer and Activator of Transcription 1–3 (STAT1–3) mediated regulation of Interferon regulatory factor 1 (IRF1). Signaling pathways involving Enhancer of zeste homolog 2 (EZH2), an epigenetic modifier inducible both by immunotherapy and cytotoxic agents, also seem crucial in SCLC. EZH2 activity is required for the acquisition of an immunosuppressive phenotype, down-regulating antigen presentation process (resistance to immune-therapy), and also for an enhanced chemo-resistance property, through the inhibition of Schlafen family member 11 (SLFN11), a negative regulator of homologous repair machinery (HRM)

Checkpoint Kinase 1 (Chk1) is one of the main transducers of G2-M checkpoint activation. After its activation, Chk1 can induce G2 cell cycle arrest through the phosphorylation of WEE1 G2 checkpoint kinase (WEE1), among the others [23]. In SCLC cells, baseline Chk1 levels are higher than in controls, both in vitro and in human tissue samples [24], suggesting a crucial role of this protein for the control of tumor progression. Moreover, Chk1 is activated by Ataxia telangiectasia Mutated (ATM)/Ataxia telangiectasia and Rad-3 related protein (ATR) pathway upon chemo-induced DNA double strand breaks, thus resulting in unbalanced levels potentially leading to chemoresistance [25]. Intriguingly, Chk1 has been demonstrated to up-regulate Programmed death ligand 1 (PD-L1) expression, through the activation of the Signal Transducer and Activator of Transcription 1–3 (STAT1-3) mediated regulation of Interferon regulatory factor 1 (IRF1, [25,26,27]). This aspect can suggest a dynamic modulation of PD-L1 expression upon chemotherapy and a potentially greater benefit from a sequential instead of concomitant administration of immunotherapy.

In the latest years, the importance of Enhancer of zeste homolog 2 (EZH2)/Schlafen family member 11 (SLFN11) pathway has also been demonstrated in relationship with both chemotherapy and immunotherapy (Fig. 1).

The epigenetic modifier EZH2 is known to be induced by immunotherapy. In melanoma models, treatment with immune-modulating agents resulted in enhanced EZH2 activity [28]. Moreover, it has been demonstrated that immunotherapy can down-regulate the processes related to antigen presentation (Major Histocompatibility Complex-I, antigen processing, immunoproteasome subunits) and that EZH2 activity is required for the acquisition of this immunosuppressive phenotype [28]. On the other hand, SLFN11, whose activity is to silence the homologous repair machinery (HRM), is suppressed after chemotherapy in SCLC patient-derived xenograft (PDX), especially in chemo-resistant models [29]. EZH2 activity is required for SLFN11 suppression, thus suggesting its role also in chemoresistance. Consistently, the addition of an EZH2 inhibitor to platinum/etoposide chemotherapy in SCLC PDX models prevents the occurrence of resistance [29]. Interestingly, as a member of the HRM, poly ADP ribose polymerase (PARP) activity is also dysregulated in SCLC [30] and it is regulated by SLFN11 [31]. PARP inhibitors are active in SCLC models and clinical trials are ongoing [23, 32]. A phase II trial evaluating the addiction of veliparib, a PARP 1–2 inhibitor, to temozolomide in patients with recurrent SCLC showed no benefit in terms of PFS and OS; however, significantly higher objective response rate (ORR) was observed in patients receiving veliparib with temozolomide. Interestingly, patients with SLFN11-positive tumors obtained increase in PFS and OS if treated with the combination, while SLFN11-negative did not [33]. Another randomized phase II study, assessing the combination of veliparib with cisplatin and etoposide in first line treatment for ED-SCLC patients, failed to reach its primary endpoint of increasing PFS [34]. These different results may suggest the need of a predictive biomarker, in order to better exploit this class of drugs.

Aurora kinase A (AURKA) is a negative regulator of G2-M transition and is crucial in MYC amplified SCLC (around 20% of SCLC tumors) [35]: the inhibition of AURKA induces cell cycle arrest and strongly suppresses tumor growth in SCLC models (Fig. 1) [23, 36]. Moreover, AURKA may have a role in tumor cell growth and migration, through its interaction with the liver kinase B1 (LKB1). Zheng and colleagues have recently demonstrated that AURKA can directly phosphorylate LKB1 at position Ser299 in NSCLC models [37]. LKB1 phosphorylation prevents its interaction with AMP-activated protein kinase (AMPK), leading to a negative regulation of the LKB1/AMPK axis, which is normally responsible of tumor suppression [37, 38]. More in depth, LKB1 activity is crucial in regulating tumor cell metabolism, since it can modulate the intracellular levels of glutathione in response to oxidative stress [39]. The loss of LKB1 activity makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy [40]. Skoulidis and colleagues recently demonstrated that KRAS-mutant lung adenocarcinomas harboring LKB1 co-mutations are associated with lower progression free survival (PFS) and OS to Protein death 1 (PD-1) blockade, thus suggesting a role of LKB1 in primary resistance to this class of drugs [41]. These data might suggest that AURKA-driven SCLCs are more sensitive to chemo-radiation treatments and resistant to ICIs.

Role of tumor immune-microenvironment in SCLC

A body of evidence has been gathered over the years on the role of the tumor immune microenvironment (TME), i.e. the milieu of lymphocytes, monocytes and other immune cells intertwined with cancer cells, in neoplastic initiation and progression. The composition of the TME differs across time and stages even in cancers with same histology and it is one of the determinants of tumor characteristics and outcome of NSCLC patients [42].

An early study focusing on the interaction between SCLC cells and their TME showed how SCLC tumor cell lines were able to inhibit activated CD4+ T-cells [43]. The inhibitory activity did not require a direct cell-to-cell contact, but was mediated by cytokine secretion by tumor cells (IL-15 in particular) that caused a de novo functional differentiation of lymphocytes towards a T-regulatory immunophenotype (FOXP3+ CD4+ T-cells). Another study has analyzed FOXP3+ infiltrate in archival biopsies from patients with SCLC and the ratio of FOXP3+ turned out to be an independent indicator of poor prognosis in these patients [43].

The histological assessment of SCLC TME was the focus of another study that evaluated the prognostic role of CD45 (a pan-inflammatory cell marker) positive immune cells [44]. The extent of CD45+ infiltrate was predictive of a longer OS independently from clinical parameters such as stage and performance status [45].

Increasing evidence has indicated that TME is able to modulate the PD-1/PD-L1 axis, promoting the innate tendency of cancer cells to escape immune-surveillance [46]. Data on distribution of PD-L1 expression in SCLC across stages are very limited; in patients with advanced disease the level of PD-L1 expression seems to be lower than in earlier stages [47, 48] and also than in NSCLC [49].

A retrospective study conducted in ED-SCLC and LD-SCLC patients treated with a multimodal approach, including surgery for early stage, showed an association between CD8+ tumor infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells, whereas FOXP3+ infiltrate showed a positive correlation with PD-L1 positive tumor-infiltrating T cells [48]. Furthermore, a stronger infiltration of FOXP3+ TILs characterized early stage disease and was associated with a better prognosis in LD-SCLC patients, shedding a new light upon the controversial role of the T regulatory subset of TILs even in this malignancy [48, 50, 51].

Immune checkpoint inhibitors in SCLC: clinical perspectives

First line

Only few data are available on ICIs as monotherapy in first line setting, because of the potential risks of not administering chemotherapy in such a rapidly progressive disease. For this reason, taking into account the potential synergism [20, 21], most trials have explored the combined approach of chemotherapy and immunotherapy.

In a randomized phase II study, patients with untreated ED-SCLC were randomized to receive chemotherapy (carboplatin plus paclitaxel) with either placebo (control arm) or ipilimumab in two alternative regimens, concurrent with chemotherapy (concurrent arm) or sequential (phased arm). In this trial the addition of ipilimumab conferred only a minimal increase in immune-related PFS for patients who received phased-ipilimumab compared to placebo, but not for patients receiving concurrent treatment [52].

Subsequently, a randomized phase III study combining ipilimumab with platinum plus etoposide failed to demonstrate a benefit in PFS or OS [53].

Despite these first disappointing results, the path of combination strategy was further pursued. IMpower133, a phase III double blind randomized trial, evaluated the efficacy and safety of atezolizumab added to carboplatin and etoposide as first-line treatment for patients with ED-SCLC. A total of 403 patients were randomized to receive atezolizumab plus chemotherapy followed by atezolizumab maintenance treatment or chemotherapy plus placebo [54]. The study met both its co-primary endpoints, showing statistically significant improved OS and PFS. The magnitude of the benefit, however, was not impressive (2 months in median OS and 0,9 month in median PFS), with no sign of plateauing of survival curve, as previously seen for NSCLC [55, 56]. Nevertheless, the latest National Comprehensive Cancer Network (NCCN) guidelines included this chemo-immunotherapy regimen as a first line option for ED-SCLC patients [57] and the combination has been recently approved by FDA.

Several clinical trials are currently exploring, in first line treatment, the combination of PD-1/PD-L1 inhibitors with chemotherapy and other ICIs, as summarized in Table 2.

Table 2 Ongoing clinical trials with immune checkpoint inhibitors in first line setting for SCLC

Another promising approach is represented by the association of radiotherapy and immunotherapy. Similarly to chemotherapy, radiation therapy can induce an immunogenic cell death [21, 58]. Clinical trials are also evaluating concurrent administration of radiotherapy and chemo-immunotherapy regimens containing pembrolizumab (NCT02934503, NCT02402920, https://www.clinicaltrials.gov).

The association of the anti-PD-L1 durvalumab with the anti-CTLA4 tremelimumab is also under investigation (NCT02658214, NCT03043872, https://www.clinicaltrials.gov). The rationale behind this combination is to exploit the different mechanisms of action: inhibiting CTLA-4 leads to differentiation of naïve T cells, which will later be able to infiltrate tumor tissues with no restraint on their anti-tumor activity mediated by PD-1/PD-L1 inhibition [59].

Maintenance

While it is hard to replace first line chemotherapy, the rapid decline of performance status and the worsening of symptoms at disease progression might prevent many patients to be eligible for immunotherapy as salvage treatment. Moreover, chemotherapy may enhance the susceptibility of the tumor to immunotherapy: all these features represent the rationale of administrating ICIs as a maintenance or consolidation treatment. A phase II single arm trial assessed the efficacy of maintenance pembrolizumab in 45 ED-SCLC patients, after response or stable disease following platinum/etoposide chemotherapy [60]. Maintenance started within 8 weeks from the last cycle of chemotherapy and continued for a total of 2 years. The primary endpoint was the improvement of median PFS to 3 months (50% increase over 2 months of the historical controls). The endpoint was not met, with a median PFS of 1.4 months (95%CI: 1.3–2.8 months); however, a subset of patients with any PD-L1 expression on cells confined in the stromal interface could gain a long lasting benefit from maintenance (6.5 months, 95%CI: 1.1–12.8 months) [60].

The same setting of treatment was evaluated in CheckMate 451 study [61]. In this phase III trial, patients with ED-SCLC, who achieved disease control after first-line platinum-based chemotherapy, were randomized to receive nivolumab alone (240 mg every 2 weeks), nivolumab (1 mg/kg every 3 weeks) with ipilimumab (3 mg/kg every 3 weeks) up to 4 cycles, followed by nivolumab (flat 240 mg every 2 weeks), or placebo until disease progression or unacceptable toxicity, for a maximum of 2 years. Primary endpoint was OS improvement for patients treated with ICI combination versus placebo. This endpoint was not met, with a disappointing median OS for the ipilimumab and nivolumab group of 9,2 months (95% CI: 8,2–10,2 months) versus 9,6 months (95% CI: 8,2–11 months) of the placebo group. This trial showed many critical issues, the first one being the fact that almost 60% of the patients received maintenance after 5 weeks or more from the last dose of first line chemotherapy [61]. Furthermore, unlike phase III NSCLC trials [62], here the dosage of the ipilimumab was 3 mg/kg, this fact being responsible of a median number of 2 doses administered to patients of the combination arm. Further analyses are in progress, in order to identify possible subgroups of patients who may benefit from ICI doublet as maintenance strategy.

A summary of the ongoing clinical trials in maintenance setting is reported in Table 3.

Table 3 Ongoing clinical trials in maintenance or consolidation setting after first line treatment for SCLC

Beyond first line

Recurrence after first line treatment is almost inevitable and few effective options at the time of progression are available. Response rate to standard second line chemotherapy is 24.3%, with a median duration of response (DOR) of around 14 weeks, at the cost of grade 3 and 4 toxicities [63]. CheckMate 032 was the first trial to evaluate immunotherapy for SCLC patients who had failed a first line platinum-based chemotherapy [49]. In this phase I/II open label trial, 216 patients were randomized to receive nivolumab alone (3 mg/kg bodyweight every 2 weeks), or different combination of nivolumab/ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg). Primary endpoint was the objective response (OR). An OR was achieved in 10, 23 and 19% of patients treated with nivolumab alone, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg and nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg respectively. Response rates were not related to PD-L1 expression on tumor cells, platinum-resistance or number of previous treatments. DOR was remarkable in every cohort, with nivolumab alone group still not reaching its median value at the time of the analysis. Safety profile was manageable, with fewer treatment-related toxic effects compared with previous trials of topotecan or amrubicin [64]. On the basis of the trial results FDA recently approved nivolumab for the treatment of SCLC in third line setting.

On the other hand, CheckMate 331 (NCT02481830), an open-label phase III trial, compared nivolumab versus standard of care chemotherapy as second line treatment for patients with SCLC progressing after first line platinum-based chemotherapy. The primary endpoint was OS and was not met. However, the authors highlighted that OS curves separate after 12 months, thus suggesting an important role for a subpopulation of patients who may derive prolonged clinical benefit, even in the presence of platinum-resistance [65].

In line with these promising results, Keynote 028, a phase Ib trial tested the activity and safety of pembrolizumab (given at 10 mg/kg every 2 weeks) in 24 extensive-stage SCLC patients selected for PD-L1 expression (TPS ≥ 1%), who had failed at least one line of standard therapy [66]. Overall response rate (ORR) and DOR were 33.3% and 19.4 months respectively; only eight patients experienced grade ≥ 3 immune-related adverse events (irAEs).

Results from the SCLC arm of Keynote 158, a phase II trial of pembrolizumab (flat dose of 200 mg every 3 weeks) in 107 pre-treated advanced SCLC patients [67], showed an ORR of 3.7% and a DOR of over 15 months (median DOR still not reached). Patients with a positive PD-L1 combined score achieved a better response (ORR: 35%), with an astonishing median OS of 14.6 months [68]. Results from a pooled analysis of these two clinical trials, Keynote 028 and 158, were recently presented. The ORR was 19.3% and median DOR was not reached. Two patients had a complete response and 14 had a partial response; 14 of 16 responders were PD-L1-positive. Median PFS and OS were 2 and 7.7 months respectively [69]. Based on these data FDA has granted the accelerated approval to pembrolizumab for patients with advanced SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

Anti-PD-L1 agents started being tested in similar treatment setting. Phase Ia study of atezolizumab in ED-SCLC patients relapsed after platinum-based chemotherapy with etoposide, showed a good safety profile of the drug, with encouraging results also in terms of efficacy and outcome, with confirmed ORR of 6%, median PFS of 1.5 months and median OS of 5.9 months [70]. A subsequent phase II trial, however, investigating the role of atezolizumab as second line treatment option, did not meet its primary endpoint of increased ORR with the anti-PD-L1 agent versus standard of care (i.e. topotecan or re-induction with carboplatin and etoposide, following investigator choice) [71]. PFS data were also quite disappointing: median PFS was 1.4 months in the atezolizumab group and 4.2 months in the chemotherapy one, with an unfavorable risk of progression (Hazard Ratio of 2,26, p = 0,004) for the experimental arm.

The first results of another anti-PD-L1 agent, durvalumab (10 mg/kg every 2 weeks), are also available. The study was performed in a PD-L1-unselected population. Primary endpoint was safety: treatment was well tolerated and all irAEs were grade 1 or 2. Secondary endpoints were also of interest with an ORR of 9.5%, a median PFS 1.5 months and a median OS 4.8 months [72]. Durvalumab showed a tolerable safety profile and a promising activity also when combined with tremelimumab, an anti-CTLA-4 agent. Initial data from a phase I dose-finding trial on heavily pre-treated ED-SCLC patients showed a 23% grade 3–4 irAEs, with a confirmed ORR of 13.3% and a median DOR of over 18 months [73].

Combination strategies have also been investigated after the failure of platinum-etoposide treatment. Positive findings about chemotherapy plus anti-PD-1 drug are coming from a phase II study that investigated the efficacy of this combination in a small group of platinum refractory ED-SCLC patients. Paclitaxel (175 mg/m2) was administered every 3 weeks up to 6 cycles and flat dose pembrolizumab (200 mg every 3 weeks) was added from the second cycle and continued until disease progression or unacceptable toxicity. ORR was 23.1%, with a disease control rate (DCR) of over 80% and median OS of 9.2 months. Toxicity was acceptable and main grade 3–4 events, such as febrile neutropenia, were related to chemotherapy [74].

A large number of trials are ongoing for this setting of treatment. ICIs are administered as single agent in single arm trial, as a single agent compared to standard treatment, or in combination either with other ICIs, or with chemotherapy, radiotherapy, or with other drugs (Table 4).

Table 4 Ongoing clinical trials in further lines of treatment for SCLC

New partners for ICIs

In order to increase the therapeutic role of ICIs in SCLC, biological rationale supports the potentiality of combining ICIs with a number of non-chemotherapy agents with the aim to obtain synergism and subsequently improve both the percentage of patients who benefit from immunotherapy and the duration of clinical benefit (Table 5).

Table 5 Ongoing clinical trials of immune-checkpoint inhibitors combined with non-cytotoxic agents

A first strategy concerns the idea that immune-tolerance mechanisms are redundant and that inhibiting more immune-suppressive targets may enhance anti-tumor activity. This is the most explored strategy and studies with the combination of nivolumab and ipilimumab have been described before.

On the other side, new drugs are under evaluation with the aim of actively promoting immune-response in combination with anti-PD1/PD-L1 antibody. For example, Utomilumab is a fully human IgG2 agonist monoclonal antibody targeting CD137, a co-stimulatory receptor expressed on activated immune cells (effector and regulatory T cells, NK cells and dendritic cells), causing an enhanced cytotoxic T-cell and NK-cell activity [75] and triggering antitumor response [76] (Fig. 2). In this case, rationale for synergism is strong: anti-PD-1/PD-L1 disrupts the PD1/PD-L1 interaction, thus avoiding tumor-induced anergy of tissue infiltrating lymphocytes, while utomilumab can boost the anti-tumor activity of different effector white blood cells.

Fig. 2
figure2

New combination strategies. Mechanisms of action of drugs that are being studied for new combination strategies in small-cell lung cancer. Panel a: utomilumab triggers CD137, a co-stimulatory receptor expressed on activated immune cells and it is studied in combination with avelumab; trilaciclib is a CDK4/6 inhibitor and it is studied with platinum/etoposide and atezolizumab; SGI110 contrasts the role of EZH2, by interfering with DNA methylation and it is under evaluation in combination with durvalumab. Panel b: another promising strategy is to associate immune checkpoint inhibitor, such as Ipilimumab, to immune stimulatory agents. INCAGN01876 is a monoclonal antibody that activates Glucocorticoid-induced TNF-receptor-related protein (GITR), a T cell co-stimulatory receptor involved in the immunological synapsis able to enhance T cell responsiveness to weakly immunogenic tumor-associated antigens. INCAGN01949, another antibody that targets and stimulates OX40, a T cell co-stimulatory receptor that potentiates TCR signalling

Other drugs act as co-stimulatory agents for T cell receptor (TCR) signaling: INCAGN01876, able to bind Glucocorticoid-induced TNF-receptor-related protein (GITR) (NCT03126110, https://www.clinicaltrials.gov), a T cell costimulatory receptor involved in the immunological synapsis during CD4+ and CD8+ T-cell priming, and INCAGN01949 (NCT03241173, https://www.clinicaltrials.gov), a fully human IgG1 monoclonal antibody that targets and stimulates OX40 (CD134), another T cell co-stimulatory receptor that potentiates TCR signaling in different processes (T-cell priming, effector cell differentiation and memory T cell recall responses).

A different strategy concerns the exploiting of other mechanisms not directly interacting with immune cells, but anyhow able to affect immune response. This is also the idea at the basis of combining chemotherapy and ICIs. Recently, the role of CDK4/6 (Cyclin-dependent kinase 4/6) is emerging in this context. This class of molecules, through the interaction with DNA-methyltransferase 1 (DNMT1), is responsible of increasing the immune-evasive T-cell phenotype [77]. The combination of platinum/etoposide and atezolizumab with the new molecule Trilaciclib, a CDK4/6 inhibitor, is currently in phase 2 clinical trial (NCT03041311, https://www.clinicaltrials.gov) (Fig. 2). Another interesting trial evaluates the combination of nivolumab and RGX-104, a small agonist ligand of liver-X receptors (LXRs) (NCT02922764 https://www.clinicaltrials.gov). LXRs belong to the nuclear receptor family and are able to regulate cellular proliferation; previous studies have shown that LXR-ligands have anti-cancer activities in a variety of cancer cell lines [78], they can induce immunogenic cell death [79] and modulate inflammatory response. In particular RGX-104 is able to deplete myeloid derived suppressor cells (MDSCs), stimulates dendritic cells and activates cytotoxic lymphocytes. The immunologic and anti-tumor activity of this drug has been demonstrated in patients with advanced refractory solid tumors and now a dose-escalation phase with nivolumab has started [80].

As mentioned before, EZH2 activity is crucial for SCLC, as it is involved in tumor sensitivity both to chemotherapy and to immunotherapy. EZH2 works mainly through histone modification and DNA-methylation. SGI-110 is a DNA methyltransferase inhibitor composed of a dinucleotide of decitabine and deoxyguanosine, that is currently being tested with durvalumab and tremelimumab in patients with ED-SCLC progressive after a platinum-based first-line chemotherapy (NCT03085849 https://www.clinicaltrials.gov) (Fig. 2). This kind of approach may be particularly promising since EZH2 is also involved in chemo-resistance mechanisms, as described before, and it is a pathway specifically involved in SCLC.

Safety of combination treatments

Immune-related toxicity represents a major concern in SCLC. Autoimmune disorders are indeed frequent in SCLC patients, who may develop autoimmune diseases as paraneoplastic syndromes [12]. In this scenario, the relation between immune-related toxicities and treatment response might be intriguing, although data are scanty since patients with autoimmune disorders were excluded from clinical trials. To address this issue, retrospective series mainly involving NSCLC and melanoma patients have been described [81, 82]. Patients with active or inactive autoimmune disease have been treated with anti-PD1/anti-PD-L1 or anti-CTLA4. An autoimmune disease flare, mostly low grade and rarely requiring systemic corticosteroids, has been reported by about 20% of patients and this did not affect treatment outcome [81, 82]. Overall, the risk of immune-related adverse events was higher among patients with pre-existing autoimmune conditions, but the toxicity had no impact on survival [82]. No cases of paraneoplastic auto-immune syndromes were included in these series [81, 82].

In the CheckMate 032 trial with combined nivolumab and ipilimumab, the most frequent adverse events were increased lipases and diarrhea [49]. A peculiar, although rare, toxicity, was limbic encephalitis and aseptic meningitis across all treatment arms, while rash and hypothyroidism, mainly low-grade, were more frequently reported in the nivolumab-ipilimumab combination arms [49]. Rash and hypothyroidism were also the most common irAEs observed in the IMpower133 trial in the chemotherapy plus atezolizumab arm [54].

Pulmonary toxicity from the association of ICIs with chest radiotherapy may also be an issue. However, in the PACIFIC study, investigating durvalumab after chemo-radiation in stage III NSCLC, there were no differences in the incidence of grade 3 and 4 pneumonitis between the durvalumab and the placebo group [83].

In our experience, treatment with second-line nivolumab in a SCLC patient who had previously received thoracic radiotherapy for limited disease showed an exceptional clinical and radiological response. In the same patient, treatment was interrupted after 6 doses due to the occurrence of pneumonitis. The patient experienced single-site progression and received radiotherapy on a peri-pancreatic lymph-node. After the radiotherapy, he experienced further response on liver lesions and a relapse of immune-related pneumonitis, seven months after the completion of nivolumab treatment [84]. This experience shows how complicated are the effects of immune-modulation induced by cancer treatments and that the administration of radiotherapy also after ICIs and at distant-site may elicit immune-related adverse events.

Predictive biomarkers of response to immune-checkpoint inhibitors in SCLC

Several trials have included correlative studies in order to find potential predictive markers of response.

In a trial combining ipilimumab 10 mg/kg with carboplatin and etoposide, the relation between baseline positivity of autoantibodies and clinical outcomes was evaluated. Patients with any positive autoimmune antibody (anti-SOX2, anti-Hu, anti-Yo, anti-VGCCA, anti-VGPCA, anti-nuclear, anti-neutrophil cytoplasmic antibodies) showed a trend for a prolonged survival (18.5 versus 17 months, p = 0.144), a significantly longer median progression free survival (8.8 versus 7.3 months, p = 0.036) and a trend for a higher response rate (p = 0.066) [85].

Differently from NSCLC trials, tumor PD-L1 expression in the Checkmate 032 was not predictive of ICIs efficacy in patients with SCLC [49]. Given this finding, samples were further analyzed: whole exome sequencing was performed and the tumor mutation burden was defined as the total number of non-synonymous somatic mutations [86]. Patients harboring higher tumor mutational load (defined as higher than the upper tertile of the mutation distribution of the study population) experienced an enhanced efficacy from the treatment, especially when the combination was administered.

Due to the limited availability of adequate tissue, there is an increased interest to use blood-based tests through cell free tumor DNA profiling. A blood-based surrogate of tissue-based tumor mutation burden evaluation has been shown to be a potential predictive tool for advanced NSCLC patients treated with atezolizumab [87]. Differently from NSCLC patients, patients with SCLC treated with atezolizumab plus carboplatin and etoposide showed a benefit in terms of OS and PFS, regardless of blood-based tumor mutational burden [54].

A retrospective study has evaluated tissue mutational burden (defined as total number of nonsynonymous mutations) of 120 patients with SCLC of all stages and the association with PD-L1 expression both on tumor and on immune cells [88]. Tissue mutational burden had no particular relationship with tumor expression of PD-L1, whereas there was a positive correlation with PD-L1 expression on immune infiltrate (p = 0.04). Gadgeel et al. have studied PD-L1 expression of cells confined in the tumor stroma of patients receiving pembrolizumab as a maintenance treatment after first line chemotherapy [60]. The stromal interface was considered PD-L1 positive if PD-L1 membrane-stained cells surrounding the tumor nests were identified at low power magnification. Patients with PD-L1 expression at the stromal interface had longer median PFS and median OS than patients with no expression (6.5 versus 1.3 months and 12.8 versus 7.6 months respectively). Exploratory analysis performed in the SCLC cohort of Keynote 158 has shown the potential of the PD-L1 combined score, i.e. the ratio of PD-L1 positive cells, including tumor cells, lymphocytes and macrophages, to the total number of tumor cells [67]. This PD-L1 score was able to define a subset of pre-treated ED-SCLC patients who achieved a better ORR (35.7% versus 6%), 1-year PFS (28.5% versus 8.2%) and 1-year OS (53.1% versus 30.7%) while on pembrolizumab.

Conclusions

The systemic treatment of SCLC represents a major challenge for medical oncologists and immunotherapy has a great appeal and solid biological rationale.

Initial clinical experiences confirm the potentialities of ICIs for this aggressive disease and indicate the need for reliable predictive biomarkers. Preliminary data suggest that predictive biomarkers of ICIs efficacy might be disease-specific and that findings validated in NSCLC cannot be translated in SCLC. In fact, a different evaluation score for PD-L1 expression has been suggested.

Responsiveness to immunotherapy is related to clinical disease course and to the host, but also to biological features of the disease. The study of molecular mechanisms at the basis of chemo-resistance and aggressiveness of the disease may help in understanding also the immune-resistance mechanisms and in individuating new combinations treatment strategies with the aim of improving clinical benefit of immunotherapy.

In addition to combining ICIs with chemotherapy and immunotherapy, new therapeutic approaches, specifically addressing molecular pathways involved in SCLC growth and chemo-resistance, need to be explored in order to contribute to improve the outcome of SCLC patients, commonly recognized as an unmet clinical need.

Availability of data and materials

Not applicable.

References

  1. 1.

    Nicholson AG, Chansky K, Crowley J, Beyruti R, Kubota K, Turrisi A, et al. The international association for the study of lung cancer lung cancer staging project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(3):300–11 PubMed PMID: 26723244.

  2. 2.

    Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R, Dahle R, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol. 2002;20(24):4665–72 PubMed PMID: 12488411.

  3. 3.

    Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan clinical oncology group study 9104. J Clin Oncol. 2002;20(14):3054–60 PubMed PMID: 12118018. Epub 2002/07/16.

  4. 4.

    Society AC. Cancer Treatment and Survivorship Facts & Figures 2014–2015 2014.

  5. 5.

    National Cancer Institute, Surveillance, Epidemiology, and End Results program (SEER). Available online. Surveillance, Epidemiology, and End Results program (SEER) [cited 2018]. Available from: https://seer.cancer.gov/archive/csr/1975_2012/browse_csr.php?sectionSEL=15&pageSEL=sect_15_table.13.

  6. 6.

    Waqar SN, Morgensztern D. Treatment advances in small cell lung cancer (SCLC). Pharmacol Ther. 2017;180:16–23 PubMed PMID: 28579387. Epub 2017/06/06.

  7. 7.

    Congress t. H.R.733 - Recalcitrant Cancer Research Act of 2012 2012 [cited 2018]. Available from: https://www.congress.gov/bill/112th-congress/house-bill/733.

  8. 8.

    Yu Y, Cui J. Present and future of cancer immunotherapy: a tumor microenvironmental perspective. Oncol Lett. 2018;16(4):4105–13 PubMed PMID: 30214551. Pubmed Central PMCID: PMC6126324. Epub 2018/09/15.

  9. 9.

    Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375(19):1823–33 PubMed PMID: 27718847. Epub 2016/10/11.

  10. 10.

    Alexandrov LB, Ju YS, Haase K, Van Loo P, Martincorena I, Nik-Zainal S, et al. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354(6312):618–22 PubMed PMID: 27811275. Pubmed Central PMCID: PMC6141049. Epub 2016/11/05.

  11. 11.

    George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53 PubMed PMID: 26168399. Pubmed Central PMCID: 4861069.

  12. 12.

    Nagy-Mignotte H, Shestaeva O, Vignoud L, Guillem P, Ruckly S, Chabre O, et al. Prognostic impact of paraneoplastic cushing's syndrome in small-cell lung cancer. J Thorac Oncol. 2014;9(4):497–505 PubMed PMID: 24736072. Epub 2014/04/17.

  13. 13.

    Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet. 1999;353(9147):117–8 PubMed PMID: 10023900. Epub 1999/02/19.

  14. 14.

    Maddison P, Gozzard P, Grainge MJ, Lang B. Long-term survival in paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2017;88(14):1334–9 PubMed PMID: 28251917. Epub 2017/03/03.

  15. 15.

    Gozzard P, Chapman C, Vincent A, Lang B, Maddison P. Novel humoral prognostic markers in small-cell lung carcinoma: a prospective study. PLoS One. 2015;10(11):e0143558 PubMed PMID: 26606748. Pubmed Central PMCID: PMC4659625. Epub 2015/11/26.

  16. 16.

    Wurschmidt F, Bunemann H, Heilmann HP. Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys. 1995;33(1):77–82 PubMed PMID: 7642434. Epub 1995/08/30.

  17. 17.

    Nakahara Y, Sasaki J, Fukui T, Otani S, Igawa S, Hayakawa K, et al. The role of prophylactic cranial irradiation for patients with small-cell lung cancer. Jpn J Clin Oncol. 2018;48(1):26–30 PubMed PMID: 29077861. Epub 2017/10/28.

  18. 18.

    Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell Death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36(28):2872–8 PubMed PMID: 30125216. Epub 2018/08/21.

  19. 19.

    Kretschmer A, Schwanbeck R, Valerius T, Rosner T. Antibody isotypes for tumor immunotherapy. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2017;44(5):320–6 PubMed PMID: 29070977. Pubmed Central PMCID: 5649311.

  20. 20.

    Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013;38(4):729–41 PubMed PMID: 23562161. Epub 2013/04/09.

  21. 21.

    Attili I, Passaro A, Pavan A, Conte P, De Marinis F, Bonanno L. Combination immunotherapy strategies in advanced non-small cell lung cancer (NSCLC): does biological rationale meet clinical needs? Crit Rev Oncol Hematol. 2017;119:30–9 PubMed PMID: 29065983.

  22. 22.

    Sen T, Gay CM, Byers LA. Targeting DNA damage repair in small cell lung cancer and the biomarker landscape. Transl Lung Cancer Res. 2018;7(1):50–68 PubMed PMID: 29535912. Pubmed Central PMCID: PMC5835589. Epub 2018/03/15.

  23. 23.

    Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14(9):549–61 PubMed PMID: 28534531.

  24. 24.

    Sen T, Tong P, Stewart CA, Cristea S, Valliani A, Shames DS, et al. CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or Olaparib. Cancer Res. 2017;77(14):3870–84 PubMed PMID: 28490518. Pubmed Central PMCID: PMC5563854. Epub 2017/05/12.

  25. 25.

    Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017;8(1):1751 PubMed PMID: 29170499. Pubmed Central PMCID: PMC5701012. Epub 2017/11/25.

  26. 26.

    Mouw KW, Konstantinopoulos PA. From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. Br J Cancer. 2018;118(7):933–5 PubMed PMID: 29531322. Pubmed Central PMCID: PMC5931110. Epub 2018/03/14.

  27. 27.

    Attili I, Karachaliou N, Bonanno L, Berenguer J, Bracht J, Codony-Servat J, et al. STAT3 as a potential immunotherapy biomarker in oncogene-addicted non-small cell lung cancer. Ther Adv Med Oncol. 2018;10:1758835918763744 PubMed PMID: 29636826. Pubmed Central PMCID: PMC5888808. Epub 2018/04/11.

  28. 28.

    Zingg D, Arenas-Ramirez N, Sahin D, Rosalia RA, Antunes AT, Haeusel J, et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 2017;20(4):854–67 PubMed PMID: 28746871. Epub 2017/07/27.

  29. 29.

    Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 Axis. Cancer Cell. 2017;31(2):286–99 PubMed PMID: 28196596. Pubmed Central PMCID: PMC5313262. Epub 2017/02/16.

  30. 30.

    Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2(9):798–811 PubMed PMID: 22961666. Pubmed Central PMCID: PMC3567922. Epub 2012/09/11.

  31. 31.

    Murai J, Feng Y, Yu GK, Ru Y, Tang SW, Shen Y, et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget. 2016;7(47):76534–50 PubMed PMID: 27708213. Pubmed Central PMCID: PMC5340226. Epub 2016/10/07.

  32. 32.

    Atrafi F, Groen HJM, Byers LA, Garralda E, Lolkema MP, Sangha RS, et al. A phase I dose-escalation study of Veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung Cancer and other solid tumors. Clin Cancer Res. 2019;25(2):496–505 PubMed PMID: 30327308.

  33. 33.

    Pietanza MC, Waqar SN, Krug LM, Dowlati A, Hann CL, Chiappori A, et al. Randomized, double-blind, phase II study of Temozolomide in combination with either Veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36(23):2386–94 PubMed PMID: 29906251. Pubmed Central PMCID: 6085179.

  34. 34.

    Owonikoko TK, Dahlberg SE, Sica GL, Wagner LI, Wade JL 3rd, Srkalovic G, et al. Randomized phase II trial of cisplatin and etoposide in combination with Veliparib or placebo for extensive-stage small-cell lung cancer: ECOG-ACRIN 2511 study. J Clin Oncol. 2019;37(3):222–9 PubMed PMID: 30523756. Pubmed Central PMCID: 6338394.

  35. 35.

    Alves Rde C, Meurer RT, Roehe AV. MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study. J Cancer Res Clin Oncol. 2014;140(12):2021–5 PubMed PMID: 25012251. Epub 2014/07/12.

  36. 36.

    Lu Y, Liu Y, Jiang J, Xi Z, Zhong N, Shi S, et al. Knocking down the expression of Aurora-a gene inhibits cell proliferation and induces G2/M phase arrest in human small cell lung cancer cells. Oncol Rep. 2014;32(1):243–9 PubMed PMID: 24841948. Epub 2014/05/21.

  37. 37.

    Zheng X, Chi J, Zhi J, Zhang H, Yue D, Zhao J, et al. Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration. Oncogene. 2018;37(4):502–11 PubMed PMID: 28967900. Epub 2017/10/03.

  38. 38.

    Bonanno L, De Paoli A, Zulato E, Esposito G, Calabrese F, Favaretto A, et al. LKB1 expression correlates with increased survival in patients with advanced non-small cell lung cancer treated with chemotherapy and bevacizumab. Clin Cancer Res. 2017;23(13):3316–24 PubMed PMID: 28119362. Epub 2017/01/26.

  39. 39.

    Bonanno L, Zulato E, Pavan A, Attili I, Pasello G, Conte P, et al. LKB1 and tumor metabolism: the interplay of immune and Angiogenic microenvironment in lung cancer. Int J Mol Sci. 2019;20(8) PubMed PMID: 30995715. Pubmed Central PMCID: 6514929.

  40. 40.

    Zulato E, Ciccarese F, Agnusdei V, Pinazza M, Nardo G, Iorio E, et al. LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and gamma-irradiation. Biochem Pharmacol. 2018;156:479–90 PubMed PMID: 30222967. Epub 2018/09/18.

  41. 41.

    Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–35 PubMed PMID: 29773717. Pubmed Central PMCID: PMC6030433. Epub 2018/05/19.

  42. 42.

    Bremnes RM, Busund LT, Kilvaer TL, Andersen S, Richardsen E, Paulsen EE, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016;11(6):789–800 PubMed PMID: 26845192. Epub 2016/02/05.

  43. 43.

    Wang W, Hodkinson P, McLaren F, MacKinnon A, Wallace W, Howie S, et al. Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate. Int J Cancer. 2012;131(6):E928–37 PubMed PMID: 22532287.

  44. 44.

    Wang W, Hodkinson P, McLaren F, Mackean MJ, Williams L, Howie SEM, et al. Histologic assessment of tumor-associated CD45(+) cell numbers is an independent predictor of prognosis in small cell lung cancer. Chest. 2013;143(1):146–51 PubMed PMID: 22847040. Epub 2012/08/01.

  45. 45.

    Bremnes RM, Sundstrom S, Aasebo U, Kaasa S, Hatlevoll R, Aamdal S, et al. The value of prognostic factors in small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow-up. Lung Cancer. 2003;39(3):303–13 PubMed PMID: 12609569. Epub 2003/03/01.

  46. 46.

    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61 PubMed PMID: 25858804. Pubmed Central PMCID: PMC4400238. Epub 2015/04/11.

  47. 47.

    Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol. 2015;10(3):426–30 PubMed PMID: 25384063. Epub 2014/11/11.

  48. 48.

    Bonanno L, Pavan A, Dieci MV, Di Liso E, Schiavon M, Comacchio G, et al. The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes. Eur J Cancer. 2018;101:191–200 PubMed PMID: 30077124.

  49. 49.

    Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883–95 PubMed PMID: 27269741.

  50. 50.

    Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179 PubMed PMID: 26462617. Pubmed Central PMCID: 4604472.

  51. 51.

    Sepesi B, Cuentes EP, Canales JR, Behrens C, Correa A, Antonoff M, et al. Tumor-Infiltrating Lymphocytes and Overall Survival in Surgically Resected Stage II and III Non–Small Cell Lung Cancer. Int J Rad Oncology • Biol • Phys. 2017;98(1):223.

  52. 52.

    Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83 PubMed PMID: 22858559. Epub 2012/08/04.

  53. 53.

    Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III randomized trial of Ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016;34(31):3740–8 PubMed PMID: 27458307. Epub 2016/07/28.

  54. 54.

    Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line Atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018; PubMed PMID: 30280641. Epub 2018/10/04.

  55. 55.

    Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92 PubMed PMID: 29658856. Epub 2018/04/17.

  56. 56.

    Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018; PubMed PMID: 30280635. Epub 2018/10/04.

  57. 57.

    Cancer NgVSCL. [cited 2018]. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx.

  58. 58.

    Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95 PubMed PMID: 24382348. Pubmed Central PMCID: 3904601.

  59. 59.

    Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275–80 PubMed PMID: 20160101. Pubmed Central PMCID: PMC2840093. Epub 2010/02/18.

  60. 60.

    Gadgeel SM, Pennell NA, Fidler MJ, Halmos B, Bonomi P, Stevenson J, et al. Phase II study of maintenance Pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC). J Thorac Oncol. 2018;13(9):1393–9 PubMed PMID: 29775808. Epub 2018/05/19.

  61. 61.

    Owonikoko T, Kim HR, Govindan R, Ready N, Reck M, Peters S, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Ann Oncol. 2019;30(Suppl 2):mdz094.

  62. 62.

    Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093–104 PubMed PMID: 29658845.

  63. 63.

    von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658–67 PubMed PMID: 10080612. Epub 1999/03/18.

  64. 64.

    von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012–9 PubMed PMID: 25385727. Epub 2014/11/12.

  65. 65.

    Reck M, Vicente D, Ciuleanu T, Gettinger S, Peters S, Horn L, et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331. Ann Oncol. 2018;29(Suppl_10).

  66. 66.

    Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, et al. Pembrolizumab in patients with extensive-stage small-cell lung Cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823–9 PubMed PMID: 28813164.

  67. 67.

    Chung HC, Lopez-Martin JA, Kao SC-H, Miller WH, Ros W, Gao B, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018;36(15_suppl):8506.

  68. 68.

    Strsberg JR, Mizuno N, Doi T, Grande E, Delord J-P, Sahira-Frommer R, et al. Pembrolizumab treatment of advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 2018;37(4_suppl).

  69. 69.

    Chung CH, Piha-Paul SA, Lopez-Martin J, Schellens JHM, Kao S, Miller WHJ, et al. Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer (SCLC): Results from the KEYNOTE-028 and KEYNOTE-158 studies. Proceedings of the 110th Annual Meeting of the American Association for Cancer Research Abstract CT073. 2019.

  70. 70.

    Sequist L, Chiang A, Gilbert J, Gordon MS, Conkling PR, Thompson D, et al. Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Ann Oncol. 2016;27(suppl_6).

  71. 71.

    Pujol JL, Greillier L, Audigier Valette C, Moro-Sibilot D, Uwer L, Hureaux J, et al. A randomized non-comparative phase II study of anti–PD-L1 ATEZOLIZUMAB or chemotherapy as second-line therapy in patients with small cell lung cancer: Results from the IFCT-1603 trial. Ann Oncol. 2018;29(suppl_8).

  72. 72.

    Goldman JW, Dowlati A, Antonia SJ, Nemunaitis JJ, Butler MO, Segal NH, et al. Safety and antitumor activity of durvalumab monotherapy in patients with pretreated extensive disease small-cell lung cancer (ED-SCLC). J Clin Oncol. 2018;36(15_suppl):8518.

  73. 73.

    Cho DC, Mahipal A, Dowlati A, Chow WA, Segal NH, Chung KY, et al. Safety and clinical activity of durvalumab in combination with tremelimumab in extensive disease small-cell lung cancer (ED-SCLC). J Clin Oncol. 2018;36(15_suppl):8517.

  74. 74.

    Kim Y, Keam B, Ock C-Y, Song S, Kim M, Kim SH, et al. A phase II study of pembrolizumab and paclitaxel in refractory extensive disease small cell lung cancer. J Clin Oncol. 2018;36(15_suppl):8575.

  75. 75.

    Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, Azpilikueta A, Etxeberria I, Bolanos E, et al. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur J Immunol. 2016;46(3):513–22 PubMed PMID: 26773716. Epub 2016/01/17.

  76. 76.

    Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, et al. Phase I study of single-agent Utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res. 2018;24(8):1816–23 PubMed PMID: 29549159. Epub 2018/03/20.

  77. 77.

    Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–5 PubMed PMID: 28813415. Pubmed Central PMCID: PMC5570667. Epub 2017/08/17.

  78. 78.

    Chuu CP, Lin HP. Antiproliferative effect of LXR agonists T0901317 and 22(R)-hydroxycholesterol on multiple human cancer cell lines. Anticancer Res. 2010;30(9):3643–8 PubMed PMID: 20944148. Epub 2010/10/15.

  79. 79.

    Wang Q, Ren M, Feng F, Chen K, Ju X. Treatment of colon cancer with liver X receptor agonists induces immunogenic cell death. Mol Carcinog. 2018;57(7):903–10 PubMed PMID: 29573475. Epub 2018/03/25.

  80. 80.

    Mita MM, Mita AC, Chmielowski B, Hamilton EP, Pant S, Waltzman RJ, et al. Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies. J Clin Oncol. 2018;36(15_suppl):3095.

  81. 81.

    Leonardi GC, Gainor JF, Altan M, Kravets S, Dahlberg SE, Gedmintas L, et al. Safety of programmed Death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J Clin Oncol. 2018;36(19):1905–12 PubMed PMID: 29746230. Epub 2018/05/11.

  82. 82.

    Danlos FX, Voisin AL, Dyevre V, Michot JM, Routier E, Taillade L, et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer. 2018;91:21–9 PubMed PMID: 29331748. Epub 2018/01/15.

  83. 83.

    Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29 PubMed PMID: 28885881. Epub 2017/09/09.

  84. 84.

    Bonanno L, Pavan A, Attili I, Pasello G, Guarneri V. Immunotherapy in SCLC: exceptional clinical benefit and Abscopal pneumonitis after radiotherapy. J Thorac Oncol. 2019;14(1):e5–7 PubMed PMID: 30579553.

  85. 85.

    Arriola E, Wheater M, Galea I, Cross N, Maishman T, Hamid D, et al. Outcome and biomarker analysis from a multicenter phase 2 study of Ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC. J Thorac Oncol. 2016;11(9):1511–21 PubMed PMID: 27296105. Pubmed Central PMCID: 5063510.

  86. 86.

    Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, et al. Tumor mutational burden and efficacy of Nivolumab monotherapy and in combination with Ipilimumab in small-cell lung cancer. Cancer Cell. 2018;33(5):853–61 e4. PubMed PMID: 29731394.

  87. 87.

    Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441–8 PubMed PMID: 30082870. Epub 2018/08/08.

  88. 88.

    Kim HS, Lee JH, Nam SJ, Ock CY, Moon JW, Yoo CW, et al. Association of PD-L1 expression with tumor-infiltrating immune cells and mutation burden in high-grade neuroendocrine carcinoma of the lung. J Thorac Oncol. 2018;13(5):636–48 PubMed PMID: 29378266. Epub 2018/01/30.

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

PA, AI and BL: conception of the manuscript, collection and analysis of literature data, drafting the manuscript. PG, GV and CPF: critical revision of the manuscript. All the authors read and approved the final version of the manuscript.

Correspondence to L. Bonanno.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • Small cell lung cancer
  • Immune checkpoint inhibitors
  • Immunotherapy
  • Tumor microenvironment
  • Combination therapy
  • Enhancer of zeste homolog 2