New developments in immunotherapy for SCLC.

Introduction

Small cell lung cancer (SCLC) is an aggressive subtype of high-grade neuroendocrine neoplasm. While initial responses to platinum therapies plus radiation are profound, they lack durability. SCLC is often refractory to second-line treatment. Platinum-doublet chemotherapy—among other regimens—has been used in this situation. 1 Depending on the stage, median overall survival (OS) is in the range of 12 months to about 3 years. SCLC treatment algorithms include extensive stage and limited stage; whereas treatment for limited stage is aimed toward curative intent, extensive stage SCLC (ES-SCLC) is treated with palliative intent. The most current treatment recommendations can be found at NCCN.org. 2 Traditionally, treatment for SCLC has relied on a platinum-based backbone, with a combination of either carboplatin or cisplatin plus etoposide. On relapse, subsequent lines of therapy can include rechallenge with platinum-based therapy (if initial response is at least 90 days or more), lurbinectedin, or irinotecan/topotecan, among others. Lurbinectedin was introduced as safe and active second-line treatment for SCLC. Disappointingly, though, the overall response was only 35%. 3 Unfortunately, in the relapsed setting, OS peaks around 6 months for each therapy option. Even with practice-changing clinical trials that have emerged within the last 5 years, multiple challenges to treatment have kept OS rates low. This review aims to address recent advancements and challenges in the use of immunotherapy for the treatment of ES-SCLC.

There have been many breakthroughs regarding the understanding of SCLC’s complex mutational landscape. Genomic sequencing has revealed a high mutational burden as well as many chromosomal rearrangements. 4 More recently, multiple molecular subsets of SCLC were described. 5 7 Gay et al described four subtypes of SCLC per expression of transcription factors ASCL1 , NEUROD1 , and POU2F3, or low expression of all three transcription factors accompanied by inflamed gene signature (SCLC-A, -N, -P, and -I). Of these, SCLC-I experiences the greatest benefit from immunotherapy in addition to chemotherapy. 6 A recent study indicated that ZFHX3 mutations predict development of immune-hot tumors and could serve as a biomarker for benefit from immune checkpoint inhibitors. 7 In this study, 112 tumors from newly diagnosed patients were divided into four subgroups according to non-negative matrix factorization (NMF): NMF1, NMF2, NMF3, and NMF4 . Of these, NMF1 and NMF2 have high neuroendocrine phenotypes which may be sensitive to treatment with an ATR inhibitor 8 or DLL3 targeted therapy. While NMF4 ( POU2F3 high expression in many) bears the signature of active myc1 and is sensitive to alisertib, an AURA/B inhibitor, the subtype NMF3 may be sensitive to receptor tyrosine kinase inhibitors such as anlotinib. Immune scores are high in NMF3 and NMF4 subgroups. It also became apparent that the tumor cells display plasticity and can switch phenotypes between different molecular states. 9

As for historical context, high doses of chemotherapy were explored more than 20 years ago, though with disappointing results. One such study reported on 103 patients treated with high-dose chemotherapy and autologous stem cell rescue. 10 These patients were treated between 1989 and 1997 and had a median age at transplantation of 50 years. While younger patients responded better to treatment than older patients, the results were not improved when compared with standard chemotherapy. Even in limited stages, less than half of the patients were alive after 3 years. 10

Checkpoint inhibitors in ES-SCLC and tumor microenvironment

Until the CASPIAN and IMpower133 studies, there had been little advancement in first-line treatment of ES-SCLC. These studies showed improved survival with traditional platinum-based chemotherapy plus a checkpoint inhibitor. 11 12 Both atezolizumab and durvalumab were approved by the Food and Drug Administration (FDA) for ES-SCLC, with improvement in survival increased by a little more than 2 months. On subgroup analysis, this survival benefit was irrespective of PD-L1 status. However, the impact of checkpoint inhibitors as monotherapy in SCLC appears limited, as only 10–15% of patients derive long-term benefits. 13 Although a retrospective analysis from the IMpower133 study suggested that responders to immunotherapy were enriched in tumors that do not express ASCL1 , NEUROD1 , or POU2F3 (also known as SCLC-I or inflammatory), this has not been shown in a prospective study. 6 In a phase III study, tiragolumab, a TIGIT inhibitor, was combined with standard-of-care chemotherapy and atezolizumab. Unfortunately, progression-free survival was similar in both arms of the study, showing no benefit from the addition of tiragolumab. 14 Similarly, the combination of ATR inhibitor with topotecan did not improve progression-free survival in relapsed/refractory SCLC and resulted in an improvement in OS of only 3.5 months compared with topotecan alone. 8

Interestingly, patients with SCLC are found to have high tumor mutation burdens but do not respond strongly to PD-L1 blockade. 15 Two studies exploring pembrolizumab and nivolumab showed infrequent response to therapy (<20%), although responders tended to have durable results after more than 1 year. While both therapies received conditional FDA approval, they failed to meet primary endpoints in phase III clinical trials. As such, their indication has been removed from use in first-line treatment in conjunction with standard-of-care chemotherapy, and in second-line treatment as monotherapy. The only exception is the use of pembrolizumab or nivolumab monotherapy in patients who have never been exposed to previous PD-L1 blockade, which is now the standard-of-care in first lines of treatment.

This modest response to PD-L1 blockade demonstrates two very important mechanisms of resistance to immune therapy: tumor microenvironment and decreased immunogenicity. SCLC has an immune-protected microenvironment that is driven or augmented by deficient MHC class I presentation. One study cites approximately 71% of SCLC cases as having ineffective or completely absent MHC-I presentation. This defective antigen presentation limits the effectiveness of therapies that rely on antigen presentation (PD-L1 blockade included) and cytotoxic T cell activation. 16 Therefore, exploration of immune therapies that bypass this deficiency should be considered when treating SCLC. Many other factors, including drug metabolism in the tumor, immunosuppressive macrophages, and trogocytosis between tumor and immune cells may result in failure; however, classic chemotherapy has shown very limited potential.

Recently, a checkpoint inhibitor (Adriatic study) was shown to improve OS and progression-free survival in limited stage SCLC when given as consolidation. 17

DLL3 and other targets for immunotherapy

Delta-like ligand 3 ( DLL3 ) is part of the inhibitory NOTCH signaling pathway. Preclinical studies in mouse models have shown that DLL3 regulates proliferation in SCLC by the Snail pathway. Knockout of the DLL3 gene leads to decreased tumor proliferation, whereas overexpression of DLL3 generally leads to increased proliferation. 18 DLL3 expression in SCLC is found across disease stages and lines of therapy. There is limited expression (primarily cytoplasmic) in normal cells including the pituitary, testes, and neurons. 19 A recent literature review based on 30 studies confirmed that most patients with SCLC can be expected to be positive for DLL3 . Thus, therapies directed at DLL3 may impart therapeutic benefit in SCLC and other high-grade neuroendocrine tumors. 8 19 20 In a recent case report, a young man with large cell neuroendocrine cancer of his lung was treated with a DLL3 -targeting bispecific antibody and achieved a partial response lasting longer than his previous line of therapy. 21

Shirasawa et al 22 performed whole exome sequencing and showed that cases with high DLL3 expression had significantly more neoantigens than low-expressing cases. As a possible explanation for why immunotherapy with checkpoint inhibitors does not improve survival in SCLC, it was found that high-expressing DLL3 cases had suppressed immune-related pathways and dendritic cell function. Their microenvironments had lower proportions of T cells, macrophages, and dendritic cells. In this study, the progression-free survival of patients on platinum, etoposide, and anti-PD-L1 antibody was significantly worse in high -DLL3 cases. 22 In mouse models , DLL3 was used as a target for radioimmunotherapy. 23 In summary, DLL3 expression is nearly ubiquitous in neuroendocrine cancer/SCLC, and cells expressing high levels of DLL3 have an immunosuppressive microenvironment, thereby giving the rationale for DLL3 targeting.

Another possible target for CAR-T cells is the ganglioside GD2 antigen, which is extensively present in neural stem cells. CAR-T cells targeting GD2 antigen for glioblastoma have shown tumor reduction in xenografts. 24 Disialoganglioside GD2 has limited expression in normal cells but is abundantly present in tumor cells, which makes it a potential target for cancer therapy. GD2 antigen has been implicated in tumor cell proliferation, migration, adhesion, and invasion. 25 GD2 CAR-T cells were evaluated in in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. In this study , GD2 was expressed in 26.7% of SCLC and NSCLC cell lines tested by flow cytometry, and in 39% of SCLCs, 72% of lung adenocarcinomas, and 56% of squamous cell carcinomas analyzed by immunohistochemistry. The authors created a vector that coexpressed IL-15 to promote T cell proliferation and persistence. The transfected cells also had an inducible caspase 9 safety switch. GD2 low/negative lung cancer cell lines were treated with tazemetostat, which upregulates GD2 expression and potentially triggers increased GD2.CAR-T cell cytotoxicity. 26 The University of North Carolina is currently conducting a phase I, open-label study ( NCT05620342 ) to test CAR-T cells against the GD2 antigen. In this study, up to 24 platinum and/or PD-L1 blockade refractory patients with ES-SCLC or stage 4 non-SCLC will be enrolled to test the safety and potential efficacy of iC9-GD2.CAR.IL-15 T cells. In addition to DLL3 and GD2 other markers on SCLC may also serve as targets for immunotherapy.

Bispecific antibodies and antibody conjugates

Bispecific antibodies or bispecific T-cell engager (BiTE) molecules are recombinant immunoglobulins with two specific targets (a tumor-associated antigen and a T cell antigen for T cell stimulation). Bispecific antibodies are special in terms of their ability to bypass the MHC-I pathway, or in other words, their ability to bypass the need for antigen presentation and recognition by T cell receptors, thereby increasing the number of T cells available to recognize tumor cells. On binding, T cells can form a cytolytic synapse, leading to pore formation and the release of cytokines. This sudden release of cytokines is the driver of two of the adverse effects of bispecific molecules: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While potentially life-threatening, these adverse effects are often limited to initial treatments and are manageable with anti-inflammatory agents and supportive care. Other possible adverse effects include neutropenia, infection, and cardiotoxicity. 27 28 However, one major advantage for BiTE molecules (particularly in fast-growing cancers such as SCLC) is the ability to be used “off the shelf”. Once developed, this treatment is universal and can be used without delay for patient-specific development, which is necessary for CAR-T cell therapy.

While BiTE molecules are a new frontier for solid tumor malignancies, they have a proven track record for treatment of hematological malignancies. Unfortunately, solid malignancies have had more limited success, which is thought to be attributable to a combination of tumor accessibility, limited target expression, and tumor microenvironment. 29

Nonetheless, recent studies for the treatment of ES-SCLC have shown early promise. Multiple bispecific antibodies targeting DLL3 are under development, with tarlatamab among the first for SCLC. Tarlatamab is a bispecific antibody with domains for DLL3 and CD3 and has shown early promise in clinical trials. Recent phase II data from the DeLLphi-301 trial have shown an objective response in 40% of patients and a median OS of 14 months in patients who have received two or more prior lines of therapy. In the DeLLphi-301 trial, patients were divided to receive either 10 mg or 100 mg of tarlatamab every 2 weeks, with interim analysis yielding similar efficacy and improved safety profile with 10 mg dosing. As expected, the most common adverse effects included 40% of patients experiencing any grade CRS (one with grade 3 or 4) on day 1 and 28% experiencing CRS on day 8 (no grade 3 or 4). Only one patient in the 10 mg arm had to discontinue therapy due to adverse effects. At the time of publication, the median OS for the 10 mg arm was 14 months, while the 100 mg arm is still ongoing. Approximately, 84% of patients expressed DLL3.

DeLLphi-304 is a phase III trial that is studying tarlatamab versus standard-of-care therapy for relapsed ES-SCLC. 30 Tarlatamab-dlle was granted accelerated FDA approval on May 16, 2024, for ES-SCLC that has progressed on or after first-line treatment. A boxed warning includes CRS and neurotoxicity. The recommended dose is 1 mg on day one, subsequently, 10 mg on days 8 and 15, continued every 2 weeks until progression or unacceptable toxicity (see figure 1 ).

Another group, including Paz-Ares et al , 31 conducted a dose escalation phase I study with tarlatamab that included 107 patients with recurrent ES-SCLC. Of these 107 patients, 44% showed ongoing responses beyond the data cut-off, with most patients having durable tumor responses after receiving doses of 10, 30, and 100 mg every 2 weeks. CRS was the most serious adverse event observed. Eight patients received tocilizumab in addition to steroids, antipyretics, and fluids for CRS. High levels of cytokines appear to trigger endothelial cell activation, disrupting the blood–brain barrier and resulting in an inflammatory cascade that can lead to diffuse brain edema. 32 33

At the time of publication, multiple phase II and phase III clinical trials with DLL3 targets are in progress. A selected number of such studies is shown in table 1 . One example is a phase II study ( NCT05882058 ) where two different doses of a DLL3- targeting bispecific antibody are given to patients with SCLC and other neuroendocrine tumors of the lung. The patients have to have progressed after platinum-based chemotherapy. The antibody is given intravenously every 21 days for a maximum of 36 cycles. To minimize infusion reactions, the antibody is given in step-up doses for the first 3 weeks. During the first cycle, steroids are given as premedication. In vitro and in mouse models, DLL3 -targeting bispecific antibodies improved cell killing when combined with a checkpoint inhibitor. 34 A further development is a trispecific antibody which targets DLL3 , CD3 , and CD137 . In in vitro and in vivo models, the trispecific antibody led to improved tumor control and a marked increase in the number of intratumoral T cells. 35 Phanes Therapeutics is currently testing a human bispecific antibody targeting DLL3 and human CD47 . This study has begun to enroll patients and is currently open at six locations in the United States ( NCT05652686 ). Data on tolerability, safety, and preliminary efficacy are not yet available.

Antibody–drug conjugates are another option for targeted treatments. Rovalpituzumab tesirine (Rova-T) is an antibody conjugate that selectively binds to DLL3 receptors present in tumor cells, and once internalized, starts the apoptosis cascade which halts the cell cycle at the G2-M stage. In the phase II TRINITY study, Rova T was tested in the third-line setting. Overall, modest clinical activity was observed with an objective response rate of 12.4% in all patients, 13.2% in DLL3-positive patients, and 14.3% in DLL3-high patients. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. In addition, adverse reactions of grades 3–5 were seen in 63% of patients. 36 The development of Rova-T eventually failed, however, due to many issues associated with the molecule, including low drug antibody ratio, very toxic payload, and a poor linker resulting in premature cleavage of the linker. 37

Chimeric antigen receptor-T cells for SCLC

Chimeric antigen receptor-T cells (CAR-T cells) are T cells that are taken from the patient, genetically modified to target tumor-specific tumor surface antigens, and then infused into the same patient. Currently, all approved CAR-T cell products are autologous, with the most common uses being for the treatment of relapsed B-cell non-Hodgkin’s lymphomas and multiple myeloma. In CD19-positive non-Hodgkin’s lymphomas, CAR-T cells have a potential for long-term remission or cure. 38 See figure 1 for the basic principles of CAR T cell and bsAb treatments. With the expression of DLL3 on the cell surface, SCLC cells offer a valid target for CAR-T cells. Zhang et al 39 generated a series of allogeneic “off-the-shelf” CAR-T cells targeting DLL3 . These CAR-T cells were genetically modified to remove part of the T cell receptor complex. The authors show that their clones have strong anti-tumor activity in vitro and in vivo in mouse models. Tumor killing was observed even with low target antigen density. In mouse models, limited off-target toxicity was observed. Some of these clones also have a rituximab-based safety switch. Jaspers et al 40 developed CAR-T cells against DLL3 which secreted the inflammatory cytokine IL-18 . In their model, both xenografts and mouse models had significant anti-tumor activity. The expression of IL-18 increased the activity of CAR-T cells and recruited endogenous tumor-infiltrating lymphocytes. In several models, human CAR-T cells against DLL3 showed an increased memory phenotype, were less exhausted, and showed durable responses. Their efficacy could be further enhanced with PD-1 blockade.

In a phase I clinical protocol ( NCT05680922 ), autologous CAR-T cells will be generated to target DLL3 . This study is currently open at four institutions in the USA. Eligible patients include those who have progressed on or failed at least one prior treatment, including standard-of-care carboplatin plus etoposide plus either durvalumab or atezolizumab. The first stage of this study explores four dose levels of viable CAR-T cells ranging from 0.3–4.0×10 6 /kg. The vector uses a CD137/4-1BB domain and an intracellular CD3ξ domain. In addition, the vector expresses a dominant negative TGFβRII receptor which is supposed to antagonize immunosuppression in the microenvironment. A total of 52 subjects will be screened and up to 41 enrolled. Table 2 shows the currently open CAR-T cell studies for SCLC in the USA.

Another strategy might involve the use of natural killer cells. Cell lines derived from SCLC were found to experience significant cytotoxicity when incubated with modified natural killer cells ( DLL3 -CAR NK-92). These cells were also active in lung cancer metastasis models and subcutaneous tumor models. 41 Figure 1 shows the basic principles of CAR T cells and bispecific antibodies targeting SCLC (or any other malignancy).

Challenges and advantages of CAR-T cells for solid tumors

Though CAR-T cells are widely used and successful for the treatment of CD19-positive lymphomas and multiple myeloma, the development of CAR-T cells for solid tumors is lagging. The reasons for this are multiple: inherent resistance to T cell killing, immunosuppressive microenvironments, stromal cells preventing access to T cells, interference of platelets with T cell killing, and interferon signaling. Moreover, solid tumors often do not have a targetable surface marker. SCLC appears to be an ideal target for CAR-T cells because the tumor cells frequently infiltrate the bone marrow, similar to leukemia cells. Like in leukemia, SCLC is thought to have a high burden of circulating tumor cells. With the highest number of circulating tumor cells from early stage, tumor cells are thought to be constantly seeding other organs, including the brain, bones, liver, adrenal glands, etc. Of patients with SCLC, 85% were found to have circulating tumor cells. 42

Recently, Larson et al 43 pointed out the critical role of IFNγR signaling in solid tumors. It is required for the adhesion of CAR-T cells to tumor cells. In their study, the loss of IFNγR in glioblastoma resulted in reduced binding duration and avidity. According to their study, productive cytotoxicity could be restored if IFNγ signaling is re-introduced.

Hagel et al 44 performed genome-scale CRISPR-Cas9 screens in mesothelin ( MSLN )-expressing pancreatic cancer cells to investigate intrinsic resistance to CAR-T cell therapy. They found both antigen-dependent and antigen-independent pathways of tumor resistance. Of note, loss of GPI anchor biosynthesis helped evade CAR-T cells to target MSLN-expressing pancreatic cells, suggesting that the presence of GPI antigens may help CAR-T cells to interact with tumor cells.

A further target is Claudin-6 expressed on solid tumors other than SCLC, including pancreatic and testicular cancers. Current studies aim at overcoming resistance in these tumors. 45 46 See table 1 for a limited series of CAR-T cell studies for solid tumors.

The side effects, some of which are life-threatening, have limited CAR-T therapy use. ICANS is a serious toxicity that commonly occurs with CAR-T cell therapy. 47 Cost to society may also be a limiting factor for the widespread use of these treatments. Despite challenges associated with time-intensive CAR-T cell development, infusion, and initial tolerability, there are still possible advantages. One such benefit includes avoiding the need for repeated infusions. After the initial development of the CAR-T product and subsequent hospitalization for infusion, patients are not required to return for repeat infusions every 1–3 weeks. Depending on the response, some patients may live for years without regular infusions. Additionally, although they have high initial toxicity and longer-term cytopenias, CAR-T therapies may become well tolerated in the long term. 43 Finally, as CAR-T and bispecific antibodies are developed, patients could theoretically receive both treatments, especially if the cellular surface targets for each treatment are different. Under some circumstances, redosing of CAR-T cells may also be feasible.

Conclusions

SCLC remains difficult to treat, with most recent advancements lagging behind those of many other malignancies. This is due in part to its immune-protected microenvironment and apparent lack of actionable mutations. In the wake of recent phase II and III data from tarlatamab, the targeting of DLL3 holds promise for ES-SCLC. Moreover, this same receptor, among others, represents a viable opportunity for emerging CAR-T cell therapies.

Acknowledgements

The University of Kentucky Markey Cancer Center’s Research Communications Office assisted with manuscript preparation. Special thanks for Lauren Tecau for help with the graphic illustration.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Patient consent for publication: Not applicable.

Provenance and peer review: Commissioned; externally peer reviewed.

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