Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: results from the exploratory, controlled, randomized, international phase II IMPULSE study

Thomas, Michael; Ponce-Aix, Santiago; Navarro, Alejandro; Riera‐Knorrenschild, Jorge; Schmidt, Manuel; Wiegert, Emanuelly Varea Maria; Kapp, Kerstin; Wittig, Burghardt; Mauri, Claudia; Gómez, M. Dómine; Kollmeier, Jens; Sadjadian, Parvis; Fröhling, K.-P.; Huber, RM; Wolf, M.; Pall, Georg; Surmont, Veerle; Bosquee, Léon; Germonpré, Paul; Brückl, W.; Grah, C.; Herzmann, Christian; Leistner, Rumo; Meyer, Andreas; Müller, Lothar; Schmalz, Oliver; Scholz, Christian W.; Schröder, M.; Serke, Monika; Wesseler, Claas; Brandts, Christian; Kopp, Hans‐Georg; Blau, Wolfgang; Griesinger, Frank; Campelo, M.R. García; García, Yolanda; Pérez, Jose

doi:10.1093/annonc/mdy326

Cited by 67 publications

(48 citation statements)

References 28 publications

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“…36 However, it should be considered that PTO-modified TLR9 agonists induce a different cytokine pattern in vitro. 8,18 The described immunomodulatory effects of lefitolimod, the potent synergistic anti-tumor responses observed in combination with CPI in murine models, during which no signs of toxicological effects have been observed, and the absence of toxic effects in more than 450 patients in clinical trials [10][11][12][13]37 renders lefitolimod as an ideal combination partner for immunotherapeutic approaches in humans. In fact, a clinical trial in melanoma patients with a combination of lefitolimod and ipilimumab is ongoing and has shown encouraging first data on increase of tumor-infiltrating lymphocytes and a favorable safety profile, and no dose-limiting toxicities have been encountered at any dose level of lefitolimod together with ipilimumab.…”

Section: Discussionmentioning

confidence: 99%

“…10 Currently, lefitolimod is under evaluation for the maintenance treatment of metastatic colon carcinoma 11,12 and data from an exploratory Phase 2 trial in ES-SCLC have recently been published. 13 Intracellular signaling triggered by TLR9 results in upregulation of two pathways: (a) activation of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) inducing the production of pro-inflammatory cytokines and acquisition of antigen-presenting function, and (b) activation of interferon (IFN) regulatory factor 7 (IRF7) leading to type I IFN (e.g. IFN-alpha) production.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors

et al. 2019

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Activation of Toll-like receptor 9 (TLR9) is known to foster innate and adaptive immune responses and thus improve immune-mediated control of malignant disease. Lefitolimod is a potent TLR9 agonist without chemical modification developed for immunotherapeutic strategies. Modulation of the tumor microenvironment (TME) is a crucial requirement for the response to various immunotherapies: Immunogenic (“hot”) tumors, characterized by their T cell-infiltrated TME, respond better compared to non-immunogenic (“cold”) tumors. It has been speculated that the mode-of-action of lefitolimod provides the necessary signals for activation of immune cells, their differentiation into anti-tumor effector cells and their recruitment into the TME. We investigated the effect of lefitolimod on TME, and its potency to induce synergistic anti-tumor effects when combined with immune checkpoint inhibitory antibodies (CPI) in a murine model. Indeed, we could show that treatment with single-agent lefitolimod beneficially modulated the TME, via infiltration of activated CD8+ cells and a shift in the macrophage population toward M1 phenotype. The result was a pronounced anti-tumor effect correlated with the magnitude of infiltrated immune cells and tumor-specific T cell responses. In line with this, lefitolimod led to persistent anti-tumor memory in the EMT-6 model after tumor re-challenge. This was accompanied by an increase of tumor-specific T cell responses and cross-reactivity against different tumor cells. Lefitolimod clearly augmented the limited anti-tumor effect of the CPI anti-PD1 in an A20 and anti-PD-L1 in a CT26 model. These properties of potent immune surveillance reactivation render lefitolimod an ideal candidate as therapeutic agent for immuno-oncology, e.g. improving CPI strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors

et al. 2019

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“…Toll-like receptor 9 (TLR9) is expressed on a variety of immune cells and plays a major role in activation of innate immunity including stimulation of cytokine production including type 1 IFNs (35). Lefitolimod (MGN1703) is a DNA molecule which functions as a TLR9-agonist and demonstrated favorable tolerability and evidence of anti-tumor immune activation in early studies (35,36). The randomized, phase II IMPULSE trial tested lefitolimod as maintenance in ES-SCLC.…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC)

2020

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Small-cell lung cancer (SCLC) accounts for 13-15% of all new lung cancer cases in the US. The tumor has a tendency to disseminate early resulting in 80-85% of patients being diagnosed with extensive disease (ES-SCLC). Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades. Nonetheless, most patients relapse and rarely survive beyond 2 years. Despite consistent overall response rates of ≥50%, until recently, median survival times and 2-year survivals only ranged between 7-10 months and 10-20%, respectively. Several chemotherapy agents possess activity against SCLC, both, as single agents and in combinations but etoposide-platinum emerged as the preferred first line regimen. Upon relapse, many patients remain candidates for additional therapy. However, the sensitivity of relapsed SCLC to further therapies is markedly reduced and dependent upon the level and duration of response to the initial treatment (platinum-sensitive vs. resistant relapse). Multiple factors suggest a therapeutic role for immunotherapy in SCLC: (1) SCLC has been associated with immune-mediated paraneoplastic processes (cerebellar degeneration, limbic encephalitis, and Lambert-Eaton syndrome) and patients presenting with these paraneoplastic syndromes have shown more favorable outcomes, suggesting an underlying immune response mechanism. (2) Comprehensive genomic profiling of SCLC indicates that the majority lack functional p53 (90%) and Rb1 (65%). These universal genetic aberrations facilitate poor genomic stability, thus perpetuating the generation of tumor associated antigens, amenable to targeting with immunotherapy. (3) SCLC has one of the highest mutational loads, likely a reflection of the myriad of insults inflicted by smoking-related carcinogens. The relationship between tumor mutational load and response to immune checkpoint inhibitors has been established in multiple solid tumors, including preliminary results in relapsed SCLC. In this manuscript, we review the early (some failed and discontinued, some partly successful, and still ongoing) attempts to incorporate immunotherapy (particularly vaccine based approaches) to the treatment of SCLC, and the latest attempts Saltos et al. Biology, Management and Treatment of SCLC (mostly incorporating the use of checkpoint inhibitors), including those with favorable but preliminary results (CheckMate 032, Keynote 028 and 158), and those with more definitive positive (iMpower 133 and CASPIAN) and negative (CheckMate 331 and 451) results.

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“…TLR9 ligands are frequently used as vaccine adjuvants (17,18), and can directly enhance proliferation and survival of T cells (19,20). Successful delivery of both TLR2 and TLR9 ligands has demonstrated promising therapeutic responses, particularly in cancer (13,(21)(22)(23). However, improved delivery approaches are needed to more easily deliver cell surface and intracellular ligands to diverse immune cells.…”

Section: Introductionmentioning

confidence: 99%

Lipid-Mediated Insertion of Toll-Like Receptor (TLR) Ligands for Facile Immune Cell Engineering

et al. 2020

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Cell-based immunotherapies have tremendous potential to treat many diseases, such as activating immunity in cancer or suppressing it in autoimmune diseases. Most cell-based cancer immunotherapies in the clinic provide adjuvant signals through genetic engineering to enhance T cell functions. However, genetically encoded signals have minimal control over dosing and persist for the life of a cell lineage. These properties make it difficult to balance increasing therapeutic efficacy with reducing toxicities. Here, we demonstrated the potential of phospholipid-coupled ligands as a non-genetic system for immune cell engineering. This system provides simple, controlled, non-genetic adjuvant delivery to immune cells via lipid-mediated insertion into plasma membranes. Lipid-mediated insertion (termed depoting) successfully delivered Toll-like receptor (TLR) ligands intracellularly and onto cell surfaces of diverse immune cells. These ligands depoted into immune cells in a dose-controlled fashion and did not compete during multiplex pairwise loading. Immune cell activation could be enhanced by autocrine and paracrine mechanisms depending on the biology of the TLR ligand tested. Depoted ligands functionally persisted on plasma membranes for up to 4 days in naïve and activated T cells, enhancing their activation, proliferation, and skewing cytokine secretion. Our data showed that depoted ligands provided a persistent yet non-permanent adjuvant signal to immune cells that may minimize the intensity and duration of toxicities compared to permanent genetic delivery. Altogether, these findings demonstrate potential for lipid-mediated depoting as a universal cell engineering approach with unique, complementary advantages to other cell engineering methods.

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Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: results from the exploratory, controlled, randomized, international phase II IMPULSE study

Cited by 67 publications

References 28 publications

Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors

Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors

Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC)

Lipid-Mediated Insertion of Toll-Like Receptor (TLR) Ligands for Facile Immune Cell Engineering

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