Nivolumab, a monoclonal antibody targeting PD-1, is currently approved for metastatic non-small cell lung cancer (mNSCLC) treatment after failure of first-line chemotherapy. However, only a quarter ...of patients benefit from this therapy with objective clinical response. In this context, there is an unmet need for improved understanding of resistance mechanisms. Thus, we studied a prospective cohort of mNSCLC (n = 61) treated in second or third-line with nivolumab. We analyzed various blood myeloid and lymphoid markers by flow cytometry (176 variables) at baseline, and after 15 and 30 days of therapy. By attempting to link the evolution of peripheral lymphoid, myeloid cells and anti-PD-1 response, we observed that accumulation of lymphoid cells and monocytic MDSC (mMDSC) expressing, respectively, Tim-3 and galectin-9 is implicated in resistance to PD-1 blockade both for patients with primary or acquired secondary resistance to anti-PD-1. In vitro, anti-Tim-3 blocking antibody reverses resistance to anti-PD-1 in PBMC from lung cancer patients and high levels of blood mMDSC negatively impact on anti-PD-1 efficacy. Together, these data underline that the galectin-9/Tim-3 pathway and mMDSC are key mechanisms of primary or secondary resistance to anti-PD-1 and could be a new target for immunotherapy drug combinations.
Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with ...sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status.
This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.
Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC.
Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC.
In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population.
NCT01658878.
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•This is the first report, to our knowledge, of immune checkpoint inhibitor therapy in patients with advanced HCC and Child-Pugh B liver function status.•Median OS with nivolumab was longer than the historical OS rate for patients treated with sorafenib (7.6 months vs. 2.5–5.4 months, respectively).•Clinically meaningful stabilisation of liver function was observed, as evidenced by maintained or improved Child-Pugh scores and albumin-bilirubin scores.•Nivolumab had a favourable safety profile with manageable toxicities when used in patients with Child-Pugh B advanced HCC and was comparable to that seen in patients with Child-Pugh A HCC.
Although the interaction between tumor immune microenvironment and angiogenesis has been well established, evidence supporting the chemo-free combination of immune checkpoint inhibitors plus ...antiangiogenic tyrosine kinase inhibitors in treatment-naive patients with advanced NSCLC is insufficient. This report provides the efficacy and safety of sintilimab combined with anlotinib as first-line therapy for advanced NSCLC from a phase 1b trial (NCT03628521).
Eligible patients who were treatment-naive and had unresectable stage IIIB/C or IV NSCLC without EGFR/ALK/ROS1 mutations received sintilimab (200 mg, day 1) and anlotinib (12 mg, day 1–14) every 3 weeks till disease progression or unacceptable toxicity. Baseline programmed death-ligand 1 expression and tumor mutation burden status was assessed in all patients. The primary end points were objective response rate and safety.
A total of 22 patients received sintilimab and anlotinib. Median follow-up was 15.8 months (range: 8.3–19.3). Sixteen patients achieved confirmed partial response with an objective response rate of 72.7% (95% confidence interval CI: 49.8%–89.3%) and disease control rate of 100% (95% CI: 84.6%–100%). Median progression-free survival was 15 months (95% CI: 8.3 m, not reached), and the 12-month progression-free survival rate was 71.4% (95% CI: 47.2%–86.0%). The incidence rate of grade 3 or higher treatment-related adverse events was 54.5%, and grade 3 hypertension was predominant (two of 22, 9.1%). No grade 4 treatment-related adverse events were observed, and one case of grade 5 immune-related pneumonitis occurred.
To the best of our knowledge, this is the first study that assessed an anti–programmed cell death protein 1 antibody combined with a multitarget antiangiogenic tyrosine kinase inhibitor in the frontline setting for patients with NSCLC. In view of its encouraging efficacy, durability, and safety profile, sintilimab plus anlotinib represents a novel chemotherapy-free regimen in this patient population.
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We ...find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
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•T cell-induced IFN-γ correlates the best to immune checkpoint blockade (ICB) therapy•Immune signatures increase in on-therapy patients regardless of response to therapy•ICB therapy decreases MYC and WNT signaling in patients with clinical response•IFN-γ exposure of melanoma cells leads to a conserved transcriptome signature
Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFN-γ signaling drive clinical responses.
Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize ...drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES+CD69+CD45RO+ effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.
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•Activated T cell signatures/populations drive response to anti-PD-1-based therapies•EOMES+CD69+CD45RO+ effector memory T cells are associated with response•EOMES+CD69+CD45RO+ expression is associated with longer PFS and tumor shrinkage•Non-responders with TIL-hot tumors express other immune drug targets
Gide et al. characterize melanoma samples from patients treated with anti-PD-1 alone or with anti-CTLA-4. Tumors from non-responders to monotherapy often express other immune checkpoints and higher gene expression profile of EOMES+CD69+CD45RO+ T cells is associated with greater tumor shrinkage in both therapies.
•cMn-MOF@CM is developed for potentiating anti-PD-1 therapy in hypoxic tumors.•cMn-MOF@CM generates strong SDT effects in hypoxic tumors, inducing ICD and subsequent DC maturation and T cell ...activation.•cMn-MOF@CM as the nanovaccine directly induces DC maturation and T cell activation.•Combination of cMn-MOF@CM upon US irradiation with anti-PD-1 antibody generates a long-term immunological memory function.
A biomimetic sonodynamic therapy (SDT)-nanovaccine integration platform (cMn-MOF@CM) is fabricated for enhanced antitumor immunity by tumor-associated antigens both in situ derived from SDT and OVA and the immune adjuvant CpG. The combination of cMn-MOF@CM -triggered SDT and anti-PD-1 antibody induces stronger systemic immune response and long-term immunological memory function to prevent tumor growth and recurrence. Display omitted
Immune checkpoint blockade (ICB) therapy has emerged as novel therapeutic modality for hard-to-treat solid tumors. However, inadequate T cell infiltration in hypoxic solid tumors limits its anticancer efficacy. Here we develop a sonodynamic therapy (SDT)-nanovaccine integration platform constructed by binding a manganese porphyrin-based metal-organic frameworks (Mn-MOF) with an immune adjuvant CpG and then coating with cell membranes derived from ovalbumin (OVA)-overexpressing melanoma B16 cells (cMn-MOF@CM) for potentiating anti-programmed death receptor 1 (PD-1) antibody in malignant melanoma therapy. cMn-MOF@CM with prolonged blood circulation and enhanced tumor targeting efficiently relieves tumor hypoxia and generates strong SDT effects and immunogenic cell death. The tumor-associated antigens both in situ derived from SDT and OVA exhibit vaccine-like functions together with the immune adjuvant CpG, eliciting a strong tumor-specific immune response by promoting DC maturation and T cell activation. Importantly, the combination of cMn-MOF@CM-triggered SDT and anti-PD-1 antibody induces stronger systemic immune response and long-term immunological memory function to prevent tumor growth and recurrence. These findings reveal that cMn-MOF@CM with US irradiation may be a potential candidate to potentiate ICB therapy for hypoxic cancer therapy.
Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with ...previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
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•Prior ICT is associated with longer PFS of melanoma patients treated with MAPKi•Anti-PD-1/L1 before MAPKi combination prolongs durability of tumor regression•Targeting M2-TAMs augments and CD8+ T cells abolishes priming-associated benefit•Anti-PD1/L1 plus anti-CTLA-4 priming may further control melanoma brain metastasis
Wang et al. couple in vivo preclinical therapeutic testing with temporal single-immune cell and T cell clonotype analysis to identify a sequential-combinatorial regimen and cellular effectors associated with the most durable control of tumor growth and brain metastasis. Initiating immune checkpoint therapy briefly before adding MAPK-targeted therapy may improve patient survival.
Immunotherapy has revolutionized cancer treatment. In non-small-cell lung cancer (NSCLC), monotherapy with immune checkpoint inhibitors has improved survival in metastatic disease. Combinations of ...immune checkpoint inhibitors have shown synergy in preclinical models and are being studied as part of the treatment armamentarium in NSCLC. This review discusses the rationale, outcomes, and challenges of combination immune checkpoint blockade. Despite the challenges, this paper also presents some solutions and ways to improve our understanding and implementation of such combinations in the future.
Despite recent advances in melanoma treatment through the use of anti-PD-1 (aPD1) immunotherapy, the efficacy of this method remains to be improved. Here we report an innovative self-degradable ...microneedle (MN) patch for the sustained delivery of aPD1 in a physiologically controllable manner. The microneedle is composed of biocompatible hyaluronic acid integrated with pH-sensitive dextran nanoparticles (NPs) that encapsulate aPD1 and glucose oxidase (GOx), which converts blood glucose to gluconic acid. The generation of acidic environment promotes the self-dissociation of NPs and subsequently results in the substantial release of aPD1. We find that a single administration of the MN patch induces robust immune responses in a B16F10 mouse melanoma model compared to MN without degradation trigger or intratumoral injection of free aPD1 with the same dose. Moreover, this administration strategy can integrate with other immunomodulators (such as anti-CTLA-4) to achieve combination therapy for enhancing antitumor efficacy.
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