Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. Significance: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection. This article is highlighted in the In This Issue feature, p. 1861
Background Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse. Methods We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion. Results In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires. Conclusion Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies. Trial Registration ClinicalTrials.gov NCT04024761. Funding Dunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.
The challenge of eradicating leukemia for patients with acute myelogenous leukemia (AML) following initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 (NCT02890329) study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either following allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304,961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent following ipilimumab exposure, which altered CD4+ T cell gene expression, in line with ongoing T cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemia cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses.
2 11 newly generated MCC lines through genomic and proteomic analysis. We then interrogated MCC lines through genome-scale gain-and loss-of-function screens for the restoration of HLA-I. These screens identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as regulators of HLA-I. We further demonstrate that pharmacologic inhibition of the PRC1.1 component USP7 can restore HLA-I expression.
Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.
BackgroundAngiogenic factors promote the growth of tumor vasculature, modulate lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein- (CTLA-4), is safe in patients with advanced melanoma.MethodsIn a phase I, 3+3 dose escalation trial, patients with metastatic or unresectable melanoma received treme in combination with MEDI3617. The primary objectives of the study were safety and determination of recommended phase II dose (RP2D). The secondary objectives included determination of 6-month and 1-year overall survival and best overall response rate. Immune cell populations and soluble factors were assessed in peripheral blood and metastatic tumors using Fluorescence activated cell sorting (FACS), Luminex, and multiplexed immunofluorescence.ResultsFifteen patients (median age: 62) were enrolled in the study (3 patients in cohort 1: treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related adverse events were rash, pruritus, fatigue, and extremity edema. No dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. There were no patients with confirmed immune-related complete response or immune-related partial response. Six of 15 patients had immune-related stable disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An increase in frequencies of circulating inducible T-cell costimulator (ICOS)+ and human leukocyte antigen (HLA)-DR+ CD4+ and CD8+ T cells and production of Interleukin-2 and Interleukin-10 was observed post therapy.ConclusionsTremelimumab in combination with MEDI3617 is safe in patients with advanced melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint inhibition warrants further exploration.Trial registration numberNCT02141542.
Ethics Approval This study was approved by the Institutional Review Boards of Dana-Farber/Harvard Cancer Center (DFCI#16-385), Washington University (#201412118) and Memorial Sloan-Kettering Cancer Center (MSKCC) (#18-379). Abstract 503 Figure 1 Dynamics of exhausted CD8 T cells expressing markers of cytotoxicity and a tissue-resident memory program in HNSCC tumors. a, Frequencies of principal phenotypes among CD8+ TILs collected from Responders (R, circles, n=3) or Non-Responders (NR, diamonds, n=4) at pre-treatment timepoints (Pre). Box plotsmedian percentage of TILs with phenotypes corresponding to CD8+ nonexhausted memory cell states (TNExM, blue), exhausted states (TEx, red), or unclassified clusters (Other, grey
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