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Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.
Nanotechnology for immuno-oncology.
Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.
Tumor-specific CD8 T cell characterization in HR+ breast cancer reveals an impaired antitumoral response in patients with lymph node metastasis.
Most breast cancers express the estrogen receptor (ER), but the immune response of hormone receptor-positive (HR+) breast cancer remains poorly characterized. Here, dendritic cells loaded with tumor lysate are used to identify tumor-reactive CD8 T cells, which are detected in most HR+ breast cancer patients, especially those with early-stage tumors. When present, the circulating antitumor CD8 response contains cytotoxic T cells with diverse specificity and T cell receptor (TCR) repertoire. Additionally, patients with blood cancer-specific T cells have significantly more CD8 tumor-infiltrating lymphocytes (TILs). Moreover, tumor-reactive TCR sequences are detected in the tumor, but at a significantly lower proportion in patients with lymph node involvement. Our data suggest that HR+ breast cancer patients with lymph node metastasis lack tumor-specific CD8 T cells with capacity to infiltrate the tumor at significant levels. However, early-stage patients have a diverse antitumor CD8 response that could be harnessed to develop immunotherapeutic approaches for late-stage HR+ patients.
A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients.
BackgroundTilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients.MethodsPatients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis.ResultsBetween 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients.ConclusionTilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required.Clinical trial registrationThis trial is registered at https://clinicaltrials.gov .Registration numberNCT04893551. EudraCT Number: 2020-001382-36.
Supplementary Tables and Figures from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Table S1: Pharmacokinetics of IVO+VEN and IVO+VEN+AZATable S2: Treatment characteristics across the four dose levels in the phase 1b study population.Table S3: Study medication adherence: (A), Adherence to protocol administered medications during DLT evaluation period (cycles 1 and 2) of protocol directed therapy. (B), Adherence to protocol administered medications during the first 12 months of protocol directed therapy.Table S4: Dose modifications in patients experiencing hematologic adverse events during the entire study period until data cut-off on March 15th, 2022.Table S5: Regions covered by institutional next-generation sequencing (NGS) interrogating the entire exonic or hotspot regions of 81-genes frequently mutated in myeloid malignancies.Table S6: Variants identified using targeted 81-gene myeloid NGS panelTable S7: CyTOF antibodies utilized.Figure S1: Molecular, cytogenetic, and IDH1 variants across the P1b study population. (A), Oncoprint of molecular mutations identified at diagnosis in 31 patients enrolled demonstrated a diverse molecular landscape. (B-C), Neither median mutation burden nor IDH1 VAF was significantly different between included disease types. (D), IDH1 variants differed across disease types, with R132C mutations most frequent at diagnosis in ND and R/R-AML. IDH1 R132L and R132S variants were not identified in patients with MDS or MPN. (E), Clonal hierarchy of baseline mutations assessed using bulk myeloid NGS panel on baseline samples.Figure S2: Pharmacokinetics of IVO+VEN or IVO+VEN+AZA (continued): (A), AUC 24 and (B), Cmax of IVO+VEN or IVO+VEN+AZA within each respective dose level demonstrated a decrease in the presence of IVO when assessed on C2D14 compared to sampling on C1D14 in the absence of co- occurring IVO administration.Figure S3: CONSORT diagram of study participantsFigure S4: Bone marrow response and recovery following IVO+VEN or IVO+VEN+AZA: (A), Bone marrow blast reduction following one cycle of therapy with IVO+AZA, or IVO+VEN+AZA among all patients with an adequate bone marrow samples (N=28). Three patients had inadequate/hypocellular EOC1 bone marrow aspirations and were excluded. One patient enrolled with MRD+ AML only. (B) Cycle lengths during the first four cycles of treatment. Patients treated with IVO+VEN had significantly shorter cycle lengths for cycle 1 compared to patients treated with IVO+VEN+AZA.Figure S5: Adverse events in patients treated with IVO+VEN or IVO+VEN+AZA: (A), Common adverse events occurring in four or more patients on study during the entire phase 1b study period demonstrated by grade, (B), by receipt of IVO+VEN vs. IVO+VEN+AZA, (C), and by dose level.Figure S6: Morphologic and MRD response to IVO+VEN in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the doublet combination of IVO+VEN 400 or VEN 800Figure S7: Morphologic and MRD response to IVO+VEN+AZA in ND-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with ND-AML treated with the triplet combination of IVO+VEN 400 or VEN 800 +AZAFigure S8: Morphologic and MRD response to IVO+VEN or IVO+VEN+AZA in R/R-AML. Morphologic response, MRD-MFC, and IDH1 ddPCR status by treatment cycle in patients with R/R-AML treated with IVO+VEN with or without AZAFigure S9: Response and outcome of patients treated with IVO+VEN or IVO+VEN+AZA. (A), Swimmer's plot of patients on study with IVO+VEN +/- AZA by dose level.Figure S10: Landmark overall survival analyses based on IDH1 mutation detection in CRc using ddPCR as though performed on patients at baseline. (A), Overall survival from treatment start. (B), Including patients surviving at least 3-months (correlating with end of cycle 3). (C), Including patients surviving at least 5- months (correlating with end of cycle 5). (D), Including patients surviving at least 7-months (correlating with end of cycle 7).Figure S11: Influence of biological pathways on survival following IVO+VEN or IVO+VEN+AZA treatment. (A), Overall survival by methylation mutations. (B), Overall survival by signaling mutations. (C), Overall survival in all patients with signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA. (D), Overall survival in patients with AML and signaling mutations based upon receipt of IVO+VEN or IVO+VEN+AZA.Figure S12: Persistent mutations in a long-term responder with ND-AML identifies mutations within a CD16+ monocytic population. (A and B), DAb-seq analysis at diagnosis and in remission in a patient with ND-AML (accession #18) and co-occurring RUNX1 p. L204Q and IDH1 p.R132H mutations treated with IVO+VEN+AZA demonstrated treatment eliminated the majority of IDH1 and RUNX1 co-mutated cells. (C and D), The predominant population of CD34+ myeloblasts was eliminated with therapy, however residual cells containing IDH1 and RUNX1 in remission were clustered with a monocytic cell population with increased CD16 expression (C and D).Figure S13: Immunophenotypic shift occurring under treatment selection with targeted therapy. Multiparameter flow cytometry in a patient with ND-AML (accession #20) demonstrating an alternative CD34+ population expanding at relapse compared to baseline, consistent with a phenotypic shift at disease.Figure S14: Increased alternative antiapoptotic protein expression levels correlate with resistance to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #11) treated with IVO+VEN+AZA who initially attained CRc followed by disease progression. Increased alternative anti-apoptotic protein levels (BCL-xL and MCL1) were observed, in addition to increased CD44 levels.Figure S15: Increased BCL2 levels relative to alternative anti-apoptotic proteins is associated with ongoing response to IVO+VEN+AZA. CyTOF analysis in a patient with ND-AML (accession #26) treated with IVO+VEN+AZA with a durable response to treatment following 18 cycles of therapy. The patient had multiple CD34+ cell populations at diagnosis, with higher BCL2 levels relative to BCL-xL or MCL-1. Following 3 cycles of therapy, marked reduction in these blast populations were observed.Figure S16: Increased alternative anti-apoptotic protein expression is observed in maturing myeloid populations with monocytic differentiation. CyTOF analysis in a patient with R/R-AML (accession #10) treated with IVO+VEN with a durable response to treatment following 41 cycles of therapy. Following cycle 3 of treatment, an expanding CD34+ cell populations with increased BCL-xL and MCL-1 levels was observed with an associated maturing CD14+ monocytic immunophenotype.</p>
Supplementary Protocol from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-Mutated Myeloid Malignancies
<p>Supplementary protocol for "Phase Ib/II Investigator Initiated Study of the IDH1-mutant inhibitor ivosidenib (AG120) with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies"</p>
RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE).
PURPOSE: Effective treatment options for melanoma after immune checkpoint blockade failure are limited. RP1 (vusolimogene oderparepvec) is an HSV-1-based oncolytic immunotherapy, here evaluated in combination with nivolumab in anti-PD-1-failed melanoma. PATIENTS AND METHODS: Patients had advanced melanoma that had confirmed progression on anti-PD-1 (≥8 weeks, last prior treatment). RP1 was administered intratumorally (≤8 doses, ≤10 mL/dose; additional doses allowed) with nivolumab (≤2 years). The objective response rate (ORR) was assessed by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Of 140 patients enrolled, 48.6% had stage IVM1b/c/d disease, 65.7% had primary anti-PD-1 resistance, 56.4% were PD-L1 negative, and 46.4% received prior anti-PD-1 and anti-CTLA-4 therapy (43.6% in combination and 2.9% sequentially). Confirmed ORR (95% CI) was 32.9% (25.2%-41.3%; 15.0% complete response). Responses occurred with similar frequency, depth, duration, and kinetics for injected and non-injected, including visceral, lesions. Median (95% CI) duration of response was 33.7 (14.1-not reached) months. Overall survival rates (95% CI) at 1 and 2 years were 75.3% (66.9%-81.9%) and 63.3% (53.6%-71.5%), respectively. Biomarker analysis demonstrated broad immune activation associated with response, including increased CD8+ T-cell infiltration and PD-L1 expression. Treatment-related adverse event rates were 77.1% grade 1/2, 9.3% grade 3, 3.6% grade 4, and no grade 5 events. CONCLUSIONS: RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti-PD-1-failed melanoma, including those with poor prognostic factors. The safety profile was favorable, with mostly grade 1/2 adverse events. (Funded by Replimune, Inc.; IGNYTE ClinicalTrials.gov, NCT03767348; EudraCT number, 2016-004548-12).
Tumor-Infiltrating Clonal Hematopoiesis.
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear. METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors. RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth. CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.
BACKGROUND: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial. METHODS: FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable. DISCUSSION: FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based. TRIAL REGISTRATION: EudraCT number: 2021-004056-42. ISRCTN: 88,102,629.