Dmitriy Zamarin

Icahn School of Medicine at Mount Sinai | MSSM · Division of Hematology and Medical Oncology

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in p...

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as SMARCA4 (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that SMARCA4 loss in OC models resul...

Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-...

Background Aldesleukin induces responses in a subset of renal cancer and melanoma patients, but severe vascular toxicities including capillary leak syndrome (CLS) limit its use. Promiscuous extravasation of lymphocytes and transient lymphopenia is associated with CLS and severe hypotension. STK-012 is a first-in-class α/β-IL-2R biased partial agoni...

Introduction We investigated whether circulating cell-free (cf)DNA sequencing analysis is associated with response to immune checkpoint inhibition (ICI) in patients with endometrial cancer (EC) enrolled on a phase II trial (NCT03241745). Methods Patients with MSI-H/dMMR/hypermutated EC and ≥1 prior cytotoxic lines received nivolumab until progress...

Introduction IPROC is a platform trial testing novel immunotherapies in PltnR-HGSC. We report sub-studies A and B, testing durvalumab + BA3011 or BA3021 which are conditionally active humanized monoclonal antibodies (IgG1) conjugated to monomethyl auristatin E targeting AXL (BA3011) and ROR2 (BA3021) in AXL+ or ROR2+ HGSC respectively. AXL and ROR...

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1–3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requir...

Introduction NRG-GY009 was a randomized clinical trial of pegylated liposomal doxorubicin (PLD), bevacizumab (BEV), and atezolizumab (ATEZO) and PLD/ATEZO compared to PLD/BEV in patients with platinum-resistant ovarian cancer (PROC) (n=444). Addition of ATEZO to PLD/BEV did not result in a statistically significant prolongation of progression-free...

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudina...

Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immu...

Objective To assess clinicopathologic features and survival outcomes of patients with endometrial carcinoma involving adnexal, full-thickness serosal, or combined involvement. Methods This international, multi-institutional, retrospective study examined patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endo...

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution in cancers with TP53 loss. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed ac...

Objective We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease. Methods Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January...

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and pro...

Preclinical and clinical studies have shown that intratumoral oncolytic viruses (OVs) can convert “cold” tumors to “hot” and overcome resistance to immune checkpoint blockade. However, their modest clinical efficacy to date highlights major gaps in our understanding of how OVs interact with the immune system, and very limited information is availab...

Background: STK-012 is a first-in-class α/β-IL-2R biased partial agonist designed to drive antitumor activity by selectively stimulating CD25+ antigen activated T cells, while avoiding hallmark IL-2 toxicities by sparing pleotropic activation of lymphocytes including NK cells. Methods: STK-012-101 is a Phase 1a/b study of STK-012 administered subcu...

Chimeric Antigen Receptor (CAR) T cells are a modality of immunotherapy that act to eliminate cancer cells by redirecting the cytolytic activity through targeting a protein overexpressed on the surface of the cancer cell. In contrast to move conventional cancer therapies, their anti-cancer activity does not depend on a cancer-specific molecular vul...

Chromosomal instability (CIN) is a major driver of tumor progression and treatment resistance in many cancers. CIN is characterized by ongoing chromosome missegregation, segmental aneuploidy and whole-genome doubling (WGD), generating copy number heterogeneity that provides a substrate for natural selection. Although well characterized in model sys...

Objective To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. Methods Patients with gynecologic cancers treated with im...

Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (...

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells. Importantly, however, the...

Introduction In this multicentre randomized, phase II/III trial, we sought to examine if the 1) combination of anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab (ATEZO) with pegylated-liposomal- doxorubicin (PLD) [Arm 1] and/or 2) addition of ATEZO to PLD and bevacizumab (BEV) [Arm 2] result in an improvement in survival for p...

Introduction Advances in RT planning enhance the need for uniform quality oversight on clinical trials. NRG GY-17 was a randomized trial of the anti PD-L1 antibody, atezolizumab, before and concurrent (Arm A) or concurrent with CRT (Arm B). We describe the prospectively collected pre-treatment RT quality and workflow. Methods 40 patients were cons...

Background MEDI1191 is an investigational therapy composed of mRNA encoding interleukin-12 (IL-12p70) in a lipid nanoparticle optimized for intratumoral injection. Previously1 2 we reported that all dose levels induce pharmacodynamic (PD) changes such as elevated serum IL-12, increased T cell infiltration and upregulation of immune gene signatures...

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activ...

Iron accumulation in cancer cells contributes to malignant progression and chemoresistance. While disrupting this process can influence various hallmarks of cancer, the immunomodulatory effects of chelating iron in tumors remain undefined. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, elicits innate immune response...

Background: Despite sharing a common causal agent and viral oncogenes, HPV-positive head and neck cancer (HPV+ HNC) and cervical cancer (HPV+ CC) have markedly distinct natural histories and therapy responses. Here we sought to elucidate how the tissue of origin and oncogenic etiology drive molecular and microenvironmental differences between these...

Since the US Food and Drug Administration first approved talimogene laherparepvec for the treatment of melanoma in 2015, the field of oncolytic immunotherapy (OI) has rapidly evolved. There are numerous ongoing clinical studies assessing the clinical activity of OIs across a wide range of tumor types. Further understanding of the mechanisms underly...

PURPOSE The Bromodomain and Extra-Terminal (BET) domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small-molecule inhibitor of BET bromo...

Purpose: Tumor genomic profiling is increasingly used to guide treatment strategy in cancer patients. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. Experimental design: Cervical cancers were prospectiv...

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. The presence of damaging mutations in the SWI/SNF chromatin remodeling complex, such as the SMARCA4 (BRG1) catalytic subunit, has been associated with improved response to ICB, however the mechanism by which this occurs is unclear. The aim of this current st...

Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced endometrial cancer. This case series highlights three patients with endometrial serous carcinoma...

Highlighting over 50 hot topics where controversy exist in management of patients with gynecologic malignancy, this book presents expertly argued opinions for and against, incorporating current evidence and clinical trials outcomes. A diverse range of topics are included that pertain to several disciplines in gynecologic oncology, including surgica...

Highlighting over 50 hot topics where controversy exist in management of patients with gynecologic malignancy, this book presents expertly argued opinions for and against, incorporating current evidence and clinical trials outcomes. A diverse range of topics are included that pertain to several disciplines in gynecologic oncology, including surgica...

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are comm...

Correction for 'Multiplexed molecular imaging with surface enhanced resonance Raman scattering nanoprobes reveals immunotherapy response in mice via multichannel image segmentation' by Chrysafis Andreou et al., Nanoscale Horiz., 2022, 7, 1540-1552, https://doi.org/10.1039/d2nh00331g.

5565 Background: BRCA1/2-associated ovarian cancer (OC) exhibits homologous recombination (HR)-deficiency (HRD) and a better prognosis than BRCA1/2-wildtype (WT) OC. However, it is unclear if patients with germline pathogenic variants (gPV) in other HR-related genes have a similar tumor phenotype. We sought to define OC molecular features from pati...

TPS5617 Background: Identifying new treatments for patients with platinum-resistant high grade serous ovarian cancer (HGSC) is a priority. Although several biological features of HGSC suggest inherent immunogenicity, immunotherapy has had limited efficacy to date. IPROC is an adaptive platform trial designed to evaluate multiple immunotherapy combi...

Chromosomal instability (CIN) is a major driver of tumor progression and treatment resistance in many cancers. CIN is characterized by ongoing chromosome missegregation, generating copy number heterogeneity that provides a substrate for natural selection. Although CIN has been well studied in model systems, the evolutionary dynamics and genomic imp...

Purpose: Using next generation sequencing (NGS), The Cancer Genome Atlas (TCGA) found that endometrial carcinomas (ECs) fall under one of four molecular subtypes, and a POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)-based surrogate has been developed. We sought to retrospectively classify and characterize a large se...

The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-m...

Background: MEDI1191 is an IT-administered lipid nanoparticle-formulated mRNA encoding IL-12. This phase 1, open-label study (NCT03946800) showed that MEDI1191 in sequential (seq) or concurrent (conc) combination with IV D (anti-PD-L1) was safe and had preliminary antitumor activity in pts with advanced/metastatic solid tumors who had progressed on...

Immune checkpoint blockade therapy has revolutionized cancer care, including the treatment of advanced metastatic disease. However, most patients derive little or no clinical benefit from these therapies and many cancer types are notoriously non-responsive. Motivated by (1) the correlation between tumor neoantigen abundance and anti-tumor immunity...

Ovarian cancer (OC) is the most lethal gynecologic cancer and the 5th leading cause of cancer-related deaths among women in the US. One of the main reasons for the poor outcome is a high recurrence rate and development of chemoresistance. The standard care involves debulking surgery and carbo-taxol chemotherapy. While most patients respond well ini...

Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (...

Simple Summary Approximately 70% of patients with advanced epithelial ovarian cancer who achieve clinical remission after initial surgery and chemotherapy have a recurrence. Wilms’ Tumor 1 (WT1), which is overexpressed in ovarian cancer cells, is a promising target for tumor-directed immunotherapy for ovarian cancer due to its prevalence and specif...

Objectives: Increased numbers of tumor infiltrating lymphocytes (TIL) in endometrial cancer (EC) are associated with improved survival, but it is unclear how this prognostic significance relates to the underlying EC molecular subtype. In this explorative hypothesis-generating study, we sought to define the immune signatures associated with the mol...

Introduction Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear. Methods We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremeli...

Functional PET imaging using a PARP inhibitor (PARPi) analog may serve as an early, dynamic biomarker of response to PARPi therapy in high-grade serous ovarian cancer. Clinically, this could help to rapidly identify PARPi nonresponders, thereby maximizing efficacy and avoiding toxicities of futile treatments. See related article by Pantel et al., p...

Despite strong recommendations for their inclusion in cancer clinical trials, people living with human immunodeficiency virus continue to be underrepresented or have inadequate data collected. This commentary highlights the deficit and emphasizes the need for active recruitment and data collection.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour...

Objectives To evaluate feasibility and outcomes of procedural interventions for oligoprogressive disease among patients with gynecologic cancer treated with immune checkpoint blockade (ICB). Methods Patients with gynecologic cancers treated with ICB between 1/2013–10/2021 who underwent procedural interventions including surgical resection (OR), in...

Objectives Most ovarian cancer (OC) patients recur after first-line treatment and develop chemoresistance, highlighting an unmet need for precision medicine in OC. Half of OCs harbor mSWI/SNF chromatin-remodeling complex alterations including 10% in the SMARCA4 gene. Studies to date have suggested that the catalytic subunits of the mSWI/SNF complex...

Objectives Genomic instability is a hallmark of human cancer, with fundamental relevance to cancer etiology and evolution, anti-tumor immunity and therapeutic response. High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability defined by distinct mutational processes, intraperitoneal spread and tumor heterogeneity. As...

Introduction: Ovarian cancer (OC) is the most lethal gynecologic cancer, and there is an urgent need to develop new therapies. Patient responses to immune checkpoint blockade have overall been disappointing, which is likely due to the immunosuppressive tumor microenvironment (TME) of most OCs that may be in part under the influence of epigenetic re...

Background MEDI1191 is an investigational therapy composed of mRNA encoding bioactive interleukin-12 (IL-12p70) in a lipid nanoparticle optimized for intratumoral injection. We hypothesized that intratumoral injection of MEDI1191 will reprogram the immunosuppressed tumor microenvironment (TME) and increase cytotoxic T-cell recruitment, proliferatio...

Visualizing the presence and distribution of multiple specific molecular markers within a tumor can reveal the composition of its microenvironment, inform diagnosis, stratify patients, and guide treatment. Raman imaging with multiple molecularly-targeted surface enhanced Raman scattering (SERS) nanoprobes could help investigate emerging cancer trea...

Purpose: Despite therapeutic advances in the treatment of ovarian cancer (OC), 5-year survival remains low, and patients eventually die from recurrent, chemotherapy-resistant disease. The National Cancer Gynecologic Cancer Steering Committee identified the integration of scientifically defined subgroups as a top strategic priority in clinical trial...

Objectives: Gastric-type endocervical adenocarcinoma (GEA) is a rare form of cervical cancer not associated with human papilloma virus (HPV) infection. We summarize our experience with GEA at a large cancer center. Methods: Clinical and demographic information on all patients diagnosed with GEA between June 1, 2002 and July 1, 2019 was obtained...

Single-cell T cell repertoire sequencing can pair both T cell receptor (TCR) and gene expression sequence data, providing an enriched view of T cell behavior. This powerful tool can identify and characterize specific clonotypes and phenotypes as well as track their changes in response to therapy, such as immune checkpoint blockade (ICB). We present...

How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-de...

Purpose: We sought to determine whether sequencing analysis of circulating cell-free (cf)DNA in prospectively accrued endometrial cancer (EC) patients captures the mutational repertoire of the primary lesion and allows for disease monitoring. Design: Peripheral blood was prospectively collected from 44 newly diagnosed EC patients over a 24-month...

Objectives: To describe endometrial carcinoma (EC) molecular classification utilizing clinical next-generation sequencing (NGS) and immunohistochemistry (IHC) and to assess the clinical, pathologic, and survival outcomes based on molecular data. Methods: We identified all primary and recurrent EC samples of 341-505 cancer-related genes undergoing N...

Objectives: To assess the prognosis of isolated tumor cells (ITCs) within sentinel lymph nodes (SLN) compared with node-negative (NN) disease in early-stage endometrioid endometrial cancer and to perform additional evaluation by molecular classification. Methods: Patients (pts) who underwent primary surgical management of uterine cancer from 2007-2...

Objectives: Immunotherapy added to standard chemoradiation (CRT) seeks to improve outcomes for patients with node-positive cervical cancer. Optimal sequencing of CRT with immunotherapy is unknown. NRG GY-17 (NCT03738228) is a randomized phase I/Ib trial of the anti-PD-L1 antibody, atezolizumab, before and concurrent (Arm A) or concurrent with CRT (...

Objectives: To compare the clinical-pathologic features and survival outcomes for patients with FIGO Stage IIIA endometrial cancer with uterine serosa or adnexal involvement. Methods: This was an international, multi-institutional, IRB- approved retrospective research collaboration spanning 2000 to 2019. Patients (pts) with surgically staged (FIGO...

Purpose: Microsatellite instability-high (MSI-H) endometrial carcinomas (ECs) are underpinned by distinct mechanisms of DNA mismatch repair deficiencies (MMR-D). We sought to characterize clinical and genetic features of MSI-H ECs harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Design: Of >1,100 E...

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutatio...

Patients with high-grade serous ovarian cancer suffer poor prognosis and variable response to treatment. Known prognostic factors for this disease include homologous recombination deficiency status, age, pathological stage and residual disease status after debulking surgery. Recent work has highlighted important prognostic information captured in c...

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, a high degree of tumor heterogeneity and intraperitoneal spread. As immunotherapies have thus far proven ineffective in this disease, we sought to establish the determinants of immune recognition, avoidance and evasion...

Preclinical and clinical studies have shown that intratumoral oncolytic viruses (OVs) can potentiate host anti-tumor immunity and overcome resistance to immune checkpoint blockade, although clinical responses to OVs have been modest to date. While