Deborah Doroshow

e16502Background: CRP is an acute phase reactant synthesized by hepatocytes in response to inflammatory cytokines including interleukin-6. Peripheral blood CRP, a routinely measured analyte, may reflect tumor microenvironments skewed towards tumor-promoting inflammation. CRP may therefore represent an attractive biomarker to select patients with bladder cancer (BCa) more likely to benefit from therapies directed at modulating tumor-promoting inflammation. Methods: A systematic review was performed to identify studies reporting outcomes based on pre-treatment CRP values in patients with localized and advanced BCa and urothelial carcinoma (UC). The hazard ratio (HR) of overall survival (OS), cancer-specific survival (CSS), relapse-free survival (RFS), and progression-free survival (PFS) between groups with high and low CRP values as defined in each study was extracted. Meta-analysis using the …

Background ZL-1218 is an anti-chemokine receptor 8 (CCR8) humanized IgG1 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. CCR8 demonstrates a preferential expression in tumor-associated Tregs over peripheral Tregs. Thus, targeting CCR8 may allow for specific depletion of intratumoral Tregs without impacting peripheral Tregs/other immune cells. ZL-1218 is intended to decrease the intratumoral Tregs by binding to both high- and low-expressing CCR8+ cells and eliciting potent ADCC activity. ZL-1218 blocked CCR8 ligand CCL1 from binding to CCR8, and reduced Treg recruitment by blocking chemotaxis of CCR8+ cells (unpublished data). Additionally, ZL-1218 demonstrated enhanced antitumor activity in preclinical models in combination with anti-PD-1.  Methods This is a Phase I study of ZL-1218 as a single agent and in combination with pembrolizumab (P) to …

Myeloid cells are known to suppress antitumour immunity. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells …

LB_A14: Factors associated with enrollment, participation, and survival of patients on early phase cancer clinical trialsElena Baldwin, Grace Van Hyfte, Natalie Lucas, Kathy Wu, Gary Shelton, Suzan Aird, Grace Chung, Gabriela Fazilov, Lisa Fitzgerald, Olivia Hapanowicz, Khadijah Holley, Paula King, Ashley Lu, Nathasha Melukkaran, Miriam San Lucas, Issamar Urena, Aleksandra Wawrzyniak, Marshall Posner, Matthew D Galsky, Thomas U Marron, Deborah B Doroshow

Background Although colorectal cancer (CRC) is traditionally considered to be immunologically inert, some subsets of colorectal cancer, particularly mismatch repair-deficient (MMRd) tumors, can be highly responsive to immune checkpoint blockade (ICB). Recent studies show -that even mismatch repair-proficient (MMRp) tumors can respond to combined PD-1/CTLA-4 ICB. Tumor-associated macrophages (TAMs) are an influential component of the tumor microenvironment (TME), although the exact role of these immune cells in tumor pathogenesis and progression remains enigmatic. TAMs are highly heterogenous and can be either pro-inflammatory or anti-inflammatory, and thus exhibit anti-tumorigenic or pro-tumorigenic effects respectively. Signal regulatory protein α (SIRPα) is a transmembrane protein expressed on TAMs that binds to CD47 on target cells, eliciting a ‘don’t-eat-me’ signal that inhibits …

PURPOSEPoly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical benefit for patients with solid tumors bearing germline or somatic alterations in DNA damage response (DDR) genes. Somatic alterations in DDR genes are common in advanced urothelial cancer, raising the possibility that PARP inhibition may confer therapeutic benefit in a molecularly selected subgroup of patients with metastatic urothelial cancer (mUC).METHODSThis single-arm, open-label, multi-institutional, investigator-initiated phase II study evaluated the antitumor activity of olaparib 300 mg twice a day in participants with mUC harboring somatic DDR alterations. Patients had progressed despite previous platinum-based chemotherapy, or were cisplatin-ineligible, and harbored somatic alterations in at least one of a prespecified list of DDR genes. The primary end point was objective response rate; secondary end points …

Despite our growing understanding of the genomic landscape of diffuse pleural mesotheliomas (DPM), there has been limited success in targeted therapeutic strategies for the disease. This review summarizes attempts to develop targeted therapies in DPM, focusing on the following targets being clinically explored in recent and ongoing clinical trials: vascular endothelial growth factor, mesothelin, BRCA1-associated protein 1, Wilms tumor 1 protein, NF2/YAP/TAZ, CDKN2, methylthioadenosine phosphorylase, v-domain Ig suppressor T-cell activation, and argininosuccinate synthetase 1. Although preclinical data for these targets are promising, few have efficaciously translated to benefit our patients. Future efforts should seek to expand the availability of preclinical models that faithfully recapitulate DPM biology, develop clinically relevant biomarkers, and refine patient selection criteria for clinical trials.

MethodsWe reviewed records of pts with advanced NSCLC treated with 1L osi at Mount Sinai Hospital from 2015 to 2022. Next generation sequencing of tumor tissue and/or circulating tumor DNA was assessed prior to start of 1L osi. Pts were classified as having RP if they had radiographic or clinical progression≤ 100 days from osi initiation. Characteristics of patients with vs. without RP were compared using univariate analysis, including Chi-Square and Fisher exact tests for categorical variables and t-tests or Wilcoxon Rank Sum tests for continuous variables. Survival outcomes were estimated using the Kaplan-Meier method.Results101 eligible pts treated with 1L osi were identified. 50 (49.5%) pts had Exon 19 deletion (Ex19mt) and 51 (50.5%) had Exon 21 mutations (Ex21mt). 12 pts (11.9%) experienced RP. Across the cohort, mutations in 47 distinct genes and 9 amplifications were identified. No single …

2505Background: ATRC-101 monoclonal antibody targets tumor-specific ribonucleoprotein complex (RNP) and elicits anti-tumor immunity, innate and adaptive, in preclinical models. Methods: Phase 1b is evaluating ATRC-101 as monotherapy, every 3 (3M) or 2 (2M) weeks (wk), and ATRC-101 in combination with pembrolizumab (3P) in participants (pts) with advanced solid tumors. ATRC-101 target expression is determined by CAP-CLIA IHC assay. For pts described herein, pre-treatment (tx) tumor biopsies were assessed for target expression by IHC retrospectively or prospectively. Enrollment in 3M and 3P is currently open to pts who are target positive (RNP+ve) by IHC with an H-score ≥ 50. Objectives are safety (primary), PK, immunogenicity, recommended dose for expansion, activity by RECIST1.1 and biomarker analyses in pre-tx and on-tx tumors. Results: As of Nov 18th, 2022, 67 pts received ≥1 dose of …

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.Exposures …

BackgroundIMP9064 is a potent oral ataxia telangiectasia and rad3-related (ATR) inhibitor with anti-tumor activity demonstrated in vitro and in vivo. This ongoing first-in-human study (NCT05269316) explores IMP9064 monotherapy and in combination with senaparib (IMP4297) in patients with advanced solid tumors.MethodsThis phase I/II, open-label study aims to evaluate the safety, pharmacokinetics, anti-tumor activity, maximum tolerated dose, recommended phase 2 dose for IMP9064 monotherapy and combination with senaparib. Here, we report the preliminary results in dose escalation of monotherapy stage. Patients received IMP9064 once daily, 3 days on and 4 days off per 21-day cycle using an i3+ 3 dose escalation design.ResultsAs of Feb 14th, 2023, 16 patients were enrolled: Cohort 1 (n= 1, 7.5 mg); Cohort 2 (n= 1, 15 mg); Cohort 3 (n= 4, 30 mg); Cohort 4 (n= 3, 45 mg); Cohort 5 (n= 4, 80 mg); Cohort 6 …

2559Background: Tumor-promoting inflammation is a hallmark of cancer pathogenesis and is associated with poor outcomes and treatment resistance. C-reactive protein (CRP) is a routinely measured acute phase reactant whose synthesis is stimulated by cytokines and may thereby represent a surrogate for tumor promoting inflammation. Pre-treatment CRP has been associated with resistance to immune checkpoint blockade (ICB) in several studies. However, whether post-treatment changes in CRP correlate with ICB outcomes has not been systematically examined. Methods: We performed a systematic review to identify cohort studies or clinical trials in solid tumor patients receiving ICB therapy with CRP response comparator pairs (high/low) available. We included studies that had hazard ratio (HR) of overall survival (OS), progression-free survival (PFS), or odds ratio (OR) of objective response rate (ORR …

Will Combination Therapies Replace Osimertinib Monotherapy as Standard-of-Care in Frontline EGFR-Mutant Advanced NSCLC? - Document - Gale Academic OneFile Use this link to get back to this page. Copy Skip to Content Library Menu: Google Scholar Discovery Partner English Select Language English Afrikaans العربية Bahasa Indonesia Bahasa Malaysia česky Cymraeg Dansk Deutsch English Español Français Gaeilge Hrvatski Italiano magyar ខ្មែរ Nederlands Polski Português Română Slovenščina slovenský suomi svenska Tagalog Tiếng Việt Türkçe Русский Ελληνικά বাংলা हिंदी தமிழ் ไทย 中文(简体) 中文(繁體) 日本語 한국어 Sign in with Google Save documents, citations, and highlights to Google Drive™ Sign in with Microsoft Save documents, citations, and highlights to Microsoft OneDrive™ Gale Academic OneFile…

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main …

Type-2 cytokines are hypothesized to promote an immune-permissive milieu for cancer to grow. Through scRNAseq and CITEseq on human non-small cell lung cancer (NSCLC) and the krasG12Dp53−/− lung cancer model we previously described a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the “mregDC,” that was also notable for a strong Th2 immune signature. We subsequently blocked the canonical Th2 cytokine IL-4 in vivo in tumor-bearing mice, and found that this significantly decreased lung tumor burden, which was recapitulated in multiple other tumor models. Furthermore, this effect synergized with PD-L1 blockade. Based on this data, we designed a clinical trial to assess if the addition of dupilumab, an anti-IL-4Ra antibody widely used for treatment of atopic diseases, may rescue responses to checkpoint blockade (NCT05013450). In this …

Brigatinib Versus Crizotinib in ALK inhibitor-Naïve Advanced ALK-Positive NSCLC: Results of Phase 3 ALTA-1L Trial. - Document - Gale Academic OneFile Use this link to get back to this page. Copy Skip to Content Library Menu: Google Scholar Discovery Partner English Select Language English Afrikaans العربية Bahasa Indonesia Bahasa Malaysia česky Cymraeg Dansk Deutsch English Español Français Gaeilge Hrvatski Italiano magyar ខ្មែរ Nederlands Polski Português Română Slovenščina slovenský suomi svenska Tagalog Tiếng Việt Türkçe Русский Ελληνικά বাংলা हिंदी தமிழ் ไทย 中文(简体) 中文(繁體 ) 日本語 한국어 Sign in with Google Save documents, citations, and highlights to Google Drive™ Sign in with Microsoft Save documents, citations, and highlights to Microsoft OneDrive™ Gale Academic OneFile Toolbar …

Many multicenter randomized clinical trials in oncology are conducted through the National Clinical Trials Network (NCTN), an organization consisting of 5 cooperative groups. These groups are made up of multidisciplinary investigators who work collaboratively to conduct trials that test novel therapies and establish best practice for cancer care. Unfortunately, disparities in clinical trial leadership are evident. To examine the current state of diversity, equity, and inclusion across the NCTN, an independent NCTN Task Force for Diversity in Gastrointestinal Oncology was established in 2021, the efforts of which serve as the platform for this commentary. The task force sought to assess existing data on demographics and policies across NCTN groups. Differences in infrastructure and policies were identified across groups as well as a general lack of data regarding the composition of group membership and …

Introduction: Immunotherapies such as checkpoint blockade, have demonstrated remarkable clinical efficacy yet a large percentage of patients do not respond, potentially due to a paucity of pre-existing immune priming against neoantigens. We developed a personalized genome vaccine (PGV_001) platform to generate neoantigen vaccines targeting each patient’s unique mutanome. Primary objectives of the study were to determine 1) the safety and tolerability; 2) the feasibility of PGV_001 production and administration; and 3) the immunogenicity of PGV_001. Secondary objectives included immunophenotyping vaccine driven cellular and soluble immune milieu in peripheral blood. We previously reported on the clinical efficacy, and here we report, analysis of vaccine-driven immune responses in all treated patients. Methods: The study (Trial Registration NCT02721043) enrolled patients with resected …

BACKGROUND In the first-line metastatic squamous non-small cell lung cancer (NSCLC) setting, treatment with the combination of a PD-1 checkpoint inhibitor plus platinum doublet chemotherapy has become standard of care1,2. The addition of antiangiogenic agents to immunotherapy has emerged as a promising strategy for cancer treatment3,4,5. Therefore, a combined anti-angiogenesis and PD-1 blockade strategy with a bispecific PD-1 and VEGF antibody may improve clinical outcomes. Ivonescimab (SMT112/AK112) is a novel tetravalent bispecific antibody (2 binding sites for PD-1 and 2 binding sites for VEGF) with an engineered Fc-null region and a half-life of 6-7 days. In the presence of VEGF, binding affinity to PD-1 increases more than 10-fold6. Given the correlation between VEGF and PD-1 expression in the tumor microenvironment6,7,8, simultaneous blockade of these 2 targets by ivonescimab …

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.