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Mashup Score: 5132 Racial differences in TMB measures between paired tumor/normal and tumor-only sequencing across endometrial, bladder, and non-small cell lung cancers - 18 hour(s) ago
Background Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of a tumor, is routinely used as a predictive biomarker for immunotherapy response in metastatic cancer patients. Sequencing of paired tumor and normal specimens allows for correction of TMB estimates with patient-specific germline variants. For tumor only assays, TMB estimates are corrected using germline variant annotations derived from population-scale germline variant surveys. These surveys often underrepresent minorities and individuals of non-European descent, leading to potential inaccuracies in TMB estimates in these populations. Methods Our cohort includes patients who underwent tumor genomic profiling with the Tempus xT Next Generation Sequencing (NGS) assay and diagnosed with non-small cell lung (NSCLC, n=4,583) endometrial (n=3,084), or urothelial (n=2,806) cancer. We used 654 ancestry informative markers selected to overlap the target regions of the 648-gene Tempus xT NGS assa
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Mashup Score: 34
Background Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis. Methods An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the follow
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Mashup Score: 9
Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national
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Mashup Score: 22Biomarkers for response to TIL therapy: a comprehensive review - 2 month(s) ago
Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4
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Mashup Score: 15
Background Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial ([NCT02517398][1]). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort). Methods Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity. Results Per independent review committee assessment, objective responses were observed in the ICI-n
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Mashup Score: 1Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis - 2 month(s) ago
Background Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. Methods We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin– cells, and expansion and activity in vivo in syngeneic tumor models as w
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Mashup Score: 27Inflamed immune phenotype predicts favorable clinical outcomes of immune checkpoint inhibitor therapy across multiple cancer types - 2 month(s) ago
Background The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types. Methods Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions. Results We observed an overall IIP pre
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Mashup Score: 147Gamma delta T cells in acute myeloid leukemia: biology and emerging therapeutic strategies - 2 month(s) ago
γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of relapse, enhanced graft-versus-leukemia effect, and decreased graft-versus-host disease in patients with AML who have higher reconstitution of γδ T cells following allogeneic hematopoietic stem cell transplantation. Clinical trials leveraging γδ T cell biology have used unmodified and modified allogeneic cells a
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Gamma delta T cells are a novel immunotherapy for AML. Recent review from our group https://t.co/v8MgGKyeLv We have clinical trials w Aza Ven & gd2T cell activating ICT01 for Newly Dx AML, & allogeneic gd1T cells for R/R #AML https://t.co/66peT9TKvA https://t.co/LGMVN5oyyl #leusm https://t.co/GAnAXazoBU
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Mashup Score: 8
Background Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs. Methods Leveraging the US Food and Drug Administration’s Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated. Results From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab
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Mashup Score: 7
Background Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs. Methods Leveraging the US Food and Drug Administration’s Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated. Results From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab
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Racial differences in TMB measures b/w paired tumor/normal & tumor-only sequencing across endometrial, bladder & non-small cell lung cancers [Nov 7, 2022] @ribozyme et al. @JITC #SITC22 Abs 132 https://t.co/1g4yPP91uq #PrecisionMedicine #ImmunoOnc #gyncsm #blcsm @lcsm @TempusLabs