Biology subjects

Ritz, J.

Publications and source records attributed to Ritz, J..

8 recordsLinked to original sources

bioRxiv2026

Programmable antigen-presenting scaffolds expand rare tumor-antigen-specific T cells from peripheral blood

Adoptive cellular therapies can be effective against solid tumors but rely on the identification and expansion of rare tumor-reactive T cells (TRTs). Here, we utilize antigen-presenting cell-mimetic scaffolds (APC-ms), a modular biomaterial platform that presents defined peptide-HLA and co-stimulatory ligands on a fluid lipid bilayer to selectively recover rare antigen-specific T cells from peripheral blood. Independent variation of peptide-HLA, co-stimulatory ligands, and cytokine support defined a formulation that enriched MART-1-specific T cells to above 2% of CD8+ T cells in 35 of 50 HLA-A*02:01+ healthy donors from low or undetectable baseline frequencies. Compared with mo-DCs, APC-ms achieved greater fold expansion of MART-1-specific T cells with increased functional avidity and preservation of an early differentiation phenotype, and generated a higher number of MART-1-specific clonotypes. In five of eight patients with treatment-naive melanoma, APC-ms could enrich MART-1-specific T cells to a median of 13.7% of CD8+ cells (range 0.30 - 57.2%) Moreover, APC-ms could expand T cells specific for an HLA-A*24:01-restricted personal neoantigen that were previously undetectable in peripheral blood of a patient with melanoma. These findings establish APC-ms as a tunable platform for the recovery of rare TRTs from peripheral blood, supporting its further development for therapeutic TCR discovery and personalized adoptive cell therapy.

immunology↗

bioRxiv2026

Tumor-tropic E. coli engineered as living T and NK cell engagers

Despite advances in immunotherapy, most solid tumors remain resistant to treatment. Immune cell engagers redirect cytotoxic lymphocytes against cancer, but limited tumor access, immunosuppressive microenvironments and systemic immune activation limit efficacy. Here we develop live immune modulating engagers (LIME), a modular platform where non-pathogenic, tumor-tropic Escherichia coli display tandem single-chain variable fragments targeting a tumor-associated antigen and an activating receptor on T or natural killer cells. LIME bridged effector and tumor cells, induced transcriptional programs of T cell activation, metabolism and proliferation, and enhanced cytotoxicity across cancer cell lines and patient-derived organoids. In mouse models, LIME safely accumulated in tumors, outperformed tarlatamab in small cell lung cancer, and induced durable immunity in lymphoma. RAS inhibition and PD-L1 blockade enhanced LIME activity in pancreatic cancer and induced humoral responses. Multi-lineage immune modulation remained tumor-confined, without organ toxicity. These findings establish LIME as a versatile living therapeutic platform for programmable, tumor-restricted immune orchestration.

bioengineering↗

bioRxiv2025

Early persistence of recipient stem-cells and T-cell dysregulation are associated with relapse after transplant in AML/MDS

Hematopoietic stem cell transplantation (HSCT) offers the best curative option for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), yet relapse remains common. Current relapse detection methods are often too late for effective intervention. To identify earlier predictors and therapeutic targets, we performed longitudinal single-cell RNA and T cell receptor (TCR) sequencing of bone marrow from 33 AML/MDS patients during post-transplant immune reconstitution, comparing those who relapsed to those who remained in remission. Persistence of recipient hematopoietic stem and progenitor cells (HSPCs) in the marrow was associated with relapse months later. These residual recipient HSPCs harbored copy number variations (CNVs), supporting their leukemic origin, and overexpressed PRAME and CALCRL compared to coexisting donor HSPCs. Further, in a subset of TP53-mutant disease, low TCR diversity with skewing toward dominant clonotypes foreshadowed relapse. These findings lay the groundwork for improved relapse prediction and nominate therapeutic targets for early post-transplant intervention.

cancer biology↗

bioRxiv2024

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683+GZMB+ CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.

cancer biology↗

bioRxiv2023

SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback

Therapeutic anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been extensively studied in humans, but the impact on immune memory of mAb treatment during an ongoing immune response has remained unclear. Here, we evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific defect in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating human memory B cell responses, both to infection and vaccination. These data indicate that mAb administration can promote alterations in the epitopes recognized by the B cell repertoire, and the single administration of mAb can continue to determine the fate of B cells in response to additional antigen exposures months later. SIGNIFICANCE STATEMENTEvaluating the therapeutic use of monoclonal antibodies during SARS-CoV-2 infection requires a comprehensive understanding of their impact on B cell responses at the cellular level and how these responses are shaped after vaccination. We report for the first time the effect of bamlanivimab on SARS-CoV-2 specific human memory B cells of COVID-19 infected humans receiving, or not, mRNA immunization.

immunology↗

bioRxiv2023

Early antiviral CD4 and CD8 T cell responses are associated with upper respiratory tract clearance of SARS-CoV-2

T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, samples were assessed for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4 and CD8 T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4 T cell and CD8 T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4 and CD8 T cells during acute COVID-19.

immunology↗

bioRxiv2020

Cell-free DNA Tissues-of-Origin Profiling to Predict Graft versus Host Disease and Detect Infection after Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of post-transplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a highly versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT; infection; relapse of underlying disease; and graft failure. We demonstrate that these different therapeutic complications can be informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform on infections, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure we quantify the proportion of donor and recipient specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined time points before and after allogeneic HCT. We found that the abundance of solid-organ derived cfDNA in the blood at one-month after HCT is an early predictor of acute graft-versus-host disease (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor specific cfDNA was indicative of cell chimerism, relapse and remission, and the fraction of tumor specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.

genomics↗

bioRxiv2020

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to graft-versus-leukemia

Resistance to the graft-versus-leukemia (GvL) effect remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis of GvL resistance for advanced lymphoid malignancies remains incompletely understood. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features shape GvL outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post- HSCT relapse are shaped by distinct molecular dynamics and suggest that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for HLA loss was observed, even when present in pre-transplant subpopulations. Regardless of post-transplant relapse kinetics, gain of stem cell modules was a common signature associated with leukemia relapse. These data elucidate the biological pathways that underlie GvL resistance and post-transplant relapse. One Sentence SummaryWe find that the clinical kinetics of chronic lymphocytic leukemia relapse after stem cell transplant are underwritten by distinct genetic and epigenetic evolutionary trajectories and suggest that the selection pressures of the post-transplant, immunologic bottleneck are unlike those imposed by chemotherapy.

cancer biology↗