Biology subjects

Ghimire, H.

Publications and source records attributed to Ghimire, H..

3 recordsLinked to original sources

bioRxiv2026

Focal radiotherapy improves CAR T cell therapy targeting prostate cancer

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as prostate cancer due to the immunosuppressive tumor microenvironment (TME). Combining CAR T cells with existing therapies that remodel the TME and promote endogenous immune responses, such as radiation therapy and chemotherapies, may strengthen antitumor responses. Here, we assessed the potency of combining focal radiotherapy (RT), cyclophosphamide (Cy) preconditioning, and prostate stem cell antigen (PSCA)-CAR T cells against syngeneic prostate cancer models. Focal RT alone increased T cell and dendritic cell infiltration and activation in the irradiated tumor. Furthermore, the combination of all three therapies was critical for enhanced antitumor responses and survival across multiple subcutaneous, bone-metastatic, and multifocal disease models. This combination, in the irradiated TME and tumor-draining lymph nodes (tdLN), led to greater antigen presentation by myeloid cells and endogenous T cell activation and cytotoxicity. Our study demonstrates the potency of combining focal RT with PSCA-CAR T cells, significantly improving therapeutic responses in the irradiated tumor and contributing to a more robust systemic immune response against metastatic burden in prostate cancer.

Cancer Biology↗

bioRxiv2025

Quantitative MRI Reveals Bone Marrow Regeneration Following Targeted Marrow Irradiation and Transplantation in a Sickle Cell Disease Model

Sickle cell disease (SCD) is associated with chronic bone marrow stress, altered hematopoiesis, and reduced adiposity. Whether marrow-selective conditioning followed by transplantation normalizes these abnormalities remains unclear. We investigated bone marrow remodeling in Townes mice by comparing SCD control (SCD-Con) with mice that received total marrow irradiation (TMI) followed by bone marrow transplantation (SCD-TMI-BMT). Multiparametric micro-MRI at 7 T quantified proton density water fraction (PDWF), proton density fat fraction (PDFF), and R2*(1/T2*), and micro-CT assessed trabecular structure in the femur. SCD-Con marrow showed higher water content (elevated PDWF), reduced adiposity (lower PDFF), and imaging features consistent with erythroid hyperplasia and elevated iron burden (shorter T2* with reciprocal increase in R2*). In contrast, SCD-TMI-BMT mice demonstrated smaller R2*, reduced PDWF, and partial restoration of adiposity, accompanied by reciprocal shifts in R2*, consistent with decreased cellular iron and marrow remodeling. Micro-CT revealed an improved trabecular architecture after BMT compared to SCD control. MRI imaging biomarkers aligned with histologic evidence of reduced cellularity and larger adipocyte voids. In conclusion, a TMI-BMT SCD model promotes partial normalization of the marrow microenvironment. Multiparametric MRI with micro-CT provides a practical, non-invasive framework for monitoring marrow remodeling and skeletal health after curative therapy.

bioengineering↗

bioRxiv2025

Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy

PurposeDespite advances in acute myeloid leukemia (AML) therapy, relapses remain challenging. While AML is radiation-sensitive, total body irradiation (TBI) causes organ toxicities and activates tolerogenic/proangiogenic STAT3 signaling. CSI-2, a myeloid cell-targeted STAT3 inhibitor, promotes anti-leukemic immune responses but has limited efficacy against high disease burden. We investigated whether image-guided targeted marrow irradiation (TMI), which focuses radiation on leukemia sites while sparing critical organs, could synergize with CSI-2 to improve leukemia clearance and establish durable immunity. MethodsMice were intravenously engrafted with CMM-AML cells reaching 20-30% in bone marrow (BM) infiltration (moderate-to-high disease burden) before receiving IV-injections of CSI-2 (5mg/kg) with or without TMI. Fluorescently labeled CSI-2 biodistribution was assessed using flow cytometry and quantitative multiphoton microscopy. Survival was monitored for 3-4 months before evaluating BM composition using flow cytometry and immunohistochemistry. ResultsTMI significantly improved vascular permeability and scavenger receptor/TLR9-dependent uptake of CSI-2 by AML cells and leukemia-associated myeloid cells. Combined TMI/CSI-2 treatment more effectively reduced high leukemia burden than CSI-2 alone, achieving >80% survival at 120 days with increased CD8+ cytotoxic and CD4+ helper T cell infiltration. TMI/CSI-2-treated mice were protected from AML rechallenge suggesting that they developed protective immune memory. In an aggressive MLL-AF9 AML model, TMI/CSI-2 combination significantly extended survival compared to either monotherapy. ConclusionTMI/CSI-2 strategy represents a novel organ-sparing immunoradiotherapy that synergistically enhances leukemia clearance while promoting long-term protective immunity. These findings warrant further investigation of this strategy for high-burden or relapsed AML and provide the foundation for clinical translation.

immunology↗