Introduction:PD-1/PD-L1 inhibitors lack evidence-based support in patients aged ≥75 years due to their frequent exclusion from clinical trials. This study aimed to evaluate the safety and efficacy of PRaG therapy-combining PD-1/PD-L1 inhibitors with radiotherapy-specifically in this elderly demographic. Materials and methods:Data were collected from patients aged ≥75 years who received PRaG therapy at our center between 1 January 2019, and 31 December 2024. Eligible patients were required to have at least one post-baseline efficacy evaluation. Tumor response was evaluated according to RECIST v1.1, and adverse events were graded using CTCAE v5.0. Results:A total of 36 elderly patients aged ≥75 years were included, with a median age of 77 years (range: 75-93). The objective response rate (ORR) was 23.5%, and the disease control rate (DCR) was 70.6%. After a median follow-up of 46.3 months, the median progression-free survival (mPFS) was 7.0 months (95% CI: 2.4-11.6 months) and the median overall survival (mOS) was 11.1 months (95% CI: 5.3-16.9 months). The Geriatric Nutritional Risk Index (GNRI) was associated with the efficacy of PRaG therapy, as well as PFS and OS. Any-grade treatment-related adverse events (TRAEs) occurred in 34 patients (94.4%), with 3 patients (8.3%) experiencing ≥Grade 3 TRAEs. No Grade 5 TRAEs were observed. Conclusion:The PRaG regimen appears feasible and tolerable in selected elderly patients with advanced cancer. Given the retrospective nature of this small cohort, an ongoing prospective trial (NCT06112041) will further validate these findings. Combining PRaG with robust nutritional support represents a rational hypothesis for future investigation.
Introduction:Intravenous immunoglobulin (IVIG) therapy can occasionally induce unexpected inflammatory complications. Materials and methods:A case report and literature review. Results:We report a patient with hypogammaglobulinemia and systemic autoimmunity who developed reproducible unilateral anterior uveitis following IVIG administration across multiple formulations. Discontinuation of IVIG resolved the ocular inflammation but caused underlying disease exacerbation. Transition to facilitated subcutaneous immunoglobulin (SCIG) achieved stable serum IgG levels and maintained complete ocular and systemic remission over a four-year follow-up period. Conclusion:This case demonstrates peak-driven immune activation as a plausible mechanism for IVIG-induced uveitis and highlights SCIG as a safe, effective therapeutic alternative that bypasses rapid peak IgG dynamics while preserving immune protection.
Introduction:Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of pancreatic β cells. Current insulin therapy does not address autoimmune pathology or restore endogenous β-cell function, highlighting the need for disease-modifying strategies. Methods:We developed a combination therapy integrating a proton pump inhibitor (PPI; omeprazole) with a non-Fc-binding anti-CD3 F(ab')2 antibody fragment (anti-CD3 F(ab')2) to concurrently promote β-cell neogenesis and modulate autoimmune T-cell responses. T1D was induced in nonobese diabetic (NOD) mice using a cyclophosphamide-accelerated protocol (CY-NOD). Following hyperglycemia onset, mice received combination treatment and were evaluated by blood glucose monitoring, flow cytometric analysis of T-cell populations, and assessment of pancreatic β-cell function. Therapeutic efficacy was further examined in spontaneous-onset NOD mice. Results:Combination therapy restored normoglycemia without exogenous insulin, reduced lymphocytic infiltration in pancreatic islets, and preserved endogenous insulin secretion. Treatment decreased pathogenic CD4+ and CD8+ T cells, increased regulatory T cells, and enhanced transforming growth factor-β expression. Comparable and durable glycemic control was observed in spontaneous-onset NOD mice. Conclusions:Concurrent modulation of β-cell function and autoimmune immunity achieved sustained glycemic control in T1D models. The use of clinically approved agents supports the translational potential of this non-insulin-dependent therapeutic strategy.
Abstract Introduction Irradiation and reconstitution has often been used to analyze plasma cell turnover. Here, we characterized the kinetics of plasma cell reconstitution following irradiation, focusing on representation of recipient and donor plasma cells. Materials and methods In a first setup, bone marrow chimeras were generated using congenic Ly5 allotype marked bone marrow transfer after lethal X-ray irradiation. Representation of donor and recipient B cells and plasma cells were tracked in the weeks thereafter. In a second setup, we repeated the reconstitution using plasma cell timestamp mice as recipients and BLIMP1gfp as donor bone marrow, allowing tracing of both recipient- and donor-source plasma cells with fluorescent reporters. Results In recipient spleen and bone marrow in the first setup, B cell and plasma cell numbers returned to homeostasis within 4 weeks of reconstitution. We determined that while B cells were essentially donor-derived by 4 weeks and plasma cells reached maximum donor representation at 4 weeks, they retained a significant fraction of recipient origin plasma cells to at least 8 weeks, the experiment endpoint. This clearly resolved plasma cell origin and revealed recipient plasma cells comprised both persistent and newly formed, the latter being the majority. When irradiated, timestamped mice were reconstituted with B-cell-insufficient µMT bone marrow, leaving irradiated recipient B cells as the sole source of new plasma cells, the recipients generated significantly more nascent plasma cells from endogenous B cells than occurred in the BLIMP1gfp recipients. Conclusion These data suggest that irradiated B cells are at a disadvantage to donor-derived B cells but can give rise to plasma cells when competition is alleviated, here by donor B-cell lymphopenia. Bone marrow reconstitution after irradiation thus reveals a population of radiation resistant long-lived plasma cells and B cell or early-stage plasma cell competition for production and retention.
Introduction Targeting tumour antigens is a major challenge in cancer-immunotherapy. We use active vaccination to induce antibodies targeting self-antigen Robo4, which is selectively expressed on tumour vascular endothelium, and supports vascular development. Our previous work showed that a conjugate of Robo4 with a foreign carrier protein induced autoantibodies specific to Robo4, which inhibited angiogenesis and tumour growth.Methods To translate the vaccine protocol to exploit a carrier protein used in routine human vaccination schedules, the well-characterized, non-toxic fragment C of tetanus toxin (TTc) was selected as the carrier protein. Recombinant protein Robo4-TTc (R4-TTc) was produced by Robo4 genetically linked to TTc.Results Priming with the carrier TTc followed by boost with Robo4-TTc (R4-TTc) efficiently induces strong antibody responses to Robo4 and inhibits tumour growth in LLC1 and 4T1 tumour models. The growth inhibition was correlated with anti-Robo4 IgG1 titres. Furthermore, decreased vessel formation and increased immune cell infiltration in tumours from R4-TTc vaccinated mice in the absence of detectable adverse effects on health.Conclusion The data indicate that this vaccination strategy remodels tumour vessels and probably promotes immunogenic pathway activation, therefore repressing tumour growth.
