Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSV) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T-cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell–mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine codelivering peptide antigens and Toll-like receptor 7 and 8 agonists (referred to as SNAPvax),which induces robust tumor-specific T-cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T-cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumor volume and increases in virus replication and tumor antigen–specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

Graft‐Versus‐Host disease (GVHD) is a leading contributor to morbidity and mortality following stem cell transplantation (SCT). Current GVHD prevention methods utilize a combination of immunosuppressive drugs to prevent injury to host tissues. Post‐Transplant cyclophosphamide (PTCy) for GVHD prophylaxis initially was shown to be effective in the adult haploidentical SCT setting and later in matched donor SCTs. Implementation of PTCy has increased the utilization of alternative donors in curative SCT. In pediatrics, PTCy for GVHD prophylaxis has recently demonstrated safety and efficacy. However, its widespread use still lags compared with adult use due to variability between institutions and the lack of prospective pediatric trials. In this review, we summarize the pathophysiology of GVHD and PTCy and synthesize studies in adults and children of PTCy for GVHD prophylaxis, which support its use. We focus on using PTCy in haploidentical, matched donor, and umbilical cord blood transplantation settings, and discuss the current and future role of PTCy in pediatrics. Our goal is to inform pediatric SCT physicians regarding the use of PTCy to help reduce morbidity and mortality following transplantation.

Background: Cladribine-based combination chemotherapy has demonstrated promising efficacy in patients with relapsed/refractory adult acute myeloid leukemia (AML), prompting its increased utilization in the frontline; in pediatrics, it has been typically reserved for relapsed or refractory cases. While fludarabine has been used more commonly as a purine analog in intensive regimens, cladribine may be an important alternative. Methods: We performed a retrospective study at MD Anderson Cancer Center from January 2015 to July 2023, which included patients aged 1–21 years with refractory or relapsed AML who received cladribine outside of a transplant conditioning. Results: A total of 30 patients were included, with a median age of 20 years (range, 2–21), and 55% being male. Similar to adults, cladribine exhibited good tolerability in pediatric and adolescent patients, with the most common adverse events being febrile neutropenia and myelosuppression. The most common grade 3 or 4 adverse events included febrile neutropenia (55%) and sepsis (26%), and there were no treatment discontinuations due to adverse events. Among patients with a median number of 2 (0–7) prior treatments, the overall response rate (CR/CRi) was 45%, and median event-free and overall survival were 6 and 12 months, respectively. Disease progression resulted in 4 deaths within 30 days of treatment. Conclusions: Cladribine was tolerated in pediatrics. No new safety signals were seen with cladribine regimens in this cohort. Response assessment is limited due to the heavily pretreated cohort. Further prospective studies are warranted on the safety and efficacy of cladribine and establish its role in pediatric, adolescent, and early young adult patients with AML.

Clostridioides difficile infection (CDI) represents a significant health risk to pediatric stem cell transplant (SCT) patients. In these patients, recurrent CDI is common, requiring prolonged antibiotic usage and increased hospitalization. Bezlotoxumab, a monoclonal antibody that targets the toxin responsible for CDI, has demonstrated efficacy in adult studies and was recommended for the prevention of recurrent CDI in the adult population. However, the safety and efficacy of bezlotoxumab in pediatric SCT patients have not been extensively described. Moreover, the drug was discontinued in January 2025 for reasons unknown. Here, we describe a series of cases where bezlotoxumab was used in conjunction with antibiotic therapy to effectively treat recurrent CDI in pediatric SCT patients. Bezlotoxumab was not associated with increased adverse events, did not impact management of graft‐versus‐host disease, and was safe to use in pediatric patients in the peri‐transplantation period.

Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T-cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T-cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T-cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1–mediated inhibition in antitumor T cells.

CD8 T cells transduced with RV express gp100-TCR and CA-STAT5.