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Cell therapies comprise one of the most important advances in oncology. One of the biggest challenges in the early development of cell therapies is to recommend safe and feasible doses to carry forward to middle development. The treatment involves extracting cells from a patient, expanding the cells and infusing the cells back into the patient. Each dose level being studied is defined by the number of cells infused into the trial participant. The manufacturing process may not generate enough cells for a given patient to receive their assigned dose level, making it infeasible to administer their intended dose. The primary design challenge is to efficiently use accumulated data from participants treated away from their assigned dose to efficiently allocate future trial participants and recommend a feasible maximum tolerated dose (FMTD) at the study conclusion. Currently, there are few available options for designing and implementing Phase I trials of cell therapies that can incorporate a dose feasibility endpoint. Moreover, the application of these designs is limited to a traditional dose-finding framework, where the dose-limiting toxicity (DLT) endpoint is observed in early cycles of therapy. This paper presents a novel phase I trial design for adoptive cell therapy that simultaneously accounts for dose feasibility and late-onset toxicities. We apply our design to a phase I dose-escalation trial of Rituximab-based bispecific activated T-cells combined with a fixed dose of Nivolumab. Our simulation results demonstrate that our proposed method can reduce trial duration without significantly hindering trial accuracy. [ABSTRACT FROM AUTHOR]

Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66–12.42) and liso-cel (OR:4.26; 95%CrI:2.33–7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37–0.79) and tisa-cel (HR:0.47; 95%CrI:0.26–0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel. [ABSTRACT FROM AUTHOR]

Ocular toxoplasmosis appears after primary infection or during the reactivation of chronic infection by the protozoa Toxoplasma gondii. The risk of ocular involvement and the heterogeneity of clinical manifestations, their complications, and the probability of recurrences are linked to polymorphisms in immune response-related genes, cytokine networks, lymphocyte subpopulation, and parasite virulence factors. Appropriate clinical management and evidence-based advisory recommendations for patients require a clear understanding of the immunopathological mechanisms of this parasitic disease. Narrative review of the scientific literature in human ocular toxoplasmosis related to parasitological and immunological characteristics, genetic polymorphisms linked to ocular involvement, and the clinical correlations of the cytokinome in aqueous humor and experiments with peripheral blood mononuclear cells. The greater severity in people infected by South American strains is partly explained by parasite protein kinases interfering with the effector immune functions of interferon-gamma, resulting in lower antiparasitic activity and more significant inflammation. Future therapies should point to the increase in IFN-γ production (for example, by stimulating CD4+ memory T cells subset). Thus, immune-based interventions could be promising in inducing an appropriate response for treating and preventing ocular damage and recurrences. Drugs targeting tissue cysts responsible for reactivations are a current priority. Ocular toxoplasmosis is a persistent eye condition affecting patients' visual health and quality of life. This disease may manifest after a primary infection or during the reactivation of a latent infection by the protozoan Toxoplasma gondii. In our opinion, based on the principle of precaution, all recent primary infections, symptomatic or asymptomatic, caused by Toxoplasma, should be treated, as routine screening of the susceptibility genetic factors remains unavailable. Clinicians often encounter inquiries about the source of the infection, the factors contributing to ocular involvement (which, in the majority of the population, approximately 90%, remains asymptomatic), the likelihood of recurrent episodes, and the potential expansion of ocular damage. Current scientific knowledge indicates that genetic determinants governing specific immune responses, particularly the ability to produce protective cytokines while restraining inflammatory responses, may contribute to understanding the development and characteristics of ocular toxoplasmosis in humans. The role of genetic polymorphisms has been substantiated by the analysis of cytokine profiles in aqueous humor and experimental investigations using human peripheral blood mononuclear cells (PBMCs). In South America, where virulent strains of Toxoplasma prevail, the disease can manifest itself more severely. Numerous parasite protein kinases function as virulence factors, impeding the effector immune functions of interferon-gamma, decreasing antiparasitic activity, and exacerbating inflammation. The interaction between infection by virulent strains and genetic host susceptibility factors intervene in the magnitude of retinochoroidal damage. In light of these insights, developing new therapies becomes imperative for managing and preventing recurrent ocular toxoplasmosis. Additionally, pursuing drugs capable of eradicating tissue cysts responsible for recurrences and reactivations is a current research priority. [ABSTRACT FROM AUTHOR]