Simple SummaryWe hereby report on the immunomodulatory effects induced over time in patients with advanced relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphoblastic leukemia (B-ALL) treated with the commercial CAR-T-cell product tisagenlecleucel. We observed that, in addition to its anti-neoplastic activity, tisagenlecleucel was capable of exerting a marked and long-lived in vivo reshaping of the host immune system, in terms of T- and NK-cell expansion and cytokine release. These results may contribute to a further understanding of the complex field of immunotherapy and intercellular crosstalk, suggesting a role for host immune modulation in the long-term control of the disease.AbstractBackground:Chimeric antigen receptor (CAR)-T cells represent a potentially curative strategy for patients with relapsed or refractory (R/R) B-cell malignancies. To elucidate a possible host immune activation following CAR-T-cell infusion, we investigated the effects of tisagenlecleucel administration on the patients’ immune populations in 25 patients with R/R diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphoblastic leukemia (B-ALL).Methods:The modulation of CAR-T cells over time, the numeric changes, as well as the cytokine production capability of different lymphocyte populations and circulating cytokine levels, were analyzed.Results:Our results confirmed the ability of tisagenlecleucel to control the disease, with an overall response observed in 84.6% of DLBCL and in 91.7% of B-ALL patients at 1-month post-infusion, and showed that most patients who subsequently relapsed could undergo further treatment. Interestingly, we could document a significant increase in CD3+, CD4+, CD8+, and NK cells over time, as well as a decrease in Treg cells, and an increased IFNγ and TNFα production by T lymphocytes.Conclusions:Taken together, our results indicate that in patients with DLBCL and B-ALL, the administration of tisagenlecleucel is capable of inducing a marked and prolonged in vivo modulation/reshaping of the host immune system, both in children and adults.