The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single‐target CD19 or CD22 chimeric antigen receptor (CAR) T‐cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B‐ALL, it could not maintain a durable remission in most patients. To prolong relapse‐free survival, we sequentially combined CD19 and CD22 CAR‐T cells to treat post‐transplant relapsed B‐ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient‐derived donor cells were collected to produce CAR‐T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3ζ and 4–1BB. The second T‐cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR‐T treatment. Twenty‐seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR‐T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR‐T and were followed‐up for a median of 19.7 (range, 5.6–27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan–Meier survival analysis showed overall survival and event‐free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR‐T associated graft‐versus‐host disease (GVHD) occurred in 23% of patients, with 8% new‐onset acute GVHD and 15% persistent or worsened pre‐existing cGVHD before CAR‐T. This combination strategy of sequential CD19 and CD22 CAR‐T therapy significantly improved the long‐term survival in B‐ALL patients who relapsed after transplantation.

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Tributyltin (TBT), a proven endocrine-disrupting chemical, is well known to induce imposex in female gastropods. Herein we demonstrate the effects of low doses of tributyltin chloride (TBTCl) on the female offspring of KM mice. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. TBTCl dramatically advanced the age of onset of vaginal opening (VO) and first vaginal estrus, and reduced body weights at VO and first estrus. Furthermore, perinatal treatment with TBTCl significantly reduced the number of days between VO and first estrus. In addition, female offspring from dams exposed to 10 and 100 μg kg(-1) TBTCl exhibited altered patterns of estrous cyclicity in adulthood. In conclusion, perinatal exposure to low doses TBTCl result in early puberty and impaired estrous cyclicity in female mice, which suggest that TBTCl might act as an estrogen agonist or/and a disruptor on hypothalamic-pituitary function in the present study.

Exposure to endocrine disruptors (EDs) during early development might lead to adverse health outcomes later in life. Tributyltin (TBT), a proven ED, is widely used in consumer goods and industrial products. Herein we demonstrate the effects of low doses of tributyltin chloride (TBTCl) on reproduction of male KM mice. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. TBTCl dramatically decreased sperm counts and motility on postnatal days (PNDs) 49 and 152. Meanwhile, a significant increase in sperm abnormality was observed in exposed mice on PND 49, but comparable to that in the control on PND 152. The histopathological analysis of testes of treated animals showed a dose-dependent increase in sloughing of germ cells in seminiferous tubules. Mice treated with 10 μg TBTCl/kg exhibited decreased intratesticular 17β-estradiol (E2) levels on PND 49, and then followed by an obvious recovery on PND 152. While, no significant differences in serum E2, testosterone (T) levels and intratesticular T levels were detectable between control and TBTCl-exposed offspring at the sacrifice. These results suggest that perinatal TBTCl exposure is implicated in causing long lasting alterations in male reproductive system and these changes may persist far into adulthood.

Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. Methods Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4–1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0–18.0 × 105/kg). Results hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12–18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Conclusions Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Trial registration Chinese Clinical Trial Registry/WHO International Clinical Trial Registry (ChiCTR1900024456, URL: www.chictr.org.cn); registered on July 12, 2019.