Adjunct Therapy with T Regulatory Cells Decreases Inflammation and Preserves the Anti-Tumor Activity of CAR T Cells.

With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells' ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8+ T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg "cooling blanket" effect and lay the groundwork for clinical study.

Outcomes of allogeneic hematopoietic stem cell transplantation for lymphomas: a single-institution experience

ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes. Methods: All patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied. Results: Forty-one patients were reviewed: 10 (24%) had Hodgkin's and 31 (76%) had non-Hodgkin lymphomas. The median age was 50 years and 23 (56%) were male. The majority of patients (68%) had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43%) patients were in complete and seven (17%) were in partial remission. Most (95%) patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival. Conclusions: Allogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.

Transmission of lupus anticoagulant by allogeneic stem cell transplantation

Passive transmission of autoimmune diseases by allogeneic stem cell transplantation is rare and is ascribed to passive transfer of memory B-cells from donor to recipient. We hereby report a case of transmission of an asymptomatic lupus anticoagulant from a sibling donor to a recipient of transplantation for secondary acute myeloid leukemia. On pre-harvest evaluation, the sibling donor with no history of bleeding or thrombosis was found to have a lupus anticoagulant. After engraftment, the recipient was found to have a new prolonged activated partial thromboplastin time and was subsequently shown to have a lupus anticoagulant on Day +73 after stem cell transplantation. The recipient remained well with no evidence of bleeding, thrombosis, or graft-versus-host disease and was on a stable dose of tacrolimus at the time the lupus anticoagulant was detected. There was no other identifiable trigger for the appearance of a lupus anticoagulant...

Epigenetic therapy in allogeneic hematopoietic stem cell transplantation

DNA methylation and other epigenetic phenomena appear to be relevant in the pathogenesis of several malignant disorders. DNA methyltransferases add methyl groups to cytosine-phosphate-guanine (CpG) islandsleading to gene promoter silencing. The DNA methyltransferases inhibitors azacitidine and decitabine have anti-tumor activity against a broad range of malignancies, but have been investigated mostly in myelodysplastic syndrome. In addition, these agents have immunomodulatory effects that are under investigation in the allogeneic stem cell transplantation scenario. Both drugs have been used in the perioperative period of allogeneic transplantations with varying degrees of success. It has been hypothesized that low dose azacitidine may increase the graftversus-leukemia effect and have a role in the maintenance of remission after allogeneic transplantation for myeloid leukemias. It is also intriguing that this favorable effect might occur while mitigating graft-versus-host disease. Here we present a review of the rapidly growing field of epigenetic manipulation using hypomethylating agents in allogeneic transplantation.

The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.

Advances in haploidentical stem cell transplantation

Hematopoietic stem cell transplantation from haploidentical donors is an attractive method of transplantation due to the immediate donor availability, ease of stem cell procurement and the possibility to collect additional donor cells for cellular therapy, if needed. Historically, maintaining T-cells in the graft has been associated with very high rates of graft-versus-host disease, while T-cell depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and delayed immune reconstitution post-transplant. Recent approaches attempt to maintain the T-cells in the graft while effectively preventing the development of graft-versus-host disease post-transplant. Selective depletion of alloreactive T-cells post-transplant using high-dose post-transplant cyclophosphamide is under investigation as a promising alternative in haploidentical transplantation. While engraftment has improved and graft-versus-host disease is controlled with this approach, future directions should focus on optimizing conditioning regimens and the prevention of disease relapse post-transplant.

Transplante de células-tronco de doador não aparentado com sucesso após transplante de células de cordão umbilical não aparentado em paciente com leucemia linfocítica aguda: À procura do efeito enxerto versus leucemia: [carta ao editor] / Successful stem cell transplantation from an unrelated donor after an unrelated cord blood transplantation in an acute lymphocytic leukemia patient: searching for the graft versus leukemia effect: [letter to editor]

Segundo transplante homólogo é uma opção terapêutica parapacientes com leucemia linfoblástica aguda (LLA) que têmrecorrência após o primeiro transplante. Entretanto, para pacientessem parentes compatíveis, pode ser difícil encontrar umsegundo doador não aparentado. Uma moça de 19 anos com pro-B LLA desde 1997 recebeu quimioterapia e entrou em remissãocompleta (RC) em quatro semanas. Alta dose de citarabina foimantida por dois anos. Dois anos após o final do tratamento, apaciente apresentou recorrência, e recebeu o protocolo Hyper-CVAD (ciclofosfamida, doxorrubicina, vincristina e dexametasona).Um doador de cordão umbilical compatível 6/6 foi identificado eusado. Não havia sinais de doença do enxerto versus hospedeiro(DEVH) aguda. Segunda recorrência foi diagnosticada 32 mesesapós o transplante. O tratamento consistiu novamente no protocoloHyper-CVAD), sem resposta, e, subsequentemente, citarabina dealta dosagem com mitoxantrona de alta dosagem, resultando numaterceira RC. Um doador não aparentado, 10/10 HLA compatível,foi identificado. A despeito da terapia profilática, a pacientedesenvolveu DEVH aguda e crônica e múltiplos episódios deinfecções, mas se recuperou completamente. Ela está viva, emboa performance e em remissão completa 24 meses após o segundotransplante. Houve tempo para encontrar um doador nãoaparentado após o transplante inicial de células de cordão apenasporque a paciente entrou numa terceira RC após quimioterapia.Segundo transplante de célula-tronco alogênico, de doador nãoaparentado, pode ser oferecido a pacientes selecionados apóstransplante de células de cordão, especialmente após recorrência,sem DEVH e/ou o fenômeno enxerto versus leucemia.

Secondary malignancies after hematopoietic stem cell transplantation.

Advances in the field of hematopoietic stem cell transplantation have led to an increasing number of cures of malignant and non-malignant diseases with this therapeutic approach. Long-term survivorship may, however, be associated with secondary malignancies, the result of a complex interaction of treatment-, recipient- and immunosuppression-related factors. Furthermore, the increasing use of donors other than human leukocyte antigen-identical siblings is associated with more intense immunosuppression, delayed immune recovery and higher incidence of B-cell post-transplantation lymphoproliferative disorders. Here, we review the incidence and the risk factors associated with these complications of hematopoietic stem cell transplants.