Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use ...in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.
PURPOSE OF REVIEWAllogeneic hematopoietic cell transplantation (HCT), with associated graft-versus-leukemia effects, remains the best postremission strategy for patients with intermediate or ...high-risk acute myeloid leukemia (AML), with a curative potential. Here, we highlight recent advances in allogeneic HCT that broadened access, refined prognostication, and improved outcomes of AML patients undergoing this procedure.
RECENT FINDINGSEligibility for allogeneic HCT continued to expand to AML patients older than 60 years, as well as to patients lacking human leukocyte antigen (HLA)-matched donors with the advent of alternative donor sources, such as umbilical cord blood and HLA-haploidentical transplantation. Molecular profiling of AML has redefined prognostication for patients in specific AML genomic subgroups undergoing allogeneic HCT and has served as a new strategy for measuring minimal residual disease before and after allogeneic HCT. Using high intensity conditioning regimens has emerged as a potential strategy to reduce risk of relapse and improve overall survival, especially in patients with minimal residual disease prior to allogeneic HCT.
SUMMARYAs access to allogeneic HCT continues to improve, also, with more refined prognostic strategies, the field continues to move to optimize transplantation approaches by decreasing the risk of relapse and minimizing transplant-related complications.
mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant
is increasing in order to detect residual disease in AML, alongside ...flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant
in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms.
Peripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC.
RT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (<0.5% NCN by RT-PCR). Nevertheless, the positive predictive value of NGS, IHC and FC were each ≥ 80% indicating that positive results by those assays are typically associated with RT-PCR positivity. IHC, unlike bulk methods (RT-PCR, NGS and FC), is able provide information regarding cellular/architectural context of disease in biopsies. FC did not identify any
-mutated residual disease not already detected by RT-PCR, NGS or IHC.
Overall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for "deep-sequencing" NGS panels for NGS-based monitoring of residual disease in
-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for
-mutated AML. Together, these findings can help inform future clinical testing algorithms.
CSCs are a population of self-renewing and tumor repopulating cells that have been observed in hematologic and solid tumors and their presence contributes to the development of drug resistance. The ...failure to eliminate CSCs with conventional therapy is one of major obstacles in the successful treatment of cancer. Several mechanisms have been described to contribute to CSCs chemoresistance properties that include the adoption of drug-efflux pumps, drug detoxification pathways, changes in metabolism, improved DNA repair mechanisms, and deregulated survival and pro-apoptotic pathways. Thus, CSCs are therefore an attractive target to develop new anti-cancer therapies.
Introduction: Pulmonary complications constitute a major cause of morbidity and mortality in the post-hematopoietic cell transplant (HCT) period. While Chest X-ray (CXR) is customarily used for ...screening, we have utilized chest computed tomography (CT) within one month of transplant. Here we aim to characterize the prevalence of abnormalities and their impact on the eligibility for allogenic (allo) HCT and outcomes post-transplant.
Methodology: We conducted a single center retrospective study of all patients who were evaluated for allogenic HCT from January 2013 through December 2020 in New York Presbyterian Hospital - Weill Cornell Medicine (NYP-WCM). All patients who had chest CT as part of their pre-transplant evaluation were included for analysis.
Results: We identified 478 patients who had Chest CT screening. In 396 CT chest was normal or confirmed previous abnormalities. Eighty-two patients (17%) had previously undetected abnormalities (Figure 1). The most frequent abnormalities were pulmonary nodules (defined as nodules of 4 mm or greater) in 27 patients (31%), ground-glass opacities (GGO) in 21 patients (25%), Pneumonia in 18 patients (21%). Miscellaneous findings not related to the primary disease were found in 12 patients (14%) including thyroid nodules, breast nodules and hemangioma of the liver. A new malignancy was found in 6 patients (7%) and incidental pulmonary embolism (PE) in 2 patients (2%) (Figure 2). There were 5 (6%) patients who were ultimately excluded from transplant due to CT chest findings (simultaneous CXR showed abnormalities in only 1 out of 5). Three of those patients were found to have invasive fungal infection, and the other two had unrecognized metastatic lung cancer. For 19 patients (23%), transplant was delayed for diagnostic procedure and/or treatment of pulmonary findings (CXR showed abnormalities in only 3 patients out of 19). The most common reason for delay was lung infection requiring treatment. Thirty-two patients (41%) out of 77 patients with abnormal CT scan who eventually underwent transplant, have died . Sixteen died after relapse, and 16 from non-relapse mortality (NRM) with pulmonary complications playing a role in 13 patients (Figure 3).
Conclusion: 17% of patients who had a pre-transplant CT chest had abnormalities that warranted further evaluation. In 23% of these patients, these findings led to a delay in transplant for further optimization. Six percent were deemed ineligible for transplant due to absolute contraindications that were incidentally discovered on chest CT. Initial screening CXR failed to identify a significant number of abnormalities. Our data suggests that chest CT imaging should be part of the routine pre-transplant evaluation.
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No relevant conflicts of interest to declare.
The combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult ...donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease.The combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease.
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