Abstract
The omentum, a visceral adipose tissue, is a frequent site of metastasis for gastric and ovarian cancers. Advanced ovarian cancer almost always metastasizes to the omentum. Currently ...available therapies do not control tumor growth long-term and there is a frequent recurrence of tumor metastasis. In mice, tumor cells injected intraperitoneally implant in the omentum and grow progressively despite tumor-specific CD8 T cells. The lack of effective immunity is due in part, to rapid Treg recruitment in the omentum, which provides an immunosuppressive environment to support tumor growth. The Tregs in the omentum are a specialized population called visceral adipose tissue associated Tregs (VAT-Tregs). A portion of the omental VAT-associated Tregs express ST2, a receptor for Interleukin-33 (IL-33), suggesting that local IL-33 production may contribute to Treg-mediated suppression in the omentum. We also detected persistent, continuously expanding, tumor-specific CD8 T cells in the omentum. Given that IL-33 can also enhance effector function by CD8 T cells and promote their persistence in the presence of chronic antigen stimulation, we are investigating how IL-33 regulates the balance of Treg-mediated immune-suppression and CD8-mediated tumor cell killing in the context of omental adipose tissue.
R01CA216234
BackgroundNatural killer (NK) cells are a nascent cellular immunotherapy for hematologic malignancies. Target recognition of NK cell-resistant cancers remains a substantial barrier to broad ...application of NK cell therapy. One solution are bispecific engagers that trigger NK cells via an NK activating receptor when simultaneously engaging a tumor-specific antigen.MethodsHere, we investigated single NK cell responses stimulated by the tetravalent bispecific innate cell engager (ICE®) AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on several types of NK cells.ResultsMultidimensional mass cytometry revealed heterogeneity within AFM13-directed conventional (c)NK cell responses, as well as consistent polyfunctional activation of mature terminally differentiated NK cells across donors. The source of NK cells also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from Hodgkin lymphoma patients. IL-12, IL-15, and IL-18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30+ lymphoma targets directed by AFM13, compared to cNK cells. Cord-blood expanded NK cells that were pre-activated with IL-12, IL-15 and IL-18 also exhibited enhanced killing with AFM13 stimulation, via upregulation of signaling pathways related to NK cell effector function. These cells were stably pre-loaded with AFM13 enhancing responses to CD30+ lymphomas in vitro and in vivo in immunodeficient NSG mouse models.ConclusionsCollectively, these data identify promising combinations of AFM13 with cytokine-activated adult blood or cord blood NK cells against CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.
Abstract
This study explores the potential of Flavothione‐3‐Carboxylate derivatives as inhibitors of glycogen synthase kinase 3 beta (GSK‐3β) for the treatment of breast cancer. GSK‐3β plays a ...critical role in cancer cell survival, proliferation, and chemotherapy resistance. Inhibitors of GSK‐3β have emerged as promising candidates for developing new cancer therapies. Flavatione‐3‐carboxylate derivatives were synthesized in a single step through a three‐component reaction using 4‐hydroxycoumarin, 2‐nitrovinylbenzene, and alcohol, catalyzed by 4‐dimethylaminopyridine. The reaction was followed by treatment with Lawson's reagent in toluene solvent. The structures of these derivatives were elucidated by infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). Their drug‐likeness was assessed using the SwissADME tool. The antiproliferative activity of the synthesized compound was evaluated on estrogen‐dependent MCF‐7 and non‐estrogen‐dependent MDA‐MB‐231 breast cancer cell lines. Among the tested compounds, NS16 demonstrated significant antiproliferative activity with an IC
50
value of 5.69±1 μM against MCF‐7 ER+ cells, while NS04, NS05, NS07, and NS08 showed efficacy against MDA‐MB‐231 ER‐ cells with IC
50
values ranging from 4.56±1 to 7.07±1 μM. Furthermore, the GSK‐3β activity assay revealed potent inhibitory effects of nitrophenyl and halo‐phenyl Flavothiones‐3‐Carboxylate derivatives on GSK‐3β activity. However, compounds NS15 and NS16 exhibited lower efficacy in inhibiting the enzyme, despite their anticancer activity.
Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage ...chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. ...However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.
Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific ...engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation.
We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood-derived NK cells was investigated
and
.
We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30
lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and
expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13-NK complex cells exhibited enhanced responses to CD30
lymphomas
and
.
We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30
hematologic malignancies, warranting clinical trials with these novel combinations.
Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, ...expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for
-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including
variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.
Background: Aim of the study was to assess quality of life (QOL) of parents of epileptic child and its association with various factors like demographic, clinical, therapeutic and behavioral ...factors.Methods: Consenting parents of 160 epileptic children were enrolled after finishing child’s visit to the pediatrician. Parents were enquired on baseline demographic variables like age, gender, socio-economic status, parental education; clinical details like type of epilepsy, duration of seizure, seizure frequency and co-morbidity and therapeutic factors like treatment of epilepsy and adverse drug reactions. QOL was evaluated using QOLCE questionnaire and Childhood Illness-related Parenting Stress Inventory and analysed.Results: Out of 160 parents, 85% belong to 30-40 years of age and 62.5% were male. Deteriorated quality of life was reported by parents as mean score 63.46±7.69. QOL was significantly poor (p<0.05) in parents of younger child (<6 yrs), education status (upto primary school only), employment status of parent (unemployed) and lower socioeconomic status. Assessment of disease related parameters revealed that type of seizure, seizure frequency, duration and co-morbidity were factors significantly affecting quality of life of parents with lower QOL scores(p<0.05). QOL of parents of child with epilepsy undergoing polytherapy with multiple AEDs treatment, particle seizure control and having adverse drug reaction were associated with poor scores of health and well being (p<0.05). It was found that parents of epileptic child had deteriorated QOL score with respect to behaviour patterns irrespective to conditions of epilepsy due to constant stress and anxiety and poor state of mind.Conclusions: QOL of parents was compromised in Indian children with epilepsy. Demographic factors like age of child, parental education, socio-economic status and clinical factors like type of seizure, frequency & duration of seizure and co-morbid conditions significantly affect the QOL of parents. Significantly poor QOL scores was also due to therapeutic factors like treatment with polytherapy and adverse drug reactions with poor behavioral patterns which was observed in parents that should be taken care and should not be overlooked.
New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen ...receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.
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