Acute myeloid leukemia (AML) is a rapidly progressive, poor-prognosis malignancy arising from hematopoietic stem/progenitor cells. The long history of successful use of allogeneic hematopoietic cell ...transplantation (alloHCT) in AML indicates that this disease is immunoresponsive, leading to optimism that novel immunotherapies such as bispecific antibodies, chimeric antigen receptor T cells, and immune checkpoint inhibitors will generate meaningful disease control. However, emerging data on the immunoevasive tactics employed by AML blasts at diagnosis and at relapse indicate that optimism must be tempered by an understanding of this essential paradox. Furthermore, AML has a low mutational burden, thus presenting few neoantigens for attack by autologous T cells, even after attempted reversal of inhibitory receptor/ligand interactions. In this review, we outline the known AML targets, explore immune evasion mechanisms, and describe recent data and current clinical trials of single and combination immunotherapies.
Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy ...resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs
and enhance tumor growth
These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.
These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge.
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Background
The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram‐positive infections. Some of these gram‐positive bacteria are ...increasingly resistant to beta‐lactams and necessitate specific antibiotic treatment.
Objectives
To assess the effectiveness of empirical anti‐gram‐positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment.
Search methods
For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials.
Selection criteria
Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer.
Data collection and analysis
Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random‐effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention‐to‐treat and the analysis was patient‐based whenever possible.
Main results
Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate‐quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low‐quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low‐quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram‐positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.
Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram‐positive superinfections. Resistant colonisation was not documented in the studies.
Authors' conclusions
Based on very low‐ or low‐quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.
The characteristics of infections following chimeric antigen receptor T (CAR‐T) cells targeting CD19 in real‐word population are obscure. We analyzed infections' characteristics in the first month ...among consecutive patients with diffuse large B‐cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR‐T cells. ECOG performance status (PS) was 2‐3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram‐negative rod, n = 5; Gram‐positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti‐CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell‐associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C‐reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR‐T‐cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.
Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal ...(EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 95% CI: 7.8–13.6 vs. 14.1 95% CI: 10–18.1 months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 95% CI 12.5–18.2 vs. 18.4 95% CI 14.8–22.1 months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months 95% CI 9–15.5 vs. 4.28 months 95% CI 0.6–7.9, p = .010) compared to patients with >2 EN sites, respectively (16.5 months 95% CI 13.4–19.6 vs. 8.7 months 95% CI 4.6–12.8, p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.
Purpose
The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with ...otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo
18
FFDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy.
Methods
A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4–16.0) months from CAR-T infusion.
Results
In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (
Pv
< 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3;
Pv
< 0.01), LDH > 450 U/l (HR 7.7;
Pv
< 0.01), and ECOG score > 1 (HR 5.5;
Pv
= 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached,
Pv
< 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (
Pv
= 0.02) but not to TT-SUVmax (
Pv
= 0.38).
Conclusion
Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.
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