The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas.

ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

A paradox of choice: Sequencing therapy in relapsed/refractory diffuse large B-cell lymphoma.

The available treatments for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have experienced a dramatic change since 2017. Incremental advances in basic and translational science over several decades have led to innovations in immune-oncology. These innovations have culminated in eight separate approvals by the US Food and Drug Administration for the treatment of patients with R/R DLBCL over the last 10 years. High-dose therapy and autologous stem cell transplant (HDT-ASCT) remains the standard of care for transplant-eligible patients who relapse after an initial remission. For transplant-ineligible patients or for those who relapse following HDT-ASCT, multiple options exist. Monoclonal antibodies targeting CD19, antibody-drug conjugates, bispecific antibodies, immune effector cell products, and other agents with novel mechanisms of action are now available for patients with R/R DLBCL. There is increasing use of chimeric antigen receptor (CAR) T-cells as second-line therapy for patients with early relapse of DLBCL or those who are refractory to initial chemoimmunotherapy. The clinical benefits of these strategies vary and are influenced by patient and disease characteristics, as well as the type of prior therapy administered. Therefore, there are multiple clinical scenarios that clinicians might encounter when treating R/R DLBCL. An optimal sequence of drugs has not been established, and there is no evidence-based consensus on how to best order these agents. This abundance of choices introduces a paradox: proliferating treatment options are initially a boon to patients and providers, but as choices grow further they no longer liberate. Rather, more choices make the management of R/R DLBCL more challenging due to lack of direct comparisons among agents and a desire to maximize patient outcomes. Here, we provide a review of recently-approved second- and subsequent-line agents, summarize real-world data detailing the use of these medicines, and provide a framework for sequencing therapy in R/R DLBCL.

Author Correction: Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration.

Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4+ T cells through Jak-STAT signal transduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation. Antigen presentation from DCs to CD4+ T cells (T cell receptor transgenic OT-II) was measured via a [3H]-thymidine incorporation proliferation assay. MDSC from melanoma tumor models decreased the levels of proliferation more than pancreatic cancer derived MDSC. T cell proliferation was restored when MDSC were treated with inhibitors of inducible nitric oxide synthase (L-NAME and NCX-4016). A NO donor inhibited OT II T cell receptor recognition of OT II specific tetramers, thus serving as a direct measure of NO inhibition of antigen presentation. Our group has previously demonstrated that STAT1 nitration also mediates MDSC inhibitory effects on immune cells. Therefore, a novel liquid chromatography-tandem mass spectrometry assay demonstrated that nitration of the STAT1-Tyr701 occurs in PBMC derived from both pancreatic cancer and melanoma patients.

MicroRNA profiling of patient plasma for clinical trials using bioinformatics and biostatistical approaches.

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that function to repress translation of mRNA transcripts and contribute to the development of cancer. We hypothesized that miRNA array-based technologies work best for miRNA profiling of patient-derived plasma samples when the techniques and patient populations are precisely defined. METHODS: Plasma samples were obtained from five sources: melanoma clinical trial of interferon and bortezomib (12), purchased normal donor plasma samples (four), gastrointestinal tumor bank (nine), melanoma tumor bank (ten), or aged-matched normal donors (eight) for the tumor bank samples. Plasma samples were purified for miRNAs and quantified using NanoString® arrays or by the company Exiqon. Standard biostatistical array approaches were utilized for data analysis and compared to a rank-based analytical approach. RESULTS: With the prospectively collected samples, fewer plasma samples demonstrated visible hemolysis due to increased attention to eliminating factors, such as increased pressure during phlebotomy, small gauge needles, and multiple punctures. Cancer patients enrolled in a melanoma clinical study exhibited the clearest pattern of miRNA expression as compared to normal donors in both the rank-based analytical method and standard biostatistical array approaches. For the patients from the tumor banks, fewer miRNAs (<5) were found to be differentially expressed and the false positive rate was relatively high. CONCLUSION: In order to obtain consistent results for NanoString miRNA arrays, it is imperative that patient cohorts have similar clinical characteristics with a uniform sample preparation procedure. A clinical workflow has been optimized to collect patient samples to study plasma miRNAs.

Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease.

Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor-derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 ± 1.12 vs. 5.14 ± 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status ≥2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients.

A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma.

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

Myeloid-derived suppressor cells in breast cancer.

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.