Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution

BackgroundAngiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas.MethodsWe performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue.ResultsWe have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities.ConclusionsThis case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy

A high-performance matrix-matrix multiplication methodology for CPU and GPU architectures

Current compilers cannot generate code that can compete with hand-tuned code in efficiency, even for a simple kernel like matrix–matrix multiplication (MMM). A key step in program optimization is the estimation of optimal values for parameters such as tile sizes and number of levels of tiling. The scheduling parameter values selection is a very difficult and time-consuming task, since parameter values depend on each other; this is why they are found by using searching methods and empirical techniques. To overcome this problem, the scheduling sub-problems must be optimized together, as one problem and not separately. In this paper, an MMM methodology is presented where the optimum scheduling parameters are found by decreasing the search space theoretically, while the major scheduling sub-problems are addressed together as one problem and not separately according to the hardware architecture parameters and input size; for different hardware architecture parameters and/or input sizes, a different implementation is produced. This is achieved by fully exploiting the software characteristics (e.g., data reuse) and hardware architecture parameters (e.g., data caches sizes and associativities), giving high-quality solutions and a smaller search space. This methodology refers to a wide range of CPU and GPU architectures

Functional Signatures Revealed by Deep Phenotyping of CMV-Specific CD8+ T Cells Predict Risk of Early CMV Reactivation after Allogeneic Hematopoietic Cell Transplantation

Abstract CMV is the most clinically significant viral infection in HCT recipients. Control CMV reactivation after HCT is highly dependent on CMV-specific T cells. Despite dramatic technical advances, the clinical utility of functional assays of virus-specific T cells to predict CMV reactivation following HCT remains to be established. Using 13-color flow cytometry, we studied CD8+T cell responses to pp65 and IE-1 CMV peptide stimulation in cryopreserved PBMC from three clinically distinct subgroups (n=10 each) of HCT patients: 1) Elite Controllers (EC) : CMV seropositive (R+) recipients who never reactivated CMV based on weekly surveillance testing; 2) Spontaneous Controllers (SC): CMV R+ recipients who spontaneously resolved low-grade viremia (1,000 IU/mL) requiring antiviral therapy. NC had lower numbers of CD8+ T cells that simultaneously produced 3-4 cytokines in response to CMV peptides compared to EC and SC (18, 26 and 34%, respectively) suggesting that progressive CMV viremia is associated with loss of CD8+ T cell polyfunctionality. Among 15 possible cytokine signatures, we identified two CMV-specific CD8+ T cell cytokine signatures, measured at day +30, that were strongly associated with the risk of CMV reactivation (Fig. 1): i) the non-protective signature (NPS) consisting of IL-2negIFNγposTNFαnegMIP-1βpos CD8+ T cells was positively associated with CMV reactivation (4.9% of CMV-specific CD8+ T cells vs. 19.4 P=0.002 for EC vs. SC/NC; 4.9 vs. 10.8 P=0.02 for EC vs. SC; 4.9 vs. 22.8 P=0.005 for EC vs. NC for pp65 stimulated cells; similar trends were observed in IE-1 stimulated cells); ii) the protective signature (PS) consisted of quadruple producers (IL-2posIFNγposTNFαposMIP-1βpos), and was significantly reduced among NC vs. SC following pp65 and IE-1 stimulation (0.05% of CMV-specific CD8+ T cells vs. 2.85 for pp65, P= 0.02; 0 vs. 1.25 for IE-1, P= 0.02); this association was also found in superantigen-stimulated cells. Production of IFNγ alone or in combination did not predict reactivation (P=0.49). Since NC trended toward more frequent recurrence of CMV viremia compared to SC (60 vs. 10%, respectively; P=0.06), we explored the association between PS and NPS and number of episodes of CMV reactivation (Fig. 1). We observed a significant stepwise increase in the levels of the NPS in pp65-stimulated cells in patients who experienced 0 vs. 1 and ≥2 episodes of CMV reactivation (4.9, 18.3 P=0.002, and 22.4 P=0.06). In addition, patients with ≥2 episodes of CMV had the lowest levels of the PS across groups (0 vs. 2.2% for ≥2 vs. 1 episode P=0.02). Similar trends were observed in IE-1 stimulated cells. Whereas T-cell depletion, aGVHD, lymphoid malignancy and CMV donor serostatus were not associated with risk of CMV in this small cohort, a NPS >10% was associated with increased risk of CMV reactivation (OR: 21, CI95 2-215; P=0.01) and need for treatment (OR: 14, CI95 1.5-137; P=0.02); and a PS >2% was associated with trend toward reduced risk of need for treatment (OR: 0.1, CI95 0.01-1.05; P=0.06). Multivariable modeling was not performed due to sample size. Time to event curves showed that high levels of NPS (>10%) predicted risk of CMV reactivation (log-rank P=0.0002). This remained true in analyses restricted to patients with CMV reactivation after day 30 (log-rank P=0.01). High levels of NPS or low levels of PS (<2%) predicted risk of need for treatment (log-rank P=0.003 and P=0.04, respectively). Combination of the PSlow/NPShigh had the highest predictive value for risk of need for treatment (log-rank P <0.0001; fig. 2). 18 graft products were available. As expected CMV-specific responses were not detected in grafts from CMV seronegative donors. Among the 9 CMV seropositive grafts, NPS expression was null across groups suggesting that the NPS is an immune phenotype that is absent in healthy donors; there was a stepwise decrease in the number of quadruple producer CD8+ T cells in CMV seropositive grafts for EC, SC and NC: 3.4 (n=3), 2 (n=4) and 0 (n=2), respectively, suggesting that donor PS might influence recipient reactivation. In conclusion, we have identified two novel CMV-specific CD8+ T cell cytokine signatures with robust predictive value for risk of CMV reactivation and need for treatment. These biomarkers might be useful in guiding clinical decision making in HCT recipients. Disclosures No relevant conflicts of interest to declare

Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation

Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1)(n = 19): did not have evidence of CMV DNAemia on surveillance testing; (2)(n = 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3)(NC; n = 21): experienced clinically significant CMV. Two CMV-specific CD8T-cell functional subsets were strongly associated with risk of CMV: (i) the(NPS; IL-2IFN-γTNF-αMIP-1β), found at increased levels among NC; and (ii) the(PS; IL-2IFN-γTNF-αMIP-1β) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%;= .02; and 40% vs 12%;= .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%;< .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients

Correction to: Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution

Following publication of the original article [1], the authors have reported that the following sentence "While of the same IgG1 class as ipilimumab, preclinical data suggests this molecule may have enhanced activity against T regulatory cells"