Virginia Seery

Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer

Purpose: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored. Experimental Design: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4+CD25+ regulatory-type T cells. Results: The frequency of both circulating myeloid DC1 and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4− iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4+CD25+ T cells, including CD4+Foxp3+ T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4+CD25+ T cells in response to IL-2. Functionally, patient CD25+ T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25+ T cells and mostly failed to Th2 polarize iNKT. Conclusions: Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.

A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma.

Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX‐2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM.

Retrospective Analysis of the Safety and Efficacy of Interleukin-2 After Prior Vegf-targeted Therapy in Patients With Advanced Renal Cell Carcinoma

Agents targeting vascular endothelial growth factor (VEGF) signaling have been advocated as frontline therapy for advanced renal cancer. The role of interleukin 2 (IL-2) therapy after resistance to VEGF-targeted therapy remains unexplored. We conducted a retrospective analysis of the tolerability and efficacy of IL-2 therapy in patients who had previously received VEGF-targeted therapy. Twenty-three consecutive patients who received salvage IL-2 therapy were analyzed. Fifteen patients had received prior tyrosine kinase inhibitors (TKIs) (sorafenib or sunitinib), whereas 8 patients had received bevacizumab alone. Six of 23 patients did not receive week 2 of cycle 1 of treatment. All 6 of these patients had received prior TKIs. The incidence of severe cardiac toxicities, including 1 sudden cardiac death, in patients receiving prior TKI was 40% (95% confidence interval, 16.3-67.7%), significantly higher than what is expected from historical experience. Only 1 of 23 patients proceeded to receive a second cycle of IL-2. No patients achieved a partial or complete response to therapy. This retrospective analysis highlights unexpected and severe cardiac toxicities in patients receiving IL-2 after VEGF-targeted TKI therapy. The assumption that IL-2 therapy can be safely administered after TKI therapy may not be valid. Further examination of the safety of this sequential approach is necessary and more cautious patient selection seems warranted.

Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2–Induced Vascular Leak

Purpose: High-dose interleukin 2 (HDIL2) produces durable tumor regressions in 10% of patients with metastatic renal cell carcinoma and melanoma. However, a major toxicity is vascular leak syndrome (VLS). We previously reported elevated serum angiopoietin 2 (Ang2) in septic patients with vascular leak and hypothesized that Ang2 might also contribute to HDIL2 VLS. Experimental Design: Blood was collected from 14 patients receiving HDIL2 and from 4 patients receiving HDIL2 and bevacizumab, an antibody against vascular endothelial growth factor (VEGF). The effect of Ang2 was studied in vitro by incubating high Ang2 patient serum with cultured endothelial cells. Results: Pretreatment Ang2 levels were in the reference range (median, 3.3 ng/mL) and rose with each day of IL-2 therapy (median peak, 29.7 ng/mL). No trend was seen in free VEGF levels during therapy. Patients treated with HDIL2 and bevacizumab all developed VLS and elevated Ang2. High Ang2 patient sera induced propermeability structural changes in endothelial cells, an effect reversed by blockade with the competitive ligand angiopoietin 1 (Ang1). Conclusions: Ang2 may be a mediator of HDIL2 VLS as evidenced by (a) an increase in Ang2 in all patients on HDIL2; (b) the effect of high Ang2 patient serum on cultured endothelial cells; (c) rescue of those structural changes by Ang1. The lack of correlation between VLS and serum VEGF levels in patients treated with HDIL2 alone or in combination with bevacizumab suggests that VEGF is not a major contributor to VLS or Ang2 release. These data suggest that the inhibition of Ang2 may mitigate VLS in patients receiving HDIL2.

Impact of concomitant immunosuppression on the presentation and prognosis of patients with melanoma.

Melanoma has been reported to be susceptible to immune control, although the degree of impact of immunosuppression on the course of this disease is uncertain. The Beth Israel Deaconess Medical Centers Cutaneous Oncology Program database was examined to identify patients receiving immunosuppressive therapy at the time of melanoma diagnosis. Demographics and the stage of these patients were compared with the other patients in the database, and three controls matched for age, sex, stage, and tumor location were identified from the database for each case and disease outcomes for the two groups compared. Nineteen patients were identified with melanoma and concomitant immunosuppression in a database of 1839 patients. Patients were receiving immunosuppressive therapy for a variety of conditions, including solid organ transplant and inflammatory or autoimmune diseases. Compared with the remaining database, patients on immunosuppression were more likely to be women (84 vs. 44%) with an amelanotic primary melanoma (21 vs. 5.3%). Patients with immunosuppression were equally likely to relapse, but more likely to have died of melanoma than controls (42 vs. 23%) (P=0.01, log-rank test). These findings suggest that immunosuppressive therapy is associated with a more aggressive disease course in patients with melanoma. The additional observation that the stage-specific recurrence rates were similar, however, suggests that routine dermatologic screening of immunosuppressed patients may lead to earlier diagnosis and improved outcomes.

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Clinical Utility of a Blood-Based BRAFV600E Mutation Assay in Melanoma

BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAFV600E detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as “positive.” BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAFV600E values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAFV600 mutation in patients with melanoma. Mol Cancer Ther; 13(12); 3210–8. ©2014 AACR.

Utility of 3-year torso computed tomography and head imaging in asymptomatic patients with high-risk melanoma.

There is no general consensus regarding the optimal follow-up strategy for patients with melanoma. We sought to determine the utility and cost effectiveness of radiological restaging of patients with stage IIB–IIIC melanoma at the 3-year follow-up time point. A retrospective review of 210 patients diagnosed with stage IIB–IIIC melanoma seen in the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center between January, 2001 and July, 2006 was conducted. Fifty-two patients were asymptomatic and continuously disease free and underwent restaging head computed tomography (CT) or MRI and torso CT scans 3 years after completion of local-regional therapy or initiation of adjuvant treatment. True positive, false positive and normal scans were identified and the cost per diagnosis calculated. Fifty-five percent of patients developed melanoma recurrences: 88% before 3 years (median time to recurrence 12 months, 95% confidence interval: 10–16 months). The majority of patients (69%) recurred with disease symptoms. Twenty-five head CT scans, 27 head MRIs, and 52 torso CTs were performed. One false-positive head CT and five abnormal torso CT scans (three false positive, two true positive) were identified. The total cost per diagnosis was

Retrospective analysis of interleukin-2 therapy in patients with metastatic renal cell carcinoma who had received prior antiangiogenic therapy

312 990. Extensive 3-year restaging imaging seems to be of limited value for symptomatic and continuously disease-free patients with stage IIB–IIIC melanoma. Furthermore, given the low risk of recurrence beyond 3 years, it is likely that subsequent routine imaging would have similarly low utility.