Markovic, Svetomir N.

AbstractRelapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day‐cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single‐agent everolimus in this patient population. Fifty‐five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33‐85) with a median of five prior therapies (range: 1‐10). The ORR was 35% (19/55; 95% CI: 24‐48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4‐14.1), median duration of response of 11.5 months (95%‐CI: 5.7‐30.4), and a median progression‐free survival of 7.2 months (95%‐CI: 5.5‐12.5). The most common toxicity was hematologic with grades 3‐4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non‐Hodgkin lymphoma patients and is well tolerated.

Skin cancer affects more individuals in the USA than any other malignancy and malignant melanoma is particularly deadly because of its metastatic potential. Melanoma has been recognized as one of the most immunogenic malignancies; therefore, understanding the mechanisms of tumor–immune interaction is key for developing more efficient treatments. As the tumor microenvironment shows an immunosuppressive action, immunotherapeutic agents promoting endogenous immune response to cancer have been tested (interleukin-2, anticytotoxic-T-lymphocyte-associated antigen 4, and antiprogrammed cell death protein 1 monoclonal antibodies) as well as combinations of cytotoxic chemotherapy agents and inhibitors of angiogenesis (taxol/carboplatin/avastin). However, clinical outcomes are variable, with only a minority of patients achieving durable complete responses. The variability of immune homeostasis, which may be more active or more tolerant at any given time, in cancer patients and the interaction of the immune system with the tumor could explain the inconsistency in clinical outcomes among these patients. Recently, the role of the lymphocyte-to-monocyte-ratio (LMR) in the peripheral blood has been investigated and has been proven to be an independent predictor of survival in different hematological malignancies and in solid tumors. In melanoma, our group has validated the significance of LMR as a predictor of relapse after resection of advanced melanoma. In this study, we examined the dynamics in the immune system of patients with advanced melanoma by performing serial multiday concentration measurements of cytokines and immune cell subsets in the peripheral blood. The analysis of outcomes of chemotherapy administration as related to LMR on the day of treatment initiation showed that progression-free survival was improved in the patients who received chemotherapy on the day when LMR was elevated.

Ipilimumab can induce long-term survival in 20% of patients with metastatic melanoma. Concurrent chronic medications may impact the patient’s immune system, possess antimelanoma properties, and potentially affect clinical outcomes. This retrospective study sought to describe the efficacy and toxicity effects of 12 classes of chronic medications in metastatic melanoma patients treated with ipilimumab. A total of 159 adults who received ipilimumab for metastatic melanoma at Mayo Clinic (Rochester, Minnesota, USA) from 1 March 2011 through 31 December 2014 were included. Classes of chronic medications included statins, metformin, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, calcium channel blockers, aspirin, non-steroidal anti-inflammatory drugs, H1 and H2 receptor antagonists, proton pump inhibitors (PPIs), antidepressants, and vitamin D supplements. Of the 12 medication classes, only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab [odds ratio: 3.73; confidence interval (CI): 1.26–11.04; P=0.02] on the basis of a case–control analysis. Although not significant, PPI use also trended toward improved overall survival and progression-free survival (hazard ratio: 0.44; CI: 0.17–1.15; P=0.09; and hazard ratio: 0.6; CI: 0.34–1.06; P=0.08, respectively) on the basis of Kaplan–Meier and Cox proportional hazard modeling. No medication class was associated with an increased risk of grades 3–5 immune-related adverse events with ipilimumab on the basis of case–control analysis. In summary, patients on PPIs may be more likely to experience a partial response/complete response following ipilimumab therapy. Because of the small sample size and the retrospective nature of this work, these findings are only descriptive and further study should be carried out. Other classes of chronic medications did not produce statistically significant effects for any of the measured outcomes.

Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin-domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.

AbstractTo examine, in a prospective fashion, the utilization and efficacy of adjuvant radiation therapy (RT) in patients with resected desmoplastic melanoma (DM). Adult patients with resected, margin‐negative, and nonmetastatic DM were eligible for this single‐arm prospective phase II study. Patients were to receive postoperative RT, 30 Gy in five fractions, to the operative bed with 2‐ to 3‐cm margins (depending on the tumor location). Nodal basin RT was not allowed. The primary study endpoint was the 2‐year local recurrence rate (LRR). Secondary endpoints included the incidence of regional and distant metastatic disease, progression‐free survival, overall survival (OS), and treatment‐related toxicity. Twenty patients with a single de novo DM lesion meeting trial eligibility criteria were enrolled and treated. The 2‐year LRR was 10%, with two patients demonstrating a LR within 2 years of completion of protocol therapy. No regional or distant failures occurred. OS at 2 and 5 years was 95 and 77%, respectively. There were no grade 3 or higher acute or late adverse events that were related to the protocol therapy. Adjuvant RT after wide local excision (WLE) for DM is efficacious and well tolerated. It should be considered for DM patients after margin‐negative WLE. Additional study is needed to further refine low‐risk patient populations that can potentially have adjuvant RT omitted as part of the treatment plan.

Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host’s immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

Abstract Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

Uveal melanoma is a rare type of melanoma, with only five to seven cases per one million persons diagnosed each year. Patients with metastatic melanoma of uveal origin tend to have lower response rates on traditional therapies. Herein we report our experience with 10 patients with metastatic uveal melanoma (MUM) who received pembrolizumab. Eligible patients were more than or equal to 18 years old, had unresectable MUM, progressed on prior ipilimumab therapy, had good performance status (Eastern Cooperative Oncology Group of 0 or 1), and adequate organ and marrow function. Patients could have central nervous system disease, but needed to be clinically stable. Patients were treated with 2 mg/kg pembrolizumab intravenously over 30 min every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years. Between April 2014 and October 2014, we treated a total of 10 patients with MUM with pembrolizumab. Median age was 65 years, with 70% being female. As of the data cutoff date of 14 May 2015, median progression-free survival was 18 weeks (range 3.14–49.3 weeks), with four patients still currently receiving therapy. Of eight evaluable patients, there was one complete response, two partial responses, and one patient with stable disease. Four patients had rapidly progressive disease. Toxicities were as expected and were usually grade 1/2 in nature. Although this cohort of patients was small, to our knowledge this is the first such report of outcomes in uveal melanoma patients being treated with anti-PD1 therapy. In the absence of a clinical trial, treatment with pembrolizumab appears to be a viable option for patients with MUM.