Phase II Trial of Concurrent Sunitinib and Image-Guided Radiotherapy for Oligometastases

BACKGROUND: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. METHODS: Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). RESULTS: The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. CONCLUSIONS: Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00463060

Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer

The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients

Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy

Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy

Prognostic Value of Multiple Draining Lymph Node Basins in Melanoma: A Matched-Pair Analysis Based on the John Wayne Cancer Institute Experience

BackgroundThe prognostic significance of multiple draining basins is controversial in melanoma because analyses have not adequately controlled for standard prognostic variables. We hypothesized that an analysis based on prognostically matched pairs of patients with multiple versus single drainage basins would clarify any independent role of basin number.Study designWe identified patients in our 40-year prospective database, who underwent preoperative lymphoscintigraphy, intraoperative sentinel node biopsy and wide local excision for cutaneous melanoma. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were compared in patients with multiple versus single drainage basins after matching by age, sex, Breslow depth, primary site, and stage at diagnosis.ResultsWe identified 274 patients with multibasin drainage and 1,413 patients with single draining lymph node basins. Matching yielded 259 pairs (226 trunk, 27 head/neck, 6 extremity). Among matched pairs, multibasin drainage did not affect rates of lymph node metastasis (p = 0.84), OS (p = 0.23), DSS (p = 0.53), overall recurrence (p = 0.65), locoregional recurrence (p = 0.58), or distant recurrence (p = 1.0). Multivariable analysis linked higher T stage, ulceration, older age, and lymph node positivity to decreased DSS (p < 0.01) and DFS (p < 0.001). Number of drainage basins was not significant on univariable or multivariable analysis.ConclusionThis analysis, the first to match for standard prognostic factors, suggests that multiplebasin drainage as identified by lymphoscintigraphy has no independent biological or prognostic significance in primary cutaneous melanoma

A Microcosm of Disparities in Breast Cancer: Comparison Between a Private Hospital and a Safety-Net County Hospital Within Los Angeles County.

Background: Breast cancer survival is improving due to early detection and treatment advances. However, racial/ethnic differences in tumor biology, stage, and mortality remain. The objective of this study was to analyze presumed disparities at a local level. Methods: Breast cancer patients at a county hospital and private hospital from 2010 to 2012 were retrospectively reviewed. Demographic, clinical, pathologic, and surgical data were collected. Comparisons were made between hospital cohorts and between racial/ethnic groups from both hospitals combined. Results: 754 patients were included (322 from county hospital and 432 from private hospital). All patients were female. The median age was 54 years at county hospital and 60 years at private hospital (P \u3c .0001). Racial/ethnic minorities comprised 85% of county hospital patients vs. 12% of private hospital patients (P \u3c .0001). County hospital patients had a higher grade, clinical/pathologic stage, HER2-positive rate, and mastectomy rate. Compared to other racial/ethnic groups, non-Hispanic white women were more likely to have lower grade and ER-positive tumors. Hispanic/Latina women were younger and were more likely to have HER2-positive tumors. Both Hispanic/Latina and non-Hispanic black women presented at higher clinical stages and were more likely to undergo neoadjuvant chemotherapy and mastectomy. Discussion: At county hospital compared to private hospital, the proportion of racial/ethnic minorities was higher, and patients presented at younger ages with more aggressive tumors and more advanced disease. The racial/ethnic disparities that were identified locally are largely consistent with those identified in national database studies. These marked differences at hospitals within a diverse city highlight the need for further research into the disparities. Keywords: breast; socioeconomic