Antoni Ribas

Determinant spreading and tumor responses after peptide-based cancer immunotherapy

Modern immunological assays are very sensitive for detection of antigen-specific T cells. These assays are used to detect increased levels of T cells after peptide-based immunotherapy for cancer in an attempt to describe surrogate endpoints correlated with anti-tumor activity. Recent reports demonstrate that determinant spreading develops in a high frequency of subjects with tumor regression responses after this type of immunotherapy and could be valuable for trial monitoring and the design of more effective vaccines.

Exosomes as a predictor tool of acquired resistance to melanoma treatment

Background Exosomes are small endosome-derived vesicles ranging from 30-120 nm in diameter secreted from cells through exocytosis and, in cancer context, are able to prepare metastasis niche and suppress host’s immune system. Despite these pro-tumorigenic characteristics, exosomes can be useful for several Biotechnological applications such as biological anticancer vaccines, cancer diagnosis and prognosis. Due to its property of carrying parental cell’s protein and active nucleic acids there is an increasing interest to use exosomes to track cancer metabolism alterations in different conditions, for example, during drug administration [1]. One of the most common types of cancer that develops drug resistance during drug treatment is Melanoma. The majority of drugs developed against melanoma targets the oncogenic mutations in BRAF (BRAF V600E) that are present in nearly 60% of cutaneous melanoma tumors. Resistance to BRAFV600E inhibitors are classified in two main groups, Intrinsic Resistance and Acquired Resistance, the second is developed after treatment starts that happens mainly by MAPK reactivation and RTK upregulation [2]. Various methods are being studied to overcome drug resistance in melanoma, but there is a need to detect when the resistant mechanism is arising to orientate which approach to choose. This early detection has demonstrated to be a difficult task especially during advanced stages where there are several metastatic niches. With this aim, our research project was designed to create a method to follow tumor’s status through melanoma-derived exosomes. As most types of melanoma overexpress MART-1 we checked its expression, as well as PDGFR-B and others proteins, in PLX4032 (V600E mutated BRAF inhibitor) resistant and sensitive melanoma cell lines to start to understand their potential to be exosomes-associated proteins in the development of acquired resistance detection method[2].

Collaborative Care in Melanoma: The Essential Role of the Nurse

This article provides perspective from medical oncologists on the importance of this supplement from the Melanoma Nursing Initiative. The authors (a) delineate the challenges inherent in addressing adverse event (AE) management with newer melanoma therapies, particularly in the community setting; (b) illustrate how advanced practice providers with extensive clinical trial experience in melanoma are in a key position to set the agenda and educate colleagues on best practices in AE management; and

Abstract CT073: Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate 038

Introduction: Nivolumab and ipilimumab (NIVO+IPI) in combination was more efficacious than nivolumab (NIVO) alone in advanced melanoma patients (pts) in the phase 3 CheckMate 067 study (Larkin et al, NEJM. 2015). To elucidate the differential mechanisms of action of NIVO+IPI vs NIVO, we assessed biomarkers in pts with advanced melanoma treated with these agents in the CheckMate 038 study. Methods: IPI-naive pts without brain metastases from parts 1-3 of the phase 1b CA209-038 study (NCT01621490) who received NIVO+IPI Q3W (1 mg/kg+3 mg/kg, n=53) or NIVO alone Q2W (3 mg/kg, n=52) were included in the analysis. Tumor and peripheral immune markers were assessed (Table), and compared across treatment groups and by best overall response (BOR) per RECIST v1.1. Results: Increases in tumor-infiltrating CD8 T cells were observed with both NIVO+IPI and NIVO treatment, with greatest increases in NIVO+IPI pts with CR/PR or SD vs other BOR groups (Table). Increases in tumor PD-L1 expression were observed with both treatments, with 10-fold greater increases in pts with CR/PR to NIVO+IPI vs pts with PD/NE to NIVO+IPI or CR/PR to NIVO alone. Reductions in circulating MDSCs were observed with NIVO+IPI treatment across BOR groups, but only in pts with CR/PR in the NIVO-treated group. Increases in CXCL9, CXCL10 and IFN-gamma were observed irrespective of BOR in pts treated with both NIVO+IPI and NIVO alone, with the greatest increases with NIVO+IPI treatment. Conclusion: NIVO+IPI vs NIVO alone was associated with consistent reductions in MDSCs and greater increases in IFN-gamma signaling. Pts with CR/PR to NIVO+IPI had the greatest increases in CD8 T cells and PD-L1 expression, suggesting enhanced T-cell effector function. This may partly explain the higher ORR observed for NIVO+IPI vs NIVO alone in CheckMate 067. Further analyses will elucidate the differential immunomodulatory effects of NIVO+IPI in combination vs NIVO monotherapy in pts with advanced melanoma. Citation Format: Antoni Ribas, Salvador Martin-Algarra, Shailender Bhatia, Wen-Jen Hwu, Craig L. Slingluff, William H. Sharfman, F. Stephen Hodi, Walter J. Urba, Jason J. Luke, John B. Haanen, Margaret K. Callahan, Jedd D. Wolchok, Scott D. Chasalow, Petra Ross-Macdonald, Tina C. Young, Anila Qureshi, Christine E. Horak. Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate 038 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT073. doi:10.1158/1538-7445.AM2017-CT073

High frequency of brain metastases after adjuvant therapy for high-risk melanoma

The incidence of CNS progression in patients with high‐risk regional melanoma (stages IIIAN2a‐IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high‐dose interferon alfa‐2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow‐up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.

Abstract CT125: A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404

Background: Adjuvant therapy for melanoma has centered on high dose interferon for now almost 20 years. Recently, the FDA approved ipilimumab dosed at 10 mg/kg (10/kg ipi) for use in high risk resected melanoma. Though these two treatment options are available they still have limits in terms of efficacy with approximately 1 year of relapse free survival benefit (HDI and 10/kg ipi) and a modest overall survival benefit (HDI). Toxicity remains an issue as well with both therapies. S1404 is a Phase III, open label trial which seeks to compare currently available FDA approved treatments to one year of pembrolizumab in patients at high risk of relapse and death after surgery. Study Design: 1,378 patients will be randomized 1:1 to an FDA approved standard therapy, or pembrolizumab. Stratification factors include PD-L1 staining status, clinical stage, and pre-randomization selected standard treatment option. Patients: Patients must be 18 or older, and have Stage IIIA (n2), IIIB, IIIC or IV (M1a, b and c) resected melanoma to be eligible. Exclusion factors include brain metastases, ocular primary, and auto-immune disease. Prior therapy is not allowed, but radiation as adjuvant treatment is considered an option available to patients prior to treatment. Current status: As of January 2016, 30 sites are registered and 5 patients are randomized. An amendment to include 10 mg/kg ipilimumab as a treatment option is under review and will likely be finalized by the time of the meeting. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180818, CA180826, CA180858, CA180820, CA180844 Citation Format: Kenneth F. Grossmann, Vernon K. Sondak, Megan Othus, Ahmad Tarhini, Sapna Patel, John M. Kirkwood, Antoni Ribas, James Moon. A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT125.