Daohai Yu

Extended Dose Ipilimumab with a Peptide Vaccine: Immune Correlates Associated with Clinical Benefit in Patients with Resected High-Risk Stage IIIc/IV Melanoma

Purpose: To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit. Experimental Design: In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment. Results: Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035). Conclusions: Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse. Clin Cancer Res; 17(4); 896–906. ©2010 AACR.

Biomarkers on melanoma patient T Cells associated with ipilimumab treatment

BackgroundIpilimumab induces long-lasting clinical responses in a minority of patients with metastatic melanoma. To better understand the mechanism(s) of action and to identify novel biomarkers associated with the clinical benefit and toxicity of ipilimumab, baseline characteristics and changes in CD4+ and CD8+ T cells from melanoma patients receiving ipilimumab were characterized by gene profiling and flow cytometry.MethodsMicroarray analysis of flow-cytometry purified CD4+ and CD8+ T cells was employed to assess gene profiling changes induced by ipilimumab. Selected molecules were further investigated by flow cytometry on pre, 3-month and 6-month post-treatment specimens.ResultsIpilimumab up-regulated Ki67 and ICOS on CD4+ and CD8+ cells at both 3- and 6-month post ipilimumab (p ≤ 0.001), decreased CCR7 and CD25 on CD8+ at 3-month post ipilimumab (p ≤ 0.02), and increased Gata3 in CD4+ and CD8+ cells at 6-month post ipilimumab (p ≤ 0.001). Increased EOMES+CD8+, GranzymeB+EOMES+CD8+ and decreased Ki67+EOMES+CD4+ T cells at 6 months were significantly associated with relapse (all p ≤ 0.03). Decreased Ki67+CD8+ T cells were significantly associated with the development of irAE (p = 0.02). At baseline, low Ki67+EOMES+CD8+ T cells were associated with relapse (p ≤ 0.001), and low Ki67+EOMES+CD4+ T cells were associated with irAE (p ≤ 0.008).ConclusionsUp-regulation of proliferation and activation signals in CD4+ and CD8+ T cells were pharmacodynamic markers for ipilimumab. Ki67+EOMES+CD8+ and Ki67+EOMES+CD4+T cells at baseline merit further testing as biomarkers associated with outcome and irAEs, respectively.

Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma

High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.

Radiotherapy influences local control in patients with desmoplastic melanoma

Desmoplastic melanoma may have a high risk of local recurrence after wide excision. The authors hypothesized that adjuvant radiotherapy (RT) would improve local control in patients with desmoplastic melanoma, resulting in at least a 10% absolute decrease in local recurrence rate.

The Florida Melanoma Trial I: A Prospective Multicenter Phase I/II Trial of Postoperative Hypofractionated Adjuvant Radiotherapy with Concurrent Interferon-Alfa-2b in the Treatment of Advanced Stage III Melanoma with Long-Term Toxicity Follow-Up

Radiotherapy (RT) and interferon-alfa-2b (IFN α-2b) have individually been used for adjuvant therapy stage III melanoma with high-risk pathologic features. We hypothesized that concurrent adjuvant RT and IFN α-2b may decrease the risk of regional recurrence following surgery with acceptable toxicity. A prospective multicenter phase I/II study was conducted to evaluate hypofractionated RT with concurrent IFN. Induction IFN α-2b, 20 MU/m2/d, was administered IV ×5 consecutive days every week for 4 weeks. Next, RT 30 Gy in 5 fractions was given with concurrent IFN α-2b, 10 MU/m2 SQ 3 times per week on days alternating with RT. Subsequent maintenance therapy consisted of adjuvant IFN α-2b, 10 MU/m2 SQ 3 times per week to a total of 1 year. To fully evaluate patterns of failure, long-term follow-up was conducted for up to 10 years. A total of 29 consenting patients were enrolled between August 1997 and March 2000. The maximum (worst) grade of acute nonhematologic toxicity during concurrent RT/IFN α-2b (and up to 2 weeks post RT) was grade 3 skin toxicity noted in 2 patients (9%). Late effects were limited. Probability of regional control was 78% (95% CI: 55%–90%) at 12 months. The median follow-up (range) was 80 (51–106) months among ten survivors (43%). The median overall survival was 34.5 months while the median failure-free survival was 19.9 months. Postoperative concurrent hypofractionated RT with IFN α-2b for advanced stage III melanoma appears to be associated with acceptable toxicity and may provide reasonable in-field control in patients at high risk of regional failure.

Perceptions of Prostate Cancer Screening Controversy and Informed Decision Making: Implications for Development of a Targeted Decision Aid for Unaffected Male First-Degree Relatives.

Purpose. First-degree relatives (FDRs) of prostate cancer (PC) patients should consider multiple concurrent personal risk factors when engaging in informed decision making (IDM) about PC screening. This study assessed perceptions of IDM recommendations and risk-appropriate strategies for IDM among FDRs of varied race/ethnicity. Design. A cross-sectional, qualitative study design was used. Setting. Study setting was a cancer center in southwest Florida. Participants. The study comprised 44 participants (24 PC patients and 20 unaffected FDRs). Method. Focus groups and individual interviews were conducted and analyzed using content analysis and constant comparison methods. Results. Patients and FDRs found the PC screening debate and IDM recommendations to be complex and counterintuitive. They overwhelmingly believed screening saves lives and does not have associated harms. There was a strongly expressed need to improve communication between patients and FDRs. A single decision aid that addresses the needs of all FDRs, rather than one separating by race/ethnicity, was recommended as sufficient by study participants. These perspectives guided the development of an innovative decision aid that deconstructs the screening controversy and IDM processes into simpler concepts and provides step-by-step strategies for FDRs to engage in IDM. Conclusion. Implementing IDM among FDRs is challenging because the IDM paradigm departs from historical messages promoting routine screening. These contradictions should be recognized and addressed for men to participate effectively in IDM. A randomized pilot study evaluating outcomes of the resulting decision aid is underway.

Discussion of First-Degree Relatives’ Colorectal Cancer Risk: Survivors’ Perspectives

Although screening reduces colorectal cancer (CRC) incidence and mortality, screening rates are low, particularly among CRC patients’ first-degree relatives (FDRs). Little is known about discussion of family members’ risk of CRC among patients and their health care providers or with their FDRs. The purpose of this research, guided by the Protection Motivation Theory, was to assess patients’ patterns of disclosure of CRC diagnosis to adult siblings and/or children and discussion of familial risk by healthcare providers. A cross-sectional sample of patients who received care at a comprehensive cancer center was recruited to complete telephone-based interviews related to disclosure of CRC diagnosis to FDRs, recall of physician counseling about familial risk, and patients’ perception of CRC risk to FDRs. Sixty-nine patients completed the interview. Most participants (n = 67, 97%) had informed their adult children or siblings of their CRC diagnosis to keep their family informed of their health status (n = 15, 22%) and to encourage FDRs to screen for CRC (n = 14, 20%). More than half of the participants’ physicians (n = 38, 55%) discussed FDRs’ risk of developing CRC with the patient. However, a substantial proportion of patients reported no physician discussion of this risk (n = 28, 41%). Data from this study may guide the development of interventions to facilitate physician discussion and counseling of CRC patients about their FDRs’ risk for CRC. However, future studies should explore whether FDRs are likely to be screened after becoming aware of their family member’s diagnosis of CRC.