Targeting gp100 and TRP-2 with a DNA vaccine: incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial

A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2-8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p< 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p< 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p=0.027). We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease

Outcome and biomarker analysis from a multi-centre phase 2 study of ipilimumab in combination with carboplatin and etoposide (ICE) as first line therapy for extensive stage small cell lung cancer.

BACKGROUND: To evaluate safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive stage SCLC. METHODS: Chemotherapy-naïve extensive stage SCLC patients were treated with carboplatin and etoposide up to six cycles. Ipilimumab 10 mg/kg was given on day 1 of cycles 3-6 and every 12 weeks. Response was assessed by RECIST v1.0 and immune related response criteria (irRC). The primary endpoint was 1-year progression-free survival (PFS) according to RECIST. Secondary endpoints included PFS by irRC (irPFS) and overall survival (OS). Autoantibody serum levels were evaluated and correlated with clinical outcomes. RESULTS: 42 patients were enrolled between September 2011-April 2014, 39 evaluable for safety and 38 for efficacy. 6/38 patients (15.8% [95% CI: 7.4%-30.4%]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95%CI: 5.5-7.9). Median irPFS was 7.3 months (95% CI: 5.5-8.8). Median OS was 17.0 months (95% CI: 7.9-24.3). In patients evaluable for response, 21/29 patients (72.4%) achieved an objective response by RECIST and 28/33 (84.8%) by irRC. All patients experienced at least one adverse event; 35/39 (89.7%) patients developed at least one toxicity ≥ Grade 3; in 27 (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. The positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. CONCLUSION: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation

Ipilimumab-induced colitis: experience from a tertiary referral center

Background: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. Methods: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. Results: A total of 83 patients received ipilimumab. Only 19.3% ( n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. Conclusions: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea

Denosumab for treatment of bone metastases secondary to solid tumours : systematic review and network meta-analysis

Abstract Aim: To evaluate the evidence for denosumab for the treatment of bone metastases secondary to solid tumours and, using a network meta-analysis, indirectly compare denosumab with bisphosphonates and best supportive care. Data sources: MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), Cochrane Library (all sections) (issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011) and additional meeting abstracts (2010 and 2011) were searched. Study eligibility, participants and interventions: Only randomised controlled trials assessing denosumab, bisphosphonates or best supportive care in patients with bone metastases from any solid tumour were included. Synthesis: Direct evidence comparing denosumab and zoledronic acid was assessed for breast cancer, prostate cancer and other solid tumours. Denosumab was compared with pamidronate and best supportive care through a network meta-analysis for each tumour type. The primary outcomes were time to first skeletal related event (SRE) and time to first and subsequent SRE. Secondary outcomes were skeletal morbidity rate, pain, quality of life (QoL) and overall survival. Results: Denosumab was found to be more effective in delaying the time to first SRE and reducing the risk of first and subsequent SRE compared to zoledronic acid, placebo and pamidronate. In breast and prostate cancer, denosumab was effective in reducing skeletal morbidity rate compared with placebo. The lack of published data on pain and QoL meant that firm conclusions could not be made. Denosumab did not appear to have an affect on overall survival

Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma

SCIB1 is a novel DNA immunotherapy that has epitopes from gp100 and TRP-2 melanoma antigens, engineered into a human IgG1 antibody. The therapy works by direct transfection and cross presentation via CD64 of dendritic cells. Vaccination results in high avidity T cells and tumour elimination in preclinical models.(1,2) A clinical trial was conducted to determine its safety and its ability to induce cellular immune responses. Patients and Methods: The vaccine was administered via Intramuscular injection with electroporation at 3 weekly intervals for 3 vaccinations then at 3 and 6 months. In part 1 of the study, nine patients with Stage III/IV melanoma were given escalating doses of SCIB1. Due to lack of toxicity the 2mg cohort were allowed to receive 4mg doses in their booster immunisations and the 4mg cohorts were allowed to continue with 3-6 monthly immunisations for 5 years. The 4mg dose was selected for an expansion cohort (part 2). To date 8 patients with fully resected stage III and 6 with fully resected stage IV melanoma have been treated and 7/14 patients are receiving ongoing vaccination. Results: No systemic dose-limiting toxicities were observed. The most common adverse event was injection site pain. 4/6 patients in the 2mg/4mg cohorts who received >3 doses of SCIB1, are still alive with a median survival time of 24 months. One patient had multiple tumour lesions (several in her lungs). All decreased in size or disappeared following treatment except for one lesion which was resected. Immunohistochemistry demonstrated strong expression of PD.L1 on the tumour cells. All patients in part 2 remain alive and only three have progressed. The median survival time in Part 2 is 15 months from study entry and 19 months from diagnosis of metastatic disease. In part 1, one patient in the 0.4mg cohort, all three patients in the 2mg/4mg dose cohort and two patients in the 4mg dose cohort mounted a measurable immune response to the vaccine-encoded antigens. In part 2, all 14 patients responded immunologically. 12/14 patients in the proliferation assay, 13/14 patients responded after T cell expansion in-vitro followed by ELISPOT assay and 11/14 patients responded in both assays. Responses were seen against both the CD8 epitopes and against the CD4+ epitopes. Six patients responded to all four epitopes, five patients responded to three epitopes and three patients responded to two epitopes. Significant responses (p>0.0001) were seen after three, four or five immunisations, indicating that at least three doses are required for a strong immune response to develop. Conclusion: We demonstrate that SCIB1 is safe in melanoma patients. 19/20 patients showed immune responses to repeat dosing at 2 or 4 mg. Detection of an objective clinical response and overall survival times are encouraging. 1. Pudney et al (2010). Eur J Immunol 40: 899. 2. Brentville et al (2012). Plos one 7:e411

Abstract 9035: An adjuvant clinical trial of SCIB1, a DNA vaccine that targets dendritic cells in vivo, in fully resected melanoma patients

SCIB1 is a DNA vaccine encoding a human IgG1 antibody, with T cell epitopes from gp100 and TRP-2 antigens engineered into its CDRs. It targets dendritic cells in vivo via the high affinity Fc receptor. A clinical trial in stage III/IV melanoma patients showed that doses of 2-8 mg could induce T cell responses in 7/9 patients with no associated toxicity. Overall median survival was 24 months. In this study SCIB1 is used as an adjuvant therapy. Methods: 16 patients with fully resected stage III (9) or stage IV (7) melanoma, were immunised with SCIB1 by Intramuscular electroporation at 0, 3, 6, 12 and 24 weeks. Patients tolerating treatment were allowed to continue treatment for up to 5 years. Results: Thirteen patients received 4mg doses of SCIB1 on 5 occasions and one received 4 doses of 4mg followed by one dose of 2mg. One patient only tolerated administration of three 2mg doses of SCIB1. One patient received three 2mg doses and then two 4mg doses. Seven patients received additional doses of SCIB1. One patient received 3 doses prior to withdrawal due to disease progression and one patient received 5 doses. The other six patients remain on continuation: three have received 5 doses and two have received 6 doses of SCIB1. Apart from soreness at the injection site, there have been no significant toxicities. All sixteen patients showed an epitope specific proliferation response ex vivo and an IFN Elispot response in-vitroafter T cell expansion. Eleven patients responded to all 4 epitopes, three patients to 3 epitopes, one patients to 2 epitopes and one patients to 1 epitope. All patients with continued treatment showed strong T cell memory responses. Currently patients have a median survival time from trial entry of 29.5 months and from diagnosis of metastases of 34 months. Progression free survival is 78% and 72% for stage III and IV respectively and overall survival is 100% for both groups. Only 4 patients have relapsed at 4, 14, 18 and 18 months, since the last relapse there have been no further recurrences for 23 months. Conclusions: These results suggest that SCIB1 may confer protection from recurrence of melanoma with little associated toxicity. This vaccine deserves further evaluation as an adjuvant therapy. Clinical trial information: 2009-017355-10

Open Discussion

This open session will provide a forum for conference participants to discuss varied topics of interest. Examples of proposed discussion areas include risk management, financial aid, the role of NAFSA and the Association of American Law Schools in international law programs, tracking trends to inform program development, creating opportunities for US students in China and the concordance of externships with ABA Standard 305.Moderator: Diane Edelman, Director of International Programs, Villanova University School of La