7 research outputs found
Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.
PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors
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381 Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study
BackgroundIntratumoral administration of V937, a bioselected genetically unmodified Coxsackievirus A21, has shown antitumor activity both as a monotherapy and in combination with the anti–PD-1 antibody pembrolizumab.1–3 V937 induces lytic tumor cell infection and upregulation of members of immune checkpoint pathways.2 We present the results from the phase 1b MITCI study that evaluated V937 plus ipilimumab for advanced melanoma.MethodsEligible patients had unresectable or metastatic stage IIIB/C or IV melanoma amenable to intratumoral injection. Patients received intratumoral V937 3×108 TCID50 on days 1, 3, 5, 8, and 22, then Q3W for 14 more injections plus intravenous ipilimumab 3 mg/kg Q3W administered 4 times starting on day 22. Imaging was done Q6W beginning at day 106; response was assessed per immune-related response criteria (irRC). The primary endpoints were safety and ORR in the overall population and in patients whose disease progressed on prior anti–PD-1 therapy.Results50 patients were enrolled and received ≥1 dose of study treatment. At data cutoff (February 21, 2020), all had discontinued the study and study therapy. Median (range) age was 64.5 (28–88) years. Fourteen patients (28%) had stage III disease. Forty patients (80%) had received prior systemic treatment, 33 of whom had received anti–PD-1 therapy. The median number of cycles of ipilimumab was 4 (range, 1–4), and the number of intratumoral injections of V937 was 9 (range, 5–19). Among the 94% of patients who had ≥1 treatment-related AE, 14% had grade 3/4 treatment-related AEs, none of which were considered related to V937. The most common grade 3/4 treatment-related AEs were dehydration, diarrhea, and hepatotoxicity (4% each). No grade 5 treatment-related AEs occurred. The most common treatment-related AEs were pruritus (50%), fatigue (44%), diarrhea (32%), and nausea (22%). Efficacy outcomes for the overall population and by prior anti-PD-1 therapy use are presented in table 1. Tumor regression was observed in injected and noninjected lesions.Abstract 381 Table 1ConclusionsV937 plus ipilimumab was safe and the toxicities were manageable and consistent with that anticipated for the individual treatment components. ORR was robust and significantly higher than anticipated with ipilimumab monotherapy, including in patients who had received prior anti–PD-1 therapy. Most responses were durable (≥26 weeks), and responses seen in noninjected metastases provided evidence of probable systemic immune activation. The combination of V937 plus ipilimumab warrants further investigation in a larger trial in patients with advanced melanoma.AcknowledgementsMedical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT02307149ReferencesPandha H, Harrington K, Ralph C, Melcher A, Gupta S, Akerley W, et al. Abstract CT115: phase 1b KEYNOTE 200 (STORM study): a study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients. Cancer Res 2017;77(13 suppl):CT115.Andtbacka RHI, Curti BD, Kaufman H, Nemunaitis JJ, Daniels GA, Hallmeyer S, et al. Dynamics of tumor response in advanced melanoma patients treated with coxsackievirus A21. J Clin Oncol 2016;34(15 suppl):9553.Silk AW, Kaufman H, Gabrail N, Mehnert J, Bryan J, Norrell J, et al. Phase 1b study of intratumoral coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: interim results of the CAPRA clinical trial. Cancer Res 2017;77(13 suppl):CT026.Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial was conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided informed consent
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BRAFV600E induces reversible mitotic arrest in human melanocytes via microrna-mediated suppression of AURKB.
Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arising from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs-MIR211-5p and MIR328-3p-induced mitotic failure, genome duplication, and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Taken together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations
Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma
Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab
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Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.
PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors