scholarly journals 381 Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A415-A415
Author(s):  
Carlo Bifulco ◽  
Jon Richards ◽  
John Hyngstrom ◽  
Gregory Daniels ◽  
Mark Faries ◽  
...  
Keyword(s):  
Oncolytic Virus ◽  
Tumor Regression ◽  
Advanced Melanoma ◽  
Individual Treatment ◽  
List Type ◽  
Advanced Cancer Patients ◽  
Phase 1B ◽  
Coxsackievirus A21 ◽  
Melanoma Patients ◽  
Grade 3

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.

scholarly journals 673 Precision microbiome mapping identifies a microbiome signature predictive of Immune checkpoint inhibitor response across multiple research study cohorts

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Matthew Robinson ◽  
Kevin Vervier ◽  
Simon Harris ◽  
David Adams ◽  
Doreen Milne ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
List Type ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Sequencing Platform ◽  
Melanoma Patients

BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3014-3014 ◽  
Author(s):  
Brendan D. Curti ◽  
Jon M. Richards ◽  
Sigrun Hallmeyer ◽  
Mark B. Faries ◽  
Robert Hans Ingemar Andtbacka ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Phase 1 ◽  
Unmet Need ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Potential Marker ◽  
Previously Treated ◽  
Coxsackievirus A21 ◽  
Melanoma Patients

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.

scholarly journals The MITCI (phase 1b) study: a novel immunotherapy combination of coxsackievirus A21 and ipilimumab in patients with advanced melanoma

2016 ◽  
Vol 27 ◽  
pp. vi360 ◽  
Author(s):  
B. Curti ◽  
J. Richards ◽  
M. Faries ◽  
R.H.I. Andtbacka ◽  
M. Grose ◽  
...  
Keyword(s):  
Advanced Melanoma ◽  
Phase 1B ◽  
Coxsackievirus A21

Dynamics of tumor response in advanced melanoma patients treated with Coxsackievirus A21.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 9553-9553 ◽  
Author(s):  
Robert Hans Ingemar Andtbacka ◽  
Brendan D. Curti ◽  
Howard Kaufman ◽  
John J. Nemunaitis ◽  
Gregory A. Daniels ◽  
...  
Keyword(s):  
Tumor Response ◽  
Advanced Melanoma ◽  
Coxsackievirus A21 ◽  
Melanoma Patients

Keynote-200 phase 1b: A novel combination study of intravenously delivered coxsackievirus A21 and pembrolizumab in advanced cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3108-TPS3108 ◽  
Author(s):  
Hardev S. Pandha ◽  
Christy Ralph ◽  
Kevin Harrington ◽  
Brendan D. Curti ◽  
Rachel E. Sanborn ◽  
...  
Keyword(s):  
Death Receptor ◽  
Advanced Cancer Patients ◽  
Programmed Death ◽  
Combination Study ◽  
Phase 1B ◽  
Low Toxicity ◽  
Coxsackievirus A21 ◽  
Irrecist 1.1 ◽  
Ecog Ps ◽  
Tumor Biopsies

TPS3108 Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Intravenous (i.v.) CVA21 mono-therapy is generally well tolerated, with low toxicity and can successfully target tumors in patients with melanoma, NSCLC and bladder cancer as confirmed by detection of CVA21 viral RNA in post-treatment tumor biopsies (Pandha et al., 2016). Intratumoral CVA21 replication has the potential to up-regulate numerous key immune checkpoint molecules, including PD-L1 (Andtbacka et al., 2016).The combination of i.v. CVA21+pembrolizumab may translate to a potential enhanced benefit in the clinic. Methods: The Phase Ib KEYNOTE-200 (NCT02043665) Treatment: Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Patients (pts) are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment (tx) with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT.To date the combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with tx of pts in Cohort 3 currently underway. Key eligibility: Pts with advanced disease considered appropriate tx with CVA21 + pembrolizumab, lesion(s) accessible for core biopsy, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression. Clinical trial information: NCT02043665.

scholarly journals Sex-Based Differences in Treatment with Immune Checkpoint Inhibition and Targeted Therapy for Advanced Melanoma: A Nationwide Cohort Study

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4639
Author(s):  
Monique van der Kooij ◽  
Olaf Dekkers ◽  
Maureen Aarts ◽  
Franchette van den Berkmortel ◽  
Marye Boers-Sonderen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Advanced Melanoma ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Survival Difference ◽  
Melanoma Treatment ◽  
Melanoma Patients ◽  
Treatment Responses ◽  
Grade 3 ◽  
Meta Analyses

Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013–July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3–4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients ≥60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference.

Results from the phase Ib of the SENSITIZE trial combining domatinostat with pembrolizumab in advanced melanoma patients refractory to prior checkpoint inhibitor therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Jessica Cecile Hassel ◽  
Carola Berking ◽  
Max Schlaak ◽  
Thomas Eigentler ◽  
Ralf Gutzmer ◽  
...  
Keyword(s):  
Disease Control ◽  
Checkpoint Inhibitor ◽  
Significant Proportion ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Tumor Escape ◽  
Current Standard ◽  
Phase Ib ◽  
Melanoma Patients ◽  
Grade 3

9545 Background: Anti-PD-1 +/- anti-CTLA4 antibodies are the current standard of care immunotherapy for advanced melanoma. However, a significant proportion of patients do not achieve disease control. Epigenetic modulation, particularly histone deacetylase (HDAC) inhibition, can overcome tumor escape mechanisms and thus might increase the susceptibility to immunotherapy. Methods: Advanced unresectable/metastatic cutaneous melanoma patients primary refractory or non-responding to prior checkpoint inhibitor (CI) therapy were treated with domatinostat at 5 different dose levels (DL) (100 mg (QD), 200 (QD), and 200 mg (BID) using two different schedules (D1-14 and D1-21 q3w) in combination with pembrolizumab (2 mg/kg) q3w to evaluate safety and tolerability. Tumor assessments were performed every 12 weeks and assessed using irRECIST. Sequential tumor biopsies were taken for gene expression analysis and peripheral blood for pharmacokinetic (PK) analysis. Results: We report on preliminary results from the phase Ib part of the ongoing study, data cut-off Feb 1st, 2021 a total of 40 patients have been enrolled. Patient characteristics show that the median number of pretreatments at stage IV was 3, 65 % of patients stage M1c (AJCC 7 or 8) and 35 % with elevated LDH at trial inclusion. Treatment emergent adverse events (AEs) related to domatinostat reported in ≥ 10% of patients were: diarrhea (23%), nausea (20%), fatigue (20%), rash (15%), pyrexia (13%), blood alkaline phosphatase increased (13%), vomiting (10%), dyspnea (10%), all grade 1 and 2 - except one maculo-papular rash grade 3. In total, 8 patients (20 %) developed ≥ grade 3 AEs, with no treatment-related deaths. Patterns of AEs resembled the known safety profiles of domatinostat and pembrolizumab with no increase of immune related AEs for the combination. Maximum tolerated dose was not reached. Four patients discontinued treatment per protocol due to AEs grade 3. We observed clinical activity with 1 complete response, 2 confirmed partial responses and 9 stable diseases (6 confirmed), resulting in a disease control rate of 30% in highly pretreated patients throughout all DLs. Notably, 3 out of 7 patients achieved disease control in DL 3 (domatinostat 200 mg BID D1-14, q3w) and were on treatment ≥ 1.5 years, indicating a trend of dose-dependent clinical activity. Domatinostat treatment resulted in a trend to higher intra-tumoral expression of MHC/APM genes and a more inflamed tumor microenvironment reflecting enhanced T cell infiltration. Conclusions: The combination of domatinostat and pembrolizumab was safe and well tolerated. The observed clinical activity in advanced melanoma patients refractory to previous checkpoint inhibition and the favorable translational findings warrant further development of domatinostat in combination with CI in melanoma and beyond. Clinical trial information: NCT03278665.

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