453 Personalized DNA neoantigen vaccine (GNOS-PV02) in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14–17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to generate tumor-specific T cell immunity, potentially priming the immune system for anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC.MethodsGT-30 is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing, and peripheral blood collected for germline sequencing and histogenetics. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens. After progression or intolerance with first-line therapy, patients commence concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter. Pembrolizumab is delivered Q3w.ResultsWe performed a data cut-off on the first 12 patients. The median age was 66 years (range 55–75 years). GNOS-PV02 + INO-9012 with pembrolizumab has had no reported DLTs or drug related SAEs. The most common treatment-related AE were grade 1 fatigue (25%) and grade 1 injection site reactions (17%). By including up to 40 epitopes in the vaccine we were able to target all neoantigens present in 83% of the patients. The objective response rate was 25% (3/12 partial response, 5/12 stable disease, 4/12 progressive disease). Analysis of the TCR repertoire in peripheral blood and tumor tissue identified novel and significantly expanded T cell clones post-vaccination in all patients analyzed. Many of the novel peripheral T cell clones were also identified to have trafficked to the TME at week 9, potentially mediating the observed tumor regressions.ConclusionsThese data demonstrate the potential of GNOS-PV02 + INO-9012 with pembrolizumab to target multiple neoepitopes, and provide initial support for the safety and efficacy of this regimen in patients with advanced HCC.Trial RegistrationNCT04251117Ethics ApprovalThe study obtained IRB approval (IRB) and all patients signed informed consent prior to taking part in the clinical trial. NZCR EC: 20/NTA/6; JHU: IRB00227771; Mount Sinai: HS#: 20–00076

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Personalized DNA neoantigen vaccine in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps2680 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS2680-TPS2680

Author(s):

Mark Yarchoan ◽

Edward Gane ◽

Thomas Urban Marron ◽

Sarah Rochestie ◽

Neil Cooch ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

T Cell ◽

Disease Progression ◽

T Cell Responses ◽

First Line ◽

Advanced Hcc ◽

Cell Responses ◽

First Line Therapy ◽

Line Therapy

TPS2680 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14-17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to prime T cell responses, potentially enhancing responses to anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC. Methods: The GT-30 trial (NCT04251117) is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens, which includes all detected neoantigens for the majority of HCC patients. After progression or intolerance with first-line therapy, patients can commence trial therapy with concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter until disease progression. Pembrolizumab is delivered Q3w until disease progression. Immunogenicity of each of the vaccine epitopes will be determined by ex vivo ELISpot and flow cytometry. Clinical activity is assessed by RECIST1.1 at baseline and every 9 weeks. Serial biopsies will be obtained at 9 weeks and upon disease progression to evaluate changes in the exome, transcriptome and changes to the tumor microenvironment. Clinical trial information: NCT04251117.

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Safety and Efficacy of amplitude-modulated radiofrequency electromagnetic fields in advanced hepatocellular carcinoma

4open ◽

10.1051/fopen/2021003 ◽

2021 ◽

Vol 4 ◽

pp. 3

Author(s):

Arthur W. Blackstock ◽

Al B. Benson ◽

Masatoshi Kudo ◽

Hugo Jimenez ◽

Preeya F. Achari ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Electromagnetic Fields ◽

Continuous Treatment ◽

First Line ◽

Advanced Hcc ◽

First Line Therapy ◽

Line Therapy ◽

Historical Controls

Importance: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Despite the recent approval of several new agents, long-term disease control remains elusive for most patients. Administration of 27.12 MHz radiofrequency (RF) electromagnetic fields (EMF) by means of a spoon-shaped antenna (TheraBionic P1 device) placed on the anterior part of the tongue results in systemic delivery of low and safe levels of RF EMF from head to toe. Objective: To report treatment outcomes and adverse events associated with treatment with the TheraBionic P1 device in comparison to suitable historical placebo and actively treated controls. Design: Pooled case series with comparison to historical controls. Participants: Patients with advanced HCC receiving this treatment, 18 real-world patients and 41 patients from a previously reported phase II study. Historical controls from previously conducted clinical trials. Interventions: Three hours daily treatment with the TheraBionic P1 device compared with standard of care as received by historical controls in the previously conducted trials. Main outcomes and measures: Overall survival (OS), time to progression, response rate, and adverse events in the combined pooled patients and in appropriate subgroups comparable to the historical control groups. Results: In the pooled treatment group, median OS of patients with Child-Pugh A disease (n = 32) was 10.36 (95% CI 5.42–14.07) months, 4.44 (95% CI 1.64–7.13) months for patients with Child-Pugh B disease (n = 25), and 1.99 (95% CI 0.76–3.22) months for patients with Child-Pugh C disease (n = 2). Median OS for Child-Pugh A patients was 2.62 (33.9%) months longer than the 7.74 months OS of comparable historical controls (p = 0.036). The 4.73 (95% CI 1.18–8.28) months median OS for Child-Pugh B patients receiving TheraBionic P1 device as first line therapy is slightly higher than the 4.6 months median OS of historical controls receiving Sorafenib as first line therapy. Only grade 1 mucositis and fatigue were reported by patients using the device, even among Child-Pugh B and C patients. No patients discontinued treatment because of adverse events. Conclusions and Relevance: Treatment of advanced HCC with the TheraBionic P1 device is well tolerated, even in patients with severely impaired liver function, and results in improved overall survival compared to historical controls without any significant adverse events, even after many years of continuous treatment. This treatment modality appears to be well suited for patients who have failed or are intolerant to currently approved therapies.

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Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.324 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 324-324

Author(s):

Ciro Celsa ◽

Giuseppe Cabibbo ◽

Marco Enea ◽

Salvatore Battaglia ◽

Giacomo Emanuele Maria Rizzo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Survival Curve ◽

Second Line ◽

First Line ◽

Lifetime Horizon ◽

First Line Therapy ◽

Line Therapy ◽

Unresectable Hepatocellular Carcinoma ◽

Sequential Strategy

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.

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