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

Lindy G Durrant, Christian Ottensmeier, Paul Lorigan, Clive Mulatero, Ruth Plummer, Michelle Cunell, Rachael L Metheringham, Victoria A Brentville, Lee Machado

Research output: Contribution to conference typesAbstractResearch

Abstract

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:e4111
Original languageEnglish
DOIs
Publication statusPublished - 1 Oct 2014

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Immunotherapy
Melanoma
Antibodies
DNA
Epitopes
Therapeutics
Vaccination
Survival
Immunization
Vaccines
Cross-Priming
Melanoma-Specific Antigens
T-Lymphocytes
Enzyme-Linked Immunospot Assay
Secondary Immunization
Neoplasms
Aptitude
Electroporation
Intramuscular Injections
Cellular Immunity

Cite this

Durrant, Lindy G ; Ottensmeier, Christian ; Lorigan, Paul ; Mulatero, Clive ; Plummer, Ruth ; Cunell, Michelle ; Metheringham, Rachael L ; Brentville, Victoria A ; Machado, Lee. / Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma.
@conference{3ccae55026e6419b9858bdbd6ba7df36,
title = "Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma",
abstract = "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:e4111",
author = "Durrant, {Lindy G} and Christian Ottensmeier and Paul Lorigan and Clive Mulatero and Ruth Plummer and Michelle Cunell and Metheringham, {Rachael L} and Brentville, {Victoria A} and Lee Machado",
year = "2014",
month = "10",
day = "1",
doi = "10.1158/1538-7445.AM2014-CT331",
language = "English",

}

Durrant, LG, Ottensmeier, C, Lorigan, P, Mulatero, C, Plummer, R, Cunell, M, Metheringham, RL, Brentville, VA & Machado, L 2014, 'Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma'. https://doi.org/10.1158/1538-7445.AM2014-CT331

Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma. / Durrant, Lindy G; Ottensmeier, Christian; Lorigan, Paul; Mulatero, Clive; Plummer, Ruth; Cunell, Michelle; Metheringham, Rachael L; Brentville, Victoria A; Machado, Lee.

2014.

Research output: Contribution to conference typesAbstractResearch

TY - CONF

T1 - Abstract CT331: Phase I/II trial of a novel antibody DNA immunotherapy, targeting CD64, in the treatment of Melanoma

AU - Durrant, Lindy G

AU - Ottensmeier, Christian

AU - Lorigan, Paul

AU - Mulatero, Clive

AU - Plummer, Ruth

AU - Cunell, Michelle

AU - Metheringham, Rachael L

AU - Brentville, Victoria A

AU - Machado, Lee

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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:e4111

AB - 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:e4111

U2 - 10.1158/1538-7445.AM2014-CT331

DO - 10.1158/1538-7445.AM2014-CT331

M3 - Abstract

ER -