Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)
BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would...
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| Veröffentlicht in: | Journal for immunotherapy of cancer 2021-01, Vol.9 (1), p.e000934, Article 000934 |
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| creator | Slingluff, Jr, Craig L Petroni, Gina R Chianese-Bullock, Kimberly A Wages, Nolan A Olson, Walter C Smith, Kelly T Haden, Kathleen Dengel, Lynn T Dickinson, Anna Reed, Caroline Gaughan, Elizabeth M Grosh, William W Kaur, Varinder Varhegyi, Nikole Smolkin, Mark Galeassi, Nadejda V Deacon, Donna Hall, Emily H |
| description | BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses. |
| doi_str_mv | 10.1136/jitc-2020-000934 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1136_jitc_2020_000934</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_0f1633d6e6534feb8dfa73c25184c8d5</doaj_id><sourcerecordid>2552985505</sourcerecordid><originalsourceid>FETCH-LOGICAL-b526t-487a267191299023fd1220edfe4b2b534058773623e63f5fa4cc41e26cdf2de23</originalsourceid><addsrcrecordid>eNqNks1uEzEUhUcIRKvSPStkiU0RHfDP_DgbJBRRiBTEpqwtj32dOPLYw9gTlB2vwY5n40lwmhJaNrCwfGWf8_le6xTFU4JfEcKa1xubVEkxxSXGeMaqB8UpxTUpSUWbh3fqk-I8xk3WEMwY5_xxccJY1c4wrU-LH9ejlQ6lgGAr3SQToLQGZPt-8mEF3iqbdkh6jaI0kMtgkEQ9OOlDL9Ea3AAjGmBIVgPaSqWsBzS4KSLrVegHBxl5NcLk9c9v3yOSejNtpU-XSO2UC8M6xGEt--y-vHlmCG63mC_n6OIjuIa9eFI8MtJFOL_dz4rPV--u5x_K5af3i_nbZdnVtEllxVtJm5bMCJ3lyZjRhFIM2kDV0a5mFa5527KGMmiYqY2slKoI0EZpQzVQdlYsDlwd5EYMo-3luBNBWnFzEMaVkGOyyoHAhjSM6QaazDXQcW1kyxStCa8U13VmvTmwhqnrQSvwaZTuHvT-jbdrsQpb0XKap2EZcHELGMOXCWISvY0KXP51CFMUtOKYtVVeWfr8L-kmTKPPXyVoXdMZr2u87wgfVGoMMY5gjs0QLPZpEvs0iX2axCFN2fLs7hBHw-_sZAE_CL5CF0xUFryCoyxTGsIwr0iuMJ3bJJMNfh4mn7L15f9b_6i7fvPvvn8Byp32Fw</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2552985505</pqid></control><display><type>article</type><title>Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)</title><source>BMJ Open Access Journals</source><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>PubMed Central</source><creator>Slingluff, Jr, Craig L ; Petroni, Gina R ; Chianese-Bullock, Kimberly A ; Wages, Nolan A ; Olson, Walter C ; Smith, Kelly T ; Haden, Kathleen ; Dengel, Lynn T ; Dickinson, Anna ; Reed, Caroline ; Gaughan, Elizabeth M ; Grosh, William W ; Kaur, Varinder ; Varhegyi, Nikole ; Smolkin, Mark ; Galeassi, Nadejda V ; Deacon, Donna ; Hall, Emily H</creator><creatorcontrib>Slingluff, Jr, Craig L ; Petroni, Gina R ; Chianese-Bullock, Kimberly A ; Wages, Nolan A ; Olson, Walter C ; Smith, Kelly T ; Haden, Kathleen ; Dengel, Lynn T ; Dickinson, Anna ; Reed, Caroline ; Gaughan, Elizabeth M ; Grosh, William W ; Kaur, Varinder ; Varhegyi, Nikole ; Smolkin, Mark ; Galeassi, Nadejda V ; Deacon, Donna ; Hall, Emily H</creatorcontrib><description>BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2020-000934</identifier><identifier>PMID: 33479025</identifier><language>eng</language><publisher>LONDON: Bmj Publishing Group</publisher><subject><![CDATA[Administration, Metronomic ; Administration, Oral ; Antibodies ; Antibodies - blood ; Antigens ; Autoimmune diseases ; Biopsy ; Cancer ; Cancer Vaccines - administration & dosage ; Cancer Vaccines - adverse effects ; Cancer Vaccines - immunology ; Carboxymethylcellulose Sodium - administration & dosage ; Carboxymethylcellulose Sodium - adverse effects ; Carboxymethylcellulose Sodium - analogs & derivatives ; CD4-Positive T-Lymphocytes - metabolism ; Clinical/Translational Cancer Immunotherapy ; Combined Modality Therapy ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - adverse effects ; Female ; Freund's Adjuvant - administration & dosage ; Freund's Adjuvant - adverse effects ; Gene expression ; Humans ; Immunology ; Immunotherapy ; Life Sciences & Biomedicine ; Lipids - administration & dosage ; Lipids - adverse effects ; Lymphocytes ; Male ; Medical research ; Melanoma ; Melanoma - drug therapy ; Melanoma - immunology ; Melanoma - pathology ; Neoplasm Staging ; Oncology ; Patients ; Peptides ; Poly I-C - administration & dosage ; Poly I-C - adverse effects ; Polylysine - administration & dosage ; Polylysine - adverse effects ; Polylysine - analogs & derivatives ; Science & Technology ; T-Lymphocytes, Regulatory - metabolism ; Treatment Outcome ; Vaccines ; Vaccines, Subunit - administration & dosage ; Vaccines, Subunit - adverse effects ; Vaccines, Subunit - immunology]]></subject><ispartof>Journal for immunotherapy of cancer, 2021-01, Vol.9 (1), p.e000934, Article 000934</ispartof><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.</rights><rights>2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>14</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000613084100002</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-b526t-487a267191299023fd1220edfe4b2b534058773623e63f5fa4cc41e26cdf2de23</citedby><cites>FETCH-LOGICAL-b526t-487a267191299023fd1220edfe4b2b534058773623e63f5fa4cc41e26cdf2de23</cites><orcidid>0000-0002-6664-4373</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jitc.bmj.com/content/9/1/e000934.full.pdf$$EPDF$$P50$$Gbmj$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://jitc.bmj.com/content/9/1/e000934.full$$EHTML$$P50$$Gbmj$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,27553,27554,27928,27929,39262,53795,53797,77605,77636</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33479025$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Slingluff, Jr, Craig L</creatorcontrib><creatorcontrib>Petroni, Gina R</creatorcontrib><creatorcontrib>Chianese-Bullock, Kimberly A</creatorcontrib><creatorcontrib>Wages, Nolan A</creatorcontrib><creatorcontrib>Olson, Walter C</creatorcontrib><creatorcontrib>Smith, Kelly T</creatorcontrib><creatorcontrib>Haden, Kathleen</creatorcontrib><creatorcontrib>Dengel, Lynn T</creatorcontrib><creatorcontrib>Dickinson, Anna</creatorcontrib><creatorcontrib>Reed, Caroline</creatorcontrib><creatorcontrib>Gaughan, Elizabeth M</creatorcontrib><creatorcontrib>Grosh, William W</creatorcontrib><creatorcontrib>Kaur, Varinder</creatorcontrib><creatorcontrib>Varhegyi, Nikole</creatorcontrib><creatorcontrib>Smolkin, Mark</creatorcontrib><creatorcontrib>Galeassi, Nadejda V</creatorcontrib><creatorcontrib>Deacon, Donna</creatorcontrib><creatorcontrib>Hall, Emily H</creatorcontrib><title>Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)</title><title>Journal for immunotherapy of cancer</title><addtitle>J IMMUNOTHER CANCER</addtitle><addtitle>J Immunother Cancer</addtitle><description>BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.</description><subject>Administration, Metronomic</subject><subject>Administration, Oral</subject><subject>Antibodies</subject><subject>Antibodies - blood</subject><subject>Antigens</subject><subject>Autoimmune diseases</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Cancer Vaccines - administration & dosage</subject><subject>Cancer Vaccines - adverse effects</subject><subject>Cancer Vaccines - immunology</subject><subject>Carboxymethylcellulose Sodium - administration & dosage</subject><subject>Carboxymethylcellulose Sodium - adverse effects</subject><subject>Carboxymethylcellulose Sodium - analogs & derivatives</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Clinical/Translational Cancer Immunotherapy</subject><subject>Combined Modality Therapy</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Cyclophosphamide - adverse effects</subject><subject>Female</subject><subject>Freund's Adjuvant - administration & dosage</subject><subject>Freund's Adjuvant - adverse effects</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Life Sciences & Biomedicine</subject><subject>Lipids - administration & dosage</subject><subject>Lipids - adverse effects</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Medical research</subject><subject>Melanoma</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - immunology</subject><subject>Melanoma - pathology</subject><subject>Neoplasm Staging</subject><subject>Oncology</subject><subject>Patients</subject><subject>Peptides</subject><subject>Poly I-C - administration & dosage</subject><subject>Poly I-C - adverse effects</subject><subject>Polylysine - administration & dosage</subject><subject>Polylysine - adverse effects</subject><subject>Polylysine - analogs & derivatives</subject><subject>Science & Technology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>Treatment Outcome</subject><subject>Vaccines</subject><subject>Vaccines, Subunit - administration & dosage</subject><subject>Vaccines, Subunit - adverse effects</subject><subject>Vaccines, Subunit - immunology</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1uEzEUhUcIRKvSPStkiU0RHfDP_DgbJBRRiBTEpqwtj32dOPLYw9gTlB2vwY5n40lwmhJaNrCwfGWf8_le6xTFU4JfEcKa1xubVEkxxSXGeMaqB8UpxTUpSUWbh3fqk-I8xk3WEMwY5_xxccJY1c4wrU-LH9ejlQ6lgGAr3SQToLQGZPt-8mEF3iqbdkh6jaI0kMtgkEQ9OOlDL9Ea3AAjGmBIVgPaSqWsBzS4KSLrVegHBxl5NcLk9c9v3yOSejNtpU-XSO2UC8M6xGEt--y-vHlmCG63mC_n6OIjuIa9eFI8MtJFOL_dz4rPV--u5x_K5af3i_nbZdnVtEllxVtJm5bMCJ3lyZjRhFIM2kDV0a5mFa5527KGMmiYqY2slKoI0EZpQzVQdlYsDlwd5EYMo-3luBNBWnFzEMaVkGOyyoHAhjSM6QaazDXQcW1kyxStCa8U13VmvTmwhqnrQSvwaZTuHvT-jbdrsQpb0XKap2EZcHELGMOXCWISvY0KXP51CFMUtOKYtVVeWfr8L-kmTKPPXyVoXdMZr2u87wgfVGoMMY5gjs0QLPZpEvs0iX2axCFN2fLs7hBHw-_sZAE_CL5CF0xUFryCoyxTGsIwr0iuMJ3bJJMNfh4mn7L15f9b_6i7fvPvvn8Byp32Fw</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Slingluff, Jr, Craig L</creator><creator>Petroni, Gina R</creator><creator>Chianese-Bullock, Kimberly A</creator><creator>Wages, Nolan A</creator><creator>Olson, Walter C</creator><creator>Smith, Kelly T</creator><creator>Haden, Kathleen</creator><creator>Dengel, Lynn T</creator><creator>Dickinson, Anna</creator><creator>Reed, Caroline</creator><creator>Gaughan, Elizabeth M</creator><creator>Grosh, William W</creator><creator>Kaur, Varinder</creator><creator>Varhegyi, Nikole</creator><creator>Smolkin, Mark</creator><creator>Galeassi, Nadejda V</creator><creator>Deacon, Donna</creator><creator>Hall, Emily H</creator><general>Bmj Publishing Group</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6664-4373</orcidid></search><sort><creationdate>20210101</creationdate><title>Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)</title><author>Slingluff, Jr, Craig L ; Petroni, Gina R ; Chianese-Bullock, Kimberly A ; Wages, Nolan A ; Olson, Walter C ; Smith, Kelly T ; Haden, Kathleen ; Dengel, Lynn T ; Dickinson, Anna ; Reed, Caroline ; Gaughan, Elizabeth M ; Grosh, William W ; Kaur, Varinder ; Varhegyi, Nikole ; Smolkin, Mark ; Galeassi, Nadejda V ; Deacon, Donna ; Hall, Emily H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b526t-487a267191299023fd1220edfe4b2b534058773623e63f5fa4cc41e26cdf2de23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Administration, Metronomic</topic><topic>Administration, Oral</topic><topic>Antibodies</topic><topic>Antibodies - blood</topic><topic>Antigens</topic><topic>Autoimmune diseases</topic><topic>Biopsy</topic><topic>Cancer</topic><topic>Cancer Vaccines - administration & dosage</topic><topic>Cancer Vaccines - adverse effects</topic><topic>Cancer Vaccines - immunology</topic><topic>Carboxymethylcellulose Sodium - administration & dosage</topic><topic>Carboxymethylcellulose Sodium - adverse effects</topic><topic>Carboxymethylcellulose Sodium - analogs & derivatives</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Clinical/Translational Cancer Immunotherapy</topic><topic>Combined Modality Therapy</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Cyclophosphamide - adverse effects</topic><topic>Female</topic><topic>Freund's Adjuvant - administration & dosage</topic><topic>Freund's Adjuvant - adverse effects</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Life Sciences & Biomedicine</topic><topic>Lipids - administration & dosage</topic><topic>Lipids - adverse effects</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>Medical research</topic><topic>Melanoma</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - immunology</topic><topic>Melanoma - pathology</topic><topic>Neoplasm Staging</topic><topic>Oncology</topic><topic>Patients</topic><topic>Peptides</topic><topic>Poly I-C - administration & dosage</topic><topic>Poly I-C - adverse effects</topic><topic>Polylysine - administration & dosage</topic><topic>Polylysine - adverse effects</topic><topic>Polylysine - analogs & derivatives</topic><topic>Science & Technology</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><topic>Treatment Outcome</topic><topic>Vaccines</topic><topic>Vaccines, Subunit - administration & dosage</topic><topic>Vaccines, Subunit - adverse effects</topic><topic>Vaccines, Subunit - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Slingluff, Jr, Craig L</creatorcontrib><creatorcontrib>Petroni, Gina R</creatorcontrib><creatorcontrib>Chianese-Bullock, Kimberly A</creatorcontrib><creatorcontrib>Wages, Nolan A</creatorcontrib><creatorcontrib>Olson, Walter C</creatorcontrib><creatorcontrib>Smith, Kelly T</creatorcontrib><creatorcontrib>Haden, Kathleen</creatorcontrib><creatorcontrib>Dengel, Lynn T</creatorcontrib><creatorcontrib>Dickinson, Anna</creatorcontrib><creatorcontrib>Reed, Caroline</creatorcontrib><creatorcontrib>Gaughan, Elizabeth M</creatorcontrib><creatorcontrib>Grosh, William W</creatorcontrib><creatorcontrib>Kaur, Varinder</creatorcontrib><creatorcontrib>Varhegyi, Nikole</creatorcontrib><creatorcontrib>Smolkin, Mark</creatorcontrib><creatorcontrib>Galeassi, Nadejda V</creatorcontrib><creatorcontrib>Deacon, Donna</creatorcontrib><creatorcontrib>Hall, Emily H</creatorcontrib><collection>BMJ Open Access Journals</collection><collection>BMJ Journals:Open Access</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal for immunotherapy of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Slingluff, Jr, Craig L</au><au>Petroni, Gina R</au><au>Chianese-Bullock, Kimberly A</au><au>Wages, Nolan A</au><au>Olson, Walter C</au><au>Smith, Kelly T</au><au>Haden, Kathleen</au><au>Dengel, Lynn T</au><au>Dickinson, Anna</au><au>Reed, Caroline</au><au>Gaughan, Elizabeth M</au><au>Grosh, William W</au><au>Kaur, Varinder</au><au>Varhegyi, Nikole</au><au>Smolkin, Mark</au><au>Galeassi, Nadejda V</au><au>Deacon, Donna</au><au>Hall, Emily H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)</atitle><jtitle>Journal for immunotherapy of cancer</jtitle><stitle>J IMMUNOTHER CANCER</stitle><addtitle>J Immunother Cancer</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>9</volume><issue>1</issue><spage>e000934</spage><pages>e000934-</pages><artnum>000934</artnum><issn>2051-1426</issn><eissn>2051-1426</eissn><abstract>BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.</abstract><cop>LONDON</cop><pub>Bmj Publishing Group</pub><pmid>33479025</pmid><doi>10.1136/jitc-2020-000934</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-6664-4373</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2051-1426 |
| ispartof | Journal for immunotherapy of cancer, 2021-01, Vol.9 (1), p.e000934, Article 000934 |
| issn | 2051-1426 2051-1426 |
| language | eng |
| recordid | cdi_crossref_primary_10_1136_jitc_2020_000934 |
| source | BMJ Open Access Journals; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central |
| subjects | Administration, Metronomic Administration, Oral Antibodies Antibodies - blood Antigens Autoimmune diseases Biopsy Cancer Cancer Vaccines - administration & dosage Cancer Vaccines - adverse effects Cancer Vaccines - immunology Carboxymethylcellulose Sodium - administration & dosage Carboxymethylcellulose Sodium - adverse effects Carboxymethylcellulose Sodium - analogs & derivatives CD4-Positive T-Lymphocytes - metabolism Clinical/Translational Cancer Immunotherapy Combined Modality Therapy Cyclophosphamide - administration & dosage Cyclophosphamide - adverse effects Female Freund's Adjuvant - administration & dosage Freund's Adjuvant - adverse effects Gene expression Humans Immunology Immunotherapy Life Sciences & Biomedicine Lipids - administration & dosage Lipids - adverse effects Lymphocytes Male Medical research Melanoma Melanoma - drug therapy Melanoma - immunology Melanoma - pathology Neoplasm Staging Oncology Patients Peptides Poly I-C - administration & dosage Poly I-C - adverse effects Polylysine - administration & dosage Polylysine - adverse effects Polylysine - analogs & derivatives Science & Technology T-Lymphocytes, Regulatory - metabolism Treatment Outcome Vaccines Vaccines, Subunit - administration & dosage Vaccines, Subunit - adverse effects Vaccines, Subunit - immunology |
| title | Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63) |
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