David J Chung1,2,3,4,5,6,7, Richard D Carvajal8,9,4,5,7, Michael A Postow8,9,4,5,7, Sneh Sharma1,5, Katherine B Pronschinske1,5, Justin A Shyer1,5, Shahnaz Singh-Kandah8,9,4,5, Mark A Dickson10,9,4,5,7, Sandra P D'Angelo10,9,4,5,7, Jedd D Wolchok8,9,4,5,6,7, James W Young1,2,3,4,11,5,6,7. 1. Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. 2. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY. 3. Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. 4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 5. Memorial Sloan Kettering Cancer Center, New York, NY. 6. The Rockefeller University, New York, NY. 7. Weill Cornell Medical College, New York, NY, USA. 8. Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. 9. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. 10. Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. 11. Immunology Program, Sloan Kettering Institute for Cancer Research.
Abstract
Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 × 106 mRNA-electroporated LCs, based on absolute number of CD83+CD86brightHLA-DRbrightCD14neg LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-γ, IL-2, and TNF-α), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-β CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.
Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 × 106 mRNA-electroporated LCs, based on absolute number of CD83+CD86brightHLA-DRbrightCD14neg LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-γ, IL-2, and TNF-α), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-β CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.
Entities:
Keywords:
Langerhans-type dendritic cell; cancer vaccines; clinical immunology; melanoma; phase I trial
Authors: J Banchereau; A K Palucka; M Dhodapkar; S Burkeholder; N Taquet; A Rolland; S Taquet; S Coquery; K M Wittkowski; N Bhardwaj; L Pineiro; R Steinman; J Fay Journal: Cancer Res Date: 2001-09-01 Impact factor: 12.701
Authors: Geoffrey T Gibney; Ragini R Kudchadkar; Ronald C DeConti; Melissa S Thebeau; Maria P Czupryn; Leticia Tetteh; Cabell Eysmans; Allison Richards; Michael J Schell; Kate J Fisher; Christine E Horak; H David Inzunza; Bin Yu; Alberto J Martinez; Ibrahim Younos; Jeffrey S Weber Journal: Clin Cancer Res Date: 2014-12-18 Impact factor: 12.531
Authors: Linda Mesler Muul; Laura M Tuschong; Sherry Lau Soenen; G Jayashree Jagadeesh; W Jay Ramsey; Zhifeng Long; Charles S Carter; Elizabeth K Garabedian; Melinna Alleyne; Margaret Brown; Wendy Bernstein; Shepherd H Schurman; Thomas A Fleisher; Susan F Leitman; Cynthia E Dunbar; R Michael Blaese; Fabio Candotti Journal: Blood Date: 2002-11-27 Impact factor: 22.113
Authors: Derek Ng Tang; Yu Shen; Jingjing Sun; Sijin Wen; Jedd D Wolchok; Jianda Yuan; James P Allison; Padmanee Sharma Journal: Cancer Immunol Res Date: 2013-07-31 Impact factor: 11.151
Authors: Lavakumar Karyampudi; Purushottam Lamichhane; Adam D Scheid; Kimberly R Kalli; Barath Shreeder; James W Krempski; Marshall D Behrens; Keith L Knutson Journal: Cancer Res Date: 2014-04-11 Impact factor: 12.701
Authors: Dung T Le; Eric Lutz; Jennifer N Uram; Elizabeth A Sugar; Beth Onners; Sara Solt; Lei Zheng; Luis A Diaz; Ross C Donehower; Elizabeth M Jaffee; Daniel A Laheru Journal: J Immunother Date: 2013-09 Impact factor: 4.456
Authors: Steve Boudewijns; Rutger H T Koornstra; Harm Westdorp; Gerty Schreibelt; Alfons J M van den Eertwegh; Marnix H Geukes Foppen; John B Haanen; I Jolanda M de Vries; Carl G Figdor; Kalijn F Bol; Winald R Gerritsen Journal: Oncoimmunology Date: 2016-06-17 Impact factor: 8.110
Authors: Raquel S Laureano; Jenny Sprooten; Isaure Vanmeerbeerk; Daniel M Borras; Jannes Govaerts; Stefan Naulaerts; Zwi N Berneman; Benoit Beuselinck; Kalijn F Bol; Jannie Borst; An Coosemans; Angeliki Datsi; Jitka Fučíková; Lisa Kinget; Bart Neyns; Gerty Schreibelt; Evelien Smits; Rüdiger V Sorg; Radek Spisek; Kris Thielemans; Sandra Tuyaerts; Steven De Vleeschouwer; I Jolanda M de Vries; Yanling Xiao; Abhishek D Garg Journal: Oncoimmunology Date: 2022-07-04 Impact factor: 7.723
Authors: Xuedan He; Shiqi Zhou; Breandan Quinn; Dushyant Jahagirdar; Joaquin Ortega; Mark D Long; Scott I Abrams; Jonathan F Lovell Journal: Cancer Immunol Res Date: 2022-03-01 Impact factor: 12.020
Authors: Diana Campillo-Davo; Maxime De Laere; Gils Roex; Maarten Versteven; Donovan Flumens; Zwi N Berneman; Viggo F I Van Tendeloo; Sébastien Anguille; Eva Lion Journal: Pharmaceutics Date: 2021-03-16 Impact factor: 6.321