TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma
Brenda De Keersmaecker, Sofie Claerhout, Javier Carrasco, Isabelle Bar, Jurgen Corthals, Sofie Wilgenhof, Bart Neyns, Kris Thielemans, Brenda De Keersmaecker, Sofie Claerhout, Javier Carrasco, Isabelle Bar, Jurgen Corthals, Sofie Wilgenhof, Bart Neyns, Kris Thielemans
Abstract
Background: We previously reported that dendritic cell-based mRNA vaccination plus ipilimumab (TriMixDC-MEL IPI) results in an encouraging rate of tumor responses in patients with pretreated advanced melanoma. Here, we report the TriMixDC-MEL IPI-induced T-cell responses detected in the peripheral blood.
Methods: Monocyte-derived dendritic cells electroporated with mRNA encoding CD70, CD40 ligand, and constitutively active TLR4 (TriMix) as well as the tumor-associated antigens tyrosinase, gp100, MAGE-A3, or MAGE-C2 were administered together with IPI for four cycles. For 18/39 patients, an additional vaccine was administered before the first IPI administration. We evaluated tumor-associated antigen specific T-cell responses in previously collected peripheral blood mononuclear cells, available from 15 patients.
Results: Vaccine-induced enzyme-linked immunospot assay responses detected after in vitro T-cell stimulation were shown in 12/15 patients. Immune responses detected in patients with a complete or partial response were significantly stronger and broader, and exhibited a higher degree of multifunctionality compared with responses in patients with stable or progressive disease. CD8+ T-cell responses from patients with an ongoing clinical response, either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, exhibited the highest degree of multifunctionality.
Conclusions: TriMixDC-MEL IPI treatment results in robust CD8+ T-cell responses in a meaningful portion of stage III or IV melanoma patients, and obviously in patients with a clinical response. The levels of polyfunctional and multiantigen T-cell responses measured in patients with a complete response, particularly in patients evidently cured after 5+ years of follow-up, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission.
Trial registration number: NCT01302496.
Keywords: T-lymphocytes; dendritic cells; immunotherapy; melanoma; vaccination.
Conflict of interest statement
Competing interests: The use of dendritic cells electroporated with tumor antigen mRNA and TriMix is topic of a patent (W2009/034172) on which KT is filed as inventor. This patent has been licensed to eTheRNA immunotherapies. BDK and SC are respectively current and former employees of eTheRNA immunotherapies. BN has received financial compensation from Bristol-Myers Squibb for public speaking and participation in advisory board meetings.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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