TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma

Abstract

BackgroundWe 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.MethodsMonocyte-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.ResultsVaccine-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.ConclusionsTriMixDC-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 numberNCT01302496.

mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection

“…A joint therapy, which combined the vaccination of the DC-based mRNA, encoding TriMix and tumor antigens, plus ipilimumab (TriMixDC-MEL IPI), had been applied for advanced melanoma. It successfully induced potent tumor-associated antigen specific CD8 + T cell responses, demonstrating excellent therapeutic effects of the tumor-specific vaccine and immune checkpoint block agents [182]. Nevertheless, there existed undetectable response after in vitro T-cell stimulation in 3/15 patients, suggesting the necessity for a further study for mechanism of action about this issue.…”

Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition

“…p > 0.05, *p < 0.05, **p ≤ 0.01, ***p ≤ 0.001. might be used for different immunotherapeutic approaches (128). Thus, moDCs as well as these next generation DC vaccines might serve as combinatorial therapeutics for immune checkpoint inhibitors (128)(129)(130)(131).…”

mRNA vaccine for cancer immunotherapy

“…In one clinical study, a DC-based mRNA vaccination composed of a mixture of TAAs were administrated together with DCs electroporated with mRNA encoding CD70, CD40 ligand (CD40L), and constitutively active TLR4 (TriMix). The combination therapy resulted in an encouraging rate of tumor responses in patients with stage III or IV melanoma [ 58 ]. Costimulatory molecules CD70 and CD40L, together with active TLR4, play crucial roles in the activation of DCs and priming of CD8 + T cell responses [ 59 ].…”

“…The company has developed a TriMix mRNA-based adjuvant that consists of three naked mRNA molecules, encoding the costimulatory molecule CD70 to induce activation of CD8 + T cells, the activation stimulator CD40 ligand (CD40L) to activate CD4 + T cells, and the constitutively active TLR4 (caTLR4) to facilitate DC antigen presentation [ 137 ]. The naked TriMix mRNA and ex-vivo DC loaded TriMix mRNA evaluated in multiple clinical trials are generally well tolerated and immunogenic [ 58 , 138 , 139 ]. Delivery of mRNA encoding TAAs (e.g.…”