Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

Abstract

The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n D 22) received the vaccine without any adjuvant; the next cohort (n D 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumorspecific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p D 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators.

Trial watch: Dendritic cell-based anticancer immunotherapy

“…[136][137][138][139][140][141] However, the DC-based vaccine most commonly used so far involves the loading of DCs with a source of TAAs followed by their stimulation with defined maturation cocktails. 142,143 Ex vivo, DC loading with TAAs is typically accomplished by (1) co-culturing iDCs with either autologous or allogeneic tumor-cell lysates [71][72][73][74][75][76][77][78][79][80][144][145][146] or recombinant TAAs; [81][82][83][84][85][86][87][88]147 (2) transfecting DCs with vectors or RNAs coding for TAA(s), or even bulk RNA derived from tumor cells; 41,[148][149][150][151][152] and (3) creating fusions between DCs and incapacitated malignant cells (also known as "dendritomes").…”

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

“…As expected, this side effect has also been observed with DCs loaded with mRNA including total mRNA. Out of 31 patients vaccinated with monocyte-derived DC loaded with autologous tumor-RNA, 1 patient developed vitiligo [37]. In one of our phase I trials with stage IV melanoma patients (NCT00126685), 1 out of 8 fully evaluable patients developed vitiligo after vaccination with DC loaded with autologous tumor RNA.…”

Ribonucleic Acid Engineering of Dendritic Cells for Therapeutic Vaccination: Ready ‘N Able to Improve Clinical Outcome?

“…Throughout all published trials it stands out that toxicity of RNA-modified DC vaccination is generally limited to low-grade adverse events with commonly occurring injection site reactions or more seldom systemic immune effects such as temperature elevation and flu-like symptoms. Very rarely there has been documentation of on-target immune-mediated bystander toxicity with low-grade vitiligo and grade 3-4 thrombocytopenia in the melanoma and AML setting, respectively [74][75][76][77]. Nearly all other cases of severe (grade 3-4) adverse immunological reactions were related to concomitant ipilimumab therapy in melanoma, while one case was due to the development of auto-antibodies against the GM-CSF component and not the DC in a specific vaccine for glioblastoma [78,79].…”