Highlights in Literature 2
An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.
by Mariam Mafee, MD
Vaccines targeting specific antigens can be used to stimulate an immune response in cancer patients. Targeted immunotherapy vaccines could serve as an adjuvant therapy in melanoma patients, but trials have been disappointing thus far in advanced melanoma.
Sahin et al. evaluated the Melanoma FixVac vaccine, which targets 4 tumor-associated antigens (TAAs) prevalent in melanoma. FixVac targets immature dendritic cells in lymphoid tissue to drive TAA presentation to MHC class I and II molecules. There is restricted expression in normal tissue and high immunogenicity in melanoma, making it a targeted therapy.
This study was done in Germany and is a multicenter, open-label, dose-escalation phase 1 trial to evaluate the utility of an intravenously-administered vaccine to boost PD-1 checkpoint-inhibitor response in melanoma patients. This vaccine was previously testing in mouse models, but this is the first-in-human trial of an RNA vaccine for melanoma.
The trial included 89 patients with late-stage melanoma that expressed at least one of the 4 FixVac-encoded TAAs. Late-stage was defined as stage IIIB-C or IV per AJCC 2009 in both resected and unresected patients. Patients received a minimum of 8 vaccinations. All patients received the vaccine, however, 26 patients were simultaneously also being treated with an immune checkpoint blocker (ICB) targeting PD1. Adverse events were minimal and included mild to moderate flu-like symptoms that resolved within 24 hours.
Immune response after vaccination was evaluated by increased metabolic uptake in the spleen on PET-CT, indicating fast activation of lymphoid-tissue-resident cells. In addition, plasma levels of various cytokines and body temperature were measured after administration. CT and MRI of the brain, thorax, and abdomen were performed at baseline, and then every 90 days.
The vaccine demonstrated an increase in TAA-specific effector T cells in those who received boosters, but memory T cells persisted even in those who discontinued the vaccine. There were multiple patients with stable disease, partial response, and/or shrinkage of metastasis. Interestingly, some patients who had anti-PD1 failure prior to vaccination showed response to anti-PD1 after the vaccine upon re-trial. Of note, response to the vaccine in anti-PD1-experienced patients and those who had not received an ICB were similar.
Although anti-PD-1 immunotherapy has revolutionized the treatment of advanced melanoma, 40-45% of patients do not respond and a subset of patients progress despite initial response.1 Theories for resistance include inadequate T-cell infiltration in the tumor and tumor immunosuppressive factors. FixVac may be considered as an adjuvant therapy for patients with advanced disease, even in those patients that have failed an ICB blocking PD1 previously. FixVac may have a synergistic effect and enhance the response to anti-PD1 after the vaccine, therefore creating an opportunity for re-trial of the anti-PD1 immunotherapy in those that failed prior to vaccination.
References
- Mooradian M, Sullivan R. What to Do When Anti–PD-1 Therapy Fails in Patients With Melanoma. Oncology. 2019 Apr 15;33(4):141-8.