Dendritic Cell Vaccination Fails to Improve OS, Still Bolsters Immune Activation in Mesothelioma

Although the use of an allogeneic dendritic cell vaccine as maintenance therapy did not improve overall survival (OS) in patients with mesothelioma, this therapy may still provide benefit to patients in the advanced setting because of its demonstrated safety profile and its ability to induce immunologic responses, according to Joachim G. J. V. Aerts, MD, PhD.

At the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer, Aerts presented data from the phase 3 DENIM trial (NCT03610360) evaluating this approach in patients previously treated with chemotherapy. Analysis of the intention-to-treat population showed that the addition of dendritic cell therapy to best supportive care (BSC) produced a median OS of 16.9 months (95% CI, 12.4-20.4) vs 18.3 months (95% CI, 14.3-21.9) with BSC alone (HR, 1.10; 95% CI, 0.765-1.572). Similarly, the median progression-free survival (PFS) in the vaccine arm was 166 days (95% CI, 99-178) vs 99 days (95% CI, 93-136) in the BSC alone arm.

Notably, flow cytometric analyses revealed that dendritic cell therapy increased immune costimulator activation and Ki-67 proliferation of CD4-positive T cells in the peripheral blood, which correlated with PFS (P = .0007). Regarding safety, no serious treatment-emergent adverse effects (TEAEs) observed in this study were ascribed to the dendritic cell vaccine. Investigators hypothesize that the negative result could be attributed to the long interval between patients’ last cycle of chemotherapy and the initiation of the dendritic cell vaccination.

“Given the fact that the dendritic cells induced an immune response, we think that the treatment is effective but should be given in another stage of the disease,” said Aerts, who is a professor in pulmonary oncology and head of the Department of Pulmonary Medicine at Erasmus MC Cancer Centre in Rotterdam, Netherlands. “We are now exploring the efficacy of this treatment in patients who have [pleural] mesothelioma.”

In an interview with OncLive^®, Aerts discussed how dendritic cell vaccines could bolster historically poor responses to immunotherapy in patients with mesothelioma, reported and provided potential explanations for negative results from the DENIM trial, and discussed a potential role for this therapy in earlier lines of mesothelioma treatment.

OncLive: What unmet needs exist for patients with mesothelioma, and how might the use of a dendritic cell vaccine as maintenance therapy help to address these needs?

Aerts: Mesothelioma is a disease with a dismal prognosis. Despite the fact that some patients respond to immunotherapy with PD-1 inhibitors, most patients do not respond or only temporarily respond. We think that is because immune activation is not taking place. We hoped to induce this immune activation by giving patients dendritic cells. Dendritic cells are the most potent antigen-presenting cells in the body. By loading those dendritic cells with an antigen lysate containing antigens of mesothelioma, [we hoped to] induce an immune response [while] also [activating] CD4-positive T cells, which are active against the tumor.

What efficacy findings from the DENIM study were presented at the 2023 World Conference on Lung Cancer?

The primary end point of the study was unfortunately not met, so we didn’t see an increase in the OS of patients treated with dendritic cells compared with [the OS of those who received] BSC. Despite this, we induced a CD4-positive T-cell response in the patients we [treated] with the vaccine. We think the fact that we induced a CD4-positive T-cell response that didn’t translate to a positive finding in the study was because the interval between chemotherapy [cessation] and the start of [treatment with] the dendritic cell vaccine was too long. [This means] patients’ diseases were already progressing before we started treatment with the vaccine. This study aimed to [utilize the vaccine] as maintenance therapy, but now we think it [may be better used as] a second-line treatment.

What should colleagues know about the safety profile of this dendritic cell therapy?

The safety profile of the therapy was good. We didn’t see serious TEAEs, so the treatment was well tolerated. The only TEAEs we saw that were related to the vaccine [were injection site or infusion-related reactions]. [When we administered] the vaccine intradermally, patients experienced induration of the skin and some itching, and [when we administered the vaccine] intravenously, some patients developed a fever on the day of the injection.

What next steps are planned for this research?

This study was negative, but we think that was because patients [treated with the vaccine] were already in their second line [of therapy]. Therefore, we think we need to [utilize] the treatment earlier in the disease course. For instance, this may be given to patients as adjuvant therapy after surgery. We are now exploring the therapy in patients with pleural mesothelioma, and we already saw its efficacy [as an adjuvant treatment] in patients with abnormal mesothelioma and pancreatic cancer.

The other [next step] is to explore this vaccine in a combination [regimen with] different immunotherapies. As we see that the dendritic cells induce an immune response, we can add checkpoint inhibitors to the treatment to see whether they can increase its efficacy.

What main message should your colleagues take away from this research?

Cellular therapy seems like a complicated therapy, and it can be laborious, but it works when you know how to [harness it properly]. It can induce an immune response that most patients with mesothelioma as well as patients with lung cancer need.

What other lung cancer research were you excited to see presented at the IASLC 2023 World Conference on Lung Cancer?

We had an exciting meeting showing new data and negative data, which are important [for identifying] how we must change our treatment [approaches]. In mesothelioma, we saw the negative study about pleurectomy and decortication, which we certainly need to consider when determining the best treatments for our patients. It was exciting to have all kinds of specialties [represented] at the meeting, and we’ll see [how this research influences practice] in the next few years.

Reference

Aerts JGJV, Belderbos R, Baas P, et al. A multicenter, randomized, phase II/III study of dendritic cells (DC) loaded with allogeneic tumor cell lysate in subjects with mesothelioma as maintenance therapy after chemotherapy: DENdritic cell Immunotherapy for Mesothelioma (DENIM) trial. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA02.05.