**5. Combination therapy with ICIs**

Based on the favorable results obtained with ICI monotherapy, recent investigations tested combination treatments, with an anti-PD-1 or anti-PD-L1 antibody combined with an anti-CTLA-4 antibody. This combination was expected to maximize T-cell activation.

NIBIT-MESO-1 was open-label, non-randomized, phase II trial, in which 40 patients with MPM received at least one dose each of tremelimumab and durvalumab [25]. Eleven patients (28%) displayed an objective response. The median PFS was 5.7 months and the median OS was 16.6 months.

IFCT-1501 MAPS2 was a multicenter, open-label, randomized, phase II trial, in which 108 patients with MPM were randomly assigned to receive intravenous nivolumab or intravenous nivolumab plus ipilimumab. In the intention-to-treat population, 12-week disease control (primary endpoint) was achieved by 25/63


**Table 1.**

**69**

OS was 37 months.

*Immunotherapy in Malignant Pleural Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.95823*

interval, 0.61–0.89; P = 0.002) [28].

a new avenue of therapeutic strategies for MPM.

**7. Dendritic cell therapy**

**Table 1** .

**6. Vaccine**

(40%) patients in the nivolumab group and 32/62 (52%) patients in the combina

Overview of clinical trials of that tested ICIs for MPM was summarized in

Cancer vaccines have been tested for various cancer types. These vaccines have included tumor lysate, attenuated bacteria, and single or multiple peptides. Wilms tumor 1 (WT-1) is one of the most well investigated cancer antigens. WT-1 was expressed in tumors in 97% of patients with MPM [29]. Galinpepimut-S, a multi

valent vaccine against the WT 1 peptide, can activate both CD4+ and CD8+ T-cells [30]. The efficacy and safety of galinpepimut-S was investigated in a phase II trial. The pilot study demonstrated that the median PFS was 7.4 months in the placebo group and 10.1 months in the vaccine group. The median OS was 18.3 months in the placebo group and 22.8 months in the vaccine group. Based on th0se findings, a clinical trial is currently ongoing to investigate a combination treatment of galin

pepimut-S plus nivolumab in patients with MPM (with WT-1-positive tumors). Combining cancer vaccines with ICIs might improve the clinical outcome and open

Vaccination strategies have been developed that involve dendritic cells (DCs), which are antigen-presenting cells for T-cell activation. The DCs are pulsed with tumor lysate to overcome the shortcomings of autologous DCs. These strategies have shown remarkable anti-tumor activity, with low toxicity, in several cancer types. In the area of MPM, 9 patients received three vaccinations of autologous mature DCs loaded with autologous tumor cell lysate [31]. Among these patients,

3 showed a partial response in the first 8 weeks after the DC vaccination. However, two of those three patients had received chemotherapy before the DC vaccination, which might have influenced the anti-tumor effect. In the next step of treatment, they added cyclophosphamide to increase the anti-tumor activity by inhibiting regulatory T cells [32]. Ten patients with MPM received cyclophospha

mide and a vaccination of autologous mature DCs loaded with autologous tumor cell lysate. Of those ten patients, seven lived longer than 24 months, and the mean

Obtaining autologous tumor cell lysate is time consuming, because patients have to undergo multiple tumor biopsies. In one study, allogeneic tumor lysate obtained from a tumor cell line was applied to autologous DCs [33]. Nine patients with MPM

tion group [26]. The INITIATE study also evaluated the efficacy of nivolumab combined with ipilimumab in patients with MPM. In that study, among 34 patients included in the efficacy assessment, ten (29%) patients achieved a partial response, and 23 patients (68%) achieved 12 weeks of disease control [27]. Based on these favorable results, a phase III randomized study was conducted to compare nivolumab plus ipilimumab to platinum doublet chemotherapy as a first-line therapy in unresectable MPM. In that study, 303 patients were randomized to nivolumab plus ipilimumab and 302 patients were randomized to platinum doublet chemotherapy. With a minimum follow-up of 22 months, the primary endpoint, OS, was significantly improved with nivolumab plus ipilimumab compared to chemotherapy (median, 18.1 vs. 14.1 months; hazard ratio, 0.74; 95% confidence





*Overview of clinical trials that tested immunocheckpoint inhibitors for malignant pleural mesothelioma.*

#### *Advances in Precision Medicine Oncology*

*Immunotherapy in Malignant Pleural Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.95823*

(40%) patients in the nivolumab group and 32/62 (52%) patients in the combination group [26]. The INITIATE study also evaluated the efficacy of nivolumab combined with ipilimumab in patients with MPM. In that study, among 34 patients included in the efficacy assessment, ten (29%) patients achieved a partial response, and 23 patients (68%) achieved 12 weeks of disease control [27]. Based on these favorable results, a phase III randomized study was conducted to compare nivolumab plus ipilimumab to platinum doublet chemotherapy as a first-line therapy in unresectable MPM. In that study, 303 patients were randomized to nivolumab plus ipilimumab and 302 patients were randomized to platinum doublet chemotherapy. With a minimum follow-up of 22 months, the primary endpoint, OS, was significantly improved with nivolumab plus ipilimumab compared to chemotherapy (median, 18.1 vs. 14.1 months; hazard ratio, 0.74; 95% confidence interval, 0.61–0.89; P = 0.002) [28].

Overview of clinical trials of that tested ICIs for MPM was summarized in **Table 1**.
