Personalized tumor-loaded monocyte-derived dendritic cell vaccination in combination with atezolizumab as maintenance treatment in extensive-stage small cell lung cancer (ES-SCLC): phase Ib-II VENEZOLUNG trial.

BACKGROUND

Despite the incorporation of atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, into first-line chemotherapy regimen, survival in patients with extensive-stage small cell lung cancer (ES-SCLC) remains poor. Given the role of dendritic cells (DCs) in modulating responses to anti-programmed cell death protein 1 (PD-1) antibodies, a promising avenue is the development of vaccines based on DCs, together with the evaluation of how DC phenotypic modifications shape treatment efficacy.

MATERIALS AND

METHODS

This is a single-arm, phase Ib/II, open-label clinical trial investigating the safety and activity of combining autologous tumor lysate pulsed DCs administered intradermally with intravenous atezolizumab as maintenance therapy for patients with ES-SCLC. Following leukapheresis, monocytes were differentiated ex vivo into mature DCs and loaded with irradiated autologous tumor lysate. After standard induction therapy (four cycles of carboplatin, etoposide, and atezolizumab), patients received up to six doses of mature DCs intradermally, along with intravenous atezolizumab 1,200 mg every 3 weeks, until disease progression.

RESULTS

20 patients were enrolled, including six patients with brain metastases. 18 patients received DC vaccination, with a median of three doses (range 1-6). Most grade 3-4 treatment-related adverse events were hematological and related to chemotherapy. DC vaccination was well tolerated, with only grade 1-2 transient skin irritation at the injection site. Among 18 evaluable patients, 17 (94.4%) achieved an objective response. After a median follow-up of 31.4 months, progression-free survival at 2 years (PFS2y) was 20% (95% CI 6.4% to 39.1%), median overall survival (OS) 11.2 months (95% CI 6.3 to 26.0) and OS3y 22.5% (95% CI 6.8% to 43.6%). Six patients achieved long survival (median 30.5 months, range 23.4-36.2). Expansion of conventional type DC1 (cDC1s) XCR1+ and stem-like progenitor-exhausted (CXCR5+PD-1+) CD8+ T cells following chemotherapy plus atezolizumab was associated with improved PFS (HR 0.94, 95% CI 0.90 to 0.99 and HR 0.59, 95% CI 0.39 to 0.89).

CONCLUSION

DC immunization combined with atezolizumab maintenance following standard chemotherapy plus atezolizumab treatment is well tolerated. Its clinical activity cannot be definitively determined in this study, as it was administered as maintenance therapy; however, the observed rate of long-term survivors suggests a potential benefit. Our findings suggest a pivotal role for cDC1s in mediating the antitumor activity in long-term survivors.

TRIAL REGISTRATION NUMBER: NCT04487756.