An open-label single-center investigator-initiated exploratory clinical study in patients with refractory or recurrent solid tumors using SBRT as “in situ vaccination”: R-ISV-FOLactis trial.
Authors: Li Rutian , Dai Juanjuan , Shen Jie , Wang Xiaolu , Bao Jinfeng , Chang Xiaofeng , Zhou Yingling , Sun Wu , Wang Qin , Du Shiyao , Tan Siyi , Zhu Junmeng , Zhou Xia , Liu Qin , Zhu Lijing , Liu Baorui 
Published: August 2024

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Background: The immunotherapy of sarcomas remains a challenge. As a breakthrough tool for cancer immunotherapy, the therapeutic cancer vaccine is in rapid development. In situ vaccination can be realized by intratumoral immune injection and radiotherapy. We have developed a bifunctional engineered Lactococcus lactis (FOLactis) expressing an encoded fusion protein of fms-like tyrosine kinase 3 ligand (Flt3L) and OX40 ligand (OX40L). We hypothesized that intratumoral injection of "FOLactis" combined with SBRT will realize tumor control and the synergetic application of PD-1 mAb systematically will further improve the effect of immunotherapy. Methods: This exploratory clinical study is designed as an open-label trial aimed at treating patients with advanced solid tumors who are unresponsive or intolerable to standard treatment. Patients will be treated with SBRT, intratumoral injection of "FOLactis", and PD-1 blockade. The primary endpoint was the objective response rate (ORR) of target lesions after 3 months and 6 months. The secondary endpoint included the disease control rate (DCR) of target lesions, progression-free survival (PFS), overall survival (OS), etc. Results: From July 2022 to December 2023, 30 patients were eligible for this trial (63% were sarcomas). 53.3% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb before respectively. The ORR and DCR of target lesions after 3 months were 27.6% and 93.1%, while these of systemic efficacy were 17.2% and 55.2%, respectively. In sarcomas, the ORR, DCR of target lesions were 11.1% and 88.9%, while these of systemic efficacy were 5.5% and 50%, respectively. Considering the deferred response in sarcomas, we also calculated the ORR after 6 months as the primary endpoint. The ORR, DCR of target lesions after 6 months were 56.3% and 100%, while these in sarcomas were 41.7% and 100%, respectively. Systemic median PFS were 2.87 months. Median PFS of target lesions and mOS has not reached. Among the evaluable target lesions, 6-month EFS was 50% in sarcomas (6/12) and 50% in all patients (8/16). Expression of CD4+, CD8+ T cells and dendritic cells was significantly increased between pre-treatment and post-treatment peripheral blood in responders. The most common treatment-related adverse events (TRAEs) were fever (83.3%), lymphocytopenia (53.3%), hypocalcemia (30%), neutrophilia (26.7%) and nausea (26.7%). Grade≥3 TRAE occurred in 11 patients, including lymphocytopenia (30%), fever (6.7%), leukopenia (3.3%), anemia (3.3%) and cardiac insufficiency (3.3%). Conclusions: In situ vaccination with“FOLactis", along with SBRT was tolerable and induced anti-tumor immunity, which would also augment systemic response when synergized with PD-1 mAb. This in situ vaccination is probably a promising option for advanced solid tumors. Clinical trial information: ChiCTR2200060660 .