Anti-MUC1 CAR-T cells combined with PD-1 knockout engineered T cells for patients with non-small cell lung cancer (NSCLC): A pilot study

Background: Despite CAR-T cell therapy achieving remarkable results in the treatment of lymphoma, treatment of solid tumor using CAR-T remains an enormous challenge. It has been proposed that combinational immune-therapy may be a more efficacious approach to solid tumors. In this study, we combined anti-MUC1 CAR-T cell with PD-1 knockout (KO) T cells to treat advanced NSCLC. This represents the first attempt in the treatment of human solid cancer using PD-1 (KO) technology. Methods: Patients were recruited according to the criteria in NCT03525782. MUC1-specific CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. PD-1 gene KO in the CAR positive T cells was achieved using the CRISPR-Cas9 system and validated by sequencing. MUC1-CAR+/PD-1- KO engineered T cells at a dose of 2.5x106/KG were infused over 60 mins. Following treatment, patients' general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored at regular intervals. Changes in tumor size were examined by MRI scans. Results: 8 patients (aged 36 to 84) diagnosed with NSCLC (IIIb to IV), were recruited for this study. Data from 6 patients are included in this report. All patients had significant symptom improvements in the first 2 weeks after infusion. Serum CYFRA 21 declined following infusion and subsequently increased 4 weeks after treatment. Changes in tumor size varied between patients. In 2/6 patients, lung tumor size shrunk significantly within 4 weeks after treatment (one reduced from 25x19x22mm to 14x10x26mm). The effect on metastasis was limited. No CRS was observed although cytokine levels increased in 3/6 patients. No other adverse effects were recorded in all patients. Conclusions: Our data suggests that combined MUC1-CAR+/PD-1-KO therapy is safe and well tolerated by all patients and importantly no CRS was indicated in all cases. The efficacy of the combined therapy was case specific: some NSCLC patients responded well, while no noticeable response observed in others. This marked individual patient response to treatment indicates that other unknown factors, confer more sensitivity in a sub-set of patients. Clinical trial identification: NCT03525782. Legal entity responsible for the study: Guangzhou Anjie Biomedical Technology Co. Ltd. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.