[Introduction] Mesenchymal Stromal Cells (MSCs) have been shown to home to the sites of injury or damage and secrete immunomodulatory factors. This feature makes MSCs an ideal carrier to deliver drugs or cytokines to the tumor microenvironment (TME) and therefore have a potential therapeutic role in cancer treatment.~Interferon(IFN) has been widely used for cancer treatment for its pleiotropic antitumor effects. IFN receptor signals mediate intrinsic and extrinsic effects on tumor cells and the TME, including tumor-infiltrating lymphocytes as well as tumor-associated stroma. Additionally, IFNs also exert direct intrinsic antitumor effects including inhibition of cell proliferation by inducing cell cycle arrest, cell death via apoptosis and ferroptosis, cell differentiation, and senescence, thus acting as a tumor suppressor. Accumulating evidence suggests that IFNs play critical roles in cancer immunotherapy, however, the variations in responses and the adverse effects have reduced their popularity in clinical applications. New IFN-based strategies should be considered as a high priority.~Our team has developed a protocol to genetically express IFNα in bone marrow-derived MSCs. In vitro and in vivo experiments have shown that the MSC-IFNα cells possess a potent ability to home to TME and to secret IFNα. By changing TME, MSC-IFNα induces strong anti-tumor effects in several cancer types in animal models. In addition, preliminary data also indicated that the combination of IFNα-MSCs with chemotherapy and/or programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)blockade may bring an even stronger anti-tumor immunity.~In this study, by producing MSC-IFNα cells with human umbilical-cord-derived mesenchymal stromal cells (hUC-MSCs, passage 5 to passage 7), the investigators plan to conduct a first-in-human, prospective, open-label, phase 1/2 trial to evaluate the safety and efficacy of MSC-IFNα combined with or without immunochemotherapy in patients with locally advanced/metastatic solid tumors.~[Study design] Phase 1 Arm 1. Safety evaluation of MSC-IFNα monotherapy A total of 3-9 subjects will be enrolled for the safety evaluation of MSC-IFNα monotherapy. All treatment-related adverse events (TRAE) will be recorded for at least 28 days after cell infusion. Subjects with any grade 3-4 TRAE that lasts for 7 days or more within the 28 days after infusion will be determined as treatment intolerance (TI).~The first 3 subjects will receive MSC-IFNα infusion 1-4 times every 4-6 weeks at a dose of 2×10^6 cells/kg. If TI occurred in any of the 3 subjects, another 3 subjects will be enrolled and received a 70% reduced MSC-IFNα dose (i.e. 6×10^5 cells/kg, 2x10^5/kg, and so on) until tolerable dose (no TI in all 3 subjects) was reached.~Arm 2. Safety and efficacy evaluation of MSC-IFNα combined with immunochemotherapy.~A total of 3-9 subjects will be enrolled and receive MSC-IFNα infusion (tolerable dose determined in Arm 1) every 4-6 weeks for 4 cycles. Immunochemotherapy, namely nab-paclitaxel (125 mg/m2, 5 days before cell infusions), cyclophosphamide (200 mg/m2,4 days before cell infusions) and anti-PD-1 antibody (200mg, 7 days after infusion) will be given. From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1 antibody (200mg, 7 days after infusion) every 4-6 weeks for another 4 cycles for efficacy consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody (200mg) alone every 3 weeks for another 4 cycles for efficacy maintenance. The safety, efficacy, and other required data will be collected and the optimized combined regimen (OCR) of MSC-IFNα and immunochemotherapy will be determined. MSC-IFNα related AE will be continuously monitored in this arm, and reduced MSC-IFNα dose will be considered if necessary.~Phase 2 A total of 10-30 subjects will be enrolled and received the OCR determined in the phase 1 of the trial. The safety, efficacy, and other required data will be collected.~During the treatment, efficacy in all subjects will be assessed at baseline and every 8 weeks thereafter until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs first.~During post-treatment follow-up, efficacy and TRAEs in all subjects will be assessed every 12 weeks until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first.
The goal of this first-in-human, single-center, prospective, open-label, phase 1/2 trial is to evaluate the safety and efficacy of the interferon alpha expressing mesenchymal stromal cells (MSC-IFNα) combined with or without immunochemotherapy in patients with locally advanced/metastatic solid tumors. The main questions aimed to answer are 1) to evaluate the safety and feasibility of MSC-IFNα in the treatment of locally advanced/metastatic solid tumors;2) to evaluate the anti-tumor effects of the MSC-IFNα combined with or without immunochemotherapy in the treatment of locally advanced/metastatic solid tumors; 3) to evaluate the pharmacokinetics/pharmacodynamics of MSC-IFNα and related immune effector cells.