Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia.

Blockade of the interaction of the immune checkpoint receptor programmed cell death protein (PD)-1 and its ligand PD-L1 has been found to be a promising cancer treatment. Our previous studies identified that nABPD1 competed with PD-L1 to bind PD-1. The aim of this study was to evaluate the efficacy and safety of anti-tumor immunotherapy of ICIK cells conjugated with peptides in vivo and in vitro. Here, we synthesized the nABPD1 derivatives SBP1 and SBP2 and showed that their binding efficiency to PD-1-positive improving cytokine-induced killer (ICIK) cells was 98 and 82%, respectively. The cytotoxicity of ICIK cells to T-cell acute lymphoblastic leukemia (T-ALL) cells was increased by conjugating with SBP1 or SBP2, which was 2 times higher than that of ICIK cells alone. Furthermore, mice experiments showed that the fluorescence intensity of leukemia cells in T-ALL xenograft models was reduced by more than 95%, indicating that the peptides enhanced the therapeutic effect in vivo, while morphological evaluations showed that the peptides had no toxicity to important organs. Therefore, peptide-cell conjugates (PCCs) may be a novel method to improve the efficacy of cancer immunotherapy by blocking PD-1 in T-ALL patients.

Fission cross-section measurement for Xe135m and Xe135g in U238 reaction induced by 14MeV D-T neutrons.

In this work, the independent fission cross-sections of U(n,f)238Xe135g and U(n,f)238Xe135m reactions induced by neutrons with the energies of 14.1 MeV, 14.5 MeV, and 14.7 MeV were measured by activation methods. The neutrons from T(d,n)He4 were used in the experiments and their energies were determined by the ratio of Zr(n,2n)90Zr89 and Nb(n,2n)93Nb92m reaction cross-sections. Aluminum films were chosen as reference samples to measure the neutron fluence relative to the cross section of the Al(n,α)27Na24 reaction. The effect of self-absorption, geometry, and cascade coincidence were also considered during the data analysis. Besides, the increase in the daughter nuclide yield due to the decay of the parent nuclides in the same decay chain was deducted. As a result, the independent fission cross-sections of the U(n,f)238Xe135g reaction are 2.54 ± 0.14 mb, 3.05 ± 0.19 mb and 2.94 ± 0.19 mb, while the cross-sections of U(n,f)238Xe135m reaction are 2.11 ± 0.16 mb, 2.47 ± 0.18 mb and 2.34 ± 0.21 mb for 14.1 MeV, 14.5 MeV and 14.7 MeV neutrons, respectively. This work provides experimental data for the database of nuclear fission reactions.

Engineering a High-Affinity PD-1 Peptide for Optimized Immune Cell-Mediated Tumor Therapy.

PURPOSE: The purpose of this study was to optimize a peptide (nABP284) that binds to programmed cell death protein 1 (PD-1) by a computer-based protocol in order to increase its affinity. Then, this study aimed to determine the inhibitory effects of this peptide on cancer immune escape by coculturing improving cytokine-induced killer (ICIK) cells with cancer cells. MATERIALS AND METHODS: nABP284 that binds to PD-1 was identified by phage display technology in our previous study. AutoDock and PyMOL were used to optimize the sequence of nABP284 to design a new peptide (nABPD1). Immunofluorescence was used to demonstrate that the peptides bound to PD-1. Surface plasmon resonance was used to measure the binding affinity of the peptides. The blocking effect of the peptides on PD-1 was evaluated by a neutralization experiment with human recombinant programmed death-ligand 1 (PD-L1) protein. The inhibition of activated lymphocytes by cancer cells was simulated by coculturing of human acute T lymphocytic leukemia cells (Jurkat T cells) with human tongue squamous cell carcinoma cells (Cal27 cells). The anticancer activities were determined by coculturing ICIK cells with Cal27 cells in vitro. RESULTS: A high-affinity peptide (nABPD1, KD=11.9 nM) for PD-1 was obtained by optimizing the nABP284 peptide (KD=11.8 µM). nABPD1 showed better efficacy than nABP284 in terms of increasing the secretion of interkeulin-2 by Jurkat T cells and enhancing the in vitro antitumor activity of ICIK cells. CONCLUSION: nABPD1 possesses higher affinity for PD-1 than nABP284, which significantly enhances its ability to block the PD-1/PD-L1 interaction and to increase ICIK cell-mediated antitumor activity by armoring ICIK cells.