Abstract A014: Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy

Abstract

Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.

Minimal PD-1 expression in mouse and human NK cells under diverse conditions

“…However, there are also opposing reports demonstrating lack of expression, but instead, prevalence of other immunoregulatory markers, such as TIGIT, PD-L1, TIM-a direct impact on NK cell responses (12,23,24). To this end, anti-PD-1 therapy is already being combined with various NK-promoting strategies to directly improve their clinical efficacy (25)(26)(27)(28).…”

CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma

“…By targeting this axis in NK cells, through engineered cell therapies and combinatorial antibody/cell therapy approaches, it is possible to suppress CD155-induced inhibition and enhance the natural cytolytic functions of NK cells. Recent advances in chimeric antigen receptor (CAR)-NK therapies have allowed engineered NK cells to find their way to the clinic [95], where they have predominantly targeted CD19 on B cell malignancies [74,96,97], but also a growing number of solid tumor ligands, such as HER2 and MUC1 [98][99][100].…”

Natural Born Killers: NK Cells in Cancer Therapy

“…Thirteen patients with PD-L1 and MUC1 positive cancers, including but not limited to lung, pancreatic, ovarian and colon cancer, were enrolled in the trial and received 1 × 10 9 Muc1-CAR-NK-92 cells/infusion. Of the initial 13 patients, three were withdrawn, nine had stable disease and one patient had progressive disease [ 107 ]. A primary outcome measure was to determine the toxicity profile of Muc1-CAR-NK-92 cells, and notably, there was no evidence of cytokine storm or bone marrow suppression in any patients on trial.…”