Of the 20 mice treated with the experimental approach, 19 achieved clearance of residual tumor cells.
Human mesothelin-directed chimeric antigen receptor T-cells (CARM5) applied in a fibrin glue-based carrier (fibrin gel) to partially resected solid tumors in mouse models of triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDA) effectively eliminated residual tumor cells, according to preclinical research recently published in Science Advances.1
The study, carried out by investigators from the Perelman School of Medicine at the University of Pennsylvania, treated TNBC xenograft model mice with incomplete surgery only (n = 10), incomplete surgery and direct intracavity inoculation of human CD19-specific CAR (CAR19) T-cells in fibrin gel (n = 10), incomplete surgery and direct intracavity inoculation of CARM5 in medium (n = 10), or incomplete surgery and direct intracavity inoculation of CARM5 T-cells in fibrin gel (n = 10). It was found that all 10 mice in the group that received direct intracavity inoculation of CARM5 T-cells in fibrin gel achieved clearance of residual tumor, while only 3 of 10 mice that received CARM5 in medium achieved tumor clearance, and no mice in the other 2 cohorts achieved tumor clearance.
In the PDA xenograft mouse model, the study utilized the same 4 treatment cohorts, with similar results. Nine of 10 PDA-model mice that received surgery and direct intracavity inoculation of CARM5 in fibrin gel achieved tumor clearance, whereas only 1 of 10 mice treated with surgery and CARM5 in medium achieved tumor clearance. Tumor regrowth occurred in all mice in the other 2 cohorts.
It was additionally noted that the mice in both disease models that received CARM5 in fibrin gel reached significantly longer overall survival than the mice in the other treatment cohorts. Furthermore, signs of inflammation or wound healing complications at the site of the resected tumors were not observed in any of the mice in the study.
“As we continue to advance CAR T-cell therapy forward, finding applications for use in solid tumors is a major goal,” senior author Carl June, MD, Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies at Penn Medicine’s Abramson Cancer Center, said in a statement announcing the study’s publication.2 “Based on the promising results in this study, our colleagues have planned a clinical trial in patients with locally advanced breast cancer.”
The study also sought to evaluate whether on-target off-tumor toxicity is affected by local administration of CARM5 cells.1 A novel human mesothelin knock-in NSG (huMeso-KI-NSG) mouse model was utilized for this purpose. June and colleagues reported that “local CAR T-cells did not efficiently leave the surgical site in huMeso-KI-NSG mice,” indicating that local administration reduces the risk of on-target off-tumor toxicity for locally administered CARM5 compared to intravenous administration of CARM5. In addition, the investigators determined that huMeso-KI-NSG mice that received local administration showed significantly decreased lung and pleural immunopathology.
June and colleagues concluded that in light of the ongoing use of surgery as a first-line treatment for many solid tumor types, including head and neck cancers, ovarian cancer, prostate cancer, and breast cancer; the current rates of positive surgical margins remaining after surgery seen in these indications; and the fact that the fibrin gel utilized in their study is already FDA-approved, a clinical trial adapting the methods used in this study is warranted. The investigators noted that because even incomplete tumor resection substantially reduces tumor burden, the local approach used in this study could reduce toxicity risk by using a lower dose of CAR-T cells than is typically used in clinical trials of investigational CAR-T treatments. They also mentioned that although the planned clinical trial for their approach will begin with the use of autologous cells, an allogeneic approach could increase the availability of CAR-T cells for use immediately following surgical resection. They noted that the shorter persistence of allogeneic cells may not be a disadvantage in local tumor clearance.
“In summary, CAR-T cells can be effectively and safely used as a surgical adjuvant therapy for solid tumors that cannot be completely excised,” June and colleagues concluded. “The use of a fibrin glue-based carrier in this context may represent an effective and translatable tool to maximize CAR-T cell distribution and antitumor efficacy at the tumor resection site. This approach can be broadened to additionally deliver cytokines, oncolytic viruses, checkpoint antibodies, or other drugs/biological agents, which together might further increase the overall antitumor response.”