HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery

Abstract

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

Keywords: chimeric antigen; cytokines; immunotherapy; myeloid-derived suppressor cells; receptors; tumor microenvironment.

Conflict of interest statement

Competing interests: SCK is an advisor for TriSalus, Nkarta, Takeda, and served as an advisor for TNK Therapeutics during the study. EP serves as a consultant for TriSalus. SCK, JES, KRJ and RDS have received research funding from TriSalus.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

(A) Trial schematic. (B) Sequential imaging demonstrates complete metabolic response to intrahepatic CAR-T therapy. Each imaging time point is depicted with an image from a contrast-enhanced CT of the abdomen and a corresponding attenuation corrected PET image. The lesion, which is located adjacent to the gallbladder at the border between segments 4B and 5, is FDG avid at baseline and shows no activity on the first follow-up scan or any of the later time points. RECIST assessment of the lesion on CT shows partial response from baseline to the first time point, and stable disease from that time on. Note that there is increased peri-lesional enhancement on January 10, 2018; this is likely due to a transient perfusion abnormality and the timing of image acquisition in relationship to contrast administration. (C) H&E stain of non-neoplastic liver parenchyma (N) at baseline and HAI 3, and metastatic tumor (T) collected at HAI 3. (D) Serum CEA and CA 19–9 were trended throughout the course of the study. Both tumor markers exhibited a continuous downward trend before normalizing following CAR-T HAI. This biochemical response correlated with the radiographic imaging, in addition to the post-treatment pathologic findings. CAR-T, chimeric antigen receptor T-cells; CEA, carcinoembryonic antigen; HAI, hepatic artery infusion; IL, interleukin; PET, positron emission tomography; FDG, fluorodeoxyglucose.

Figure 2

(A) Immunohistochemical analysis of liver tissue for CAR-T detection. Detection of CAR-T in liver tissue by immunofluorescence microscopy showing CAR-T infiltrating tumor post HAI 3 and HAI 4. Liver tissue collected pre and post CAR-T therapy was stained for DAPI, CD3, and CAR. (B) Immunohistochemical analysis of liver tissue for CEA detection. CEA expression in liver tumor tissue detected by immunofluorescence microscopy showing ongoing CEA expression over the course of this study. Liver tumor tissue collected pre and post CAR-T therapy was stained for DAPI and CEA. (C) Change in tumor tissue microenvironment post CAR-T therapy. Lysates of liver tumor tissue collected at baseline (BL), HAI 3 (I3), HAI 4 (I4), and 48 days post HAI 4 (PI4) were analyzed by western blot. Signals were quantified by densitometric analysis and normalized to GAPDH. CAR-T, chimeric antigen receptor T-cells; CEA, carcinoembryonic antigen; HAI, hepatic artery infusion; IL, interleukin, DAPI, 4′,6-diamidino-2-phenylindole; IDO, indoleamine 2, 3-dioxygenase; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSF-R, granulocyte-macrophage colony-stimulating factor receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Figure 3

Changes in plasma cytokine levels throughout treatment. Plasma from peripheral blood was collected at baseline and TD 7, 15, 22, 29, 38, 44, 51, and 59 after initiation of treatment. levels of IFNɣ, TNFα, IL-6, IL-10, IL-2, and IL-8 were measured using a multiplex ELISA (human pro-inflammatory V-PLEX, meso scale discovery). Samples were run in duplicate and average cytokine concentrations were extrapolated from an 8-point standard curve. Only samples in the dynamic range of each assay and with CVs below 20% are shown; IL-2 was below the limit of detection in the baseline samples. IL, interleukin; HAI, hepatic artery infusion; TD, treatment day; IFN, interferon; TNF, tumor necrosis factor; CV, coefficient of variation.