HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases

• Published in: Cancer gene therapy Vol. 27; no. 5; pp. 341 - 355
• Main Authors: Katz, Steven C., Hardaway, John, Prince, Ethan, Guha, Prajna, Cunetta, Marissa, Moody, Ashley, Wang, Li Juan, Armenio, Vincent, Espat, N. Joseph, Junghans, Richard P.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2020; Nature Publishing Group
• Subjects: 13/31; 14/19; 14/63; 38/77; 38/90; 59/57; 59/78; 631/67/1059/2325; 631/67/1059/602; 96/106; 96/21; 96/95; Adult; Aged; Antigens; Biomedical and Life Sciences; Biomedicine; Brachytherapy - methods; Carcinoembryonic antigen; Carcinoembryonic Antigen - metabolism; Cell therapy; Cerebrospinal fluid; Chimeric antigen receptors; Clinical trials; Colonic Neoplasms - immunology; Colonic Neoplasms - mortality; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Combined Modality Therapy - methods; Cytokines; Female; Follow-Up Studies; Gene Expression; Gene Therapy; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - metabolism; Granulocyte-macrophage colony-stimulating factor; Hepatic artery; Hepatocytes; Humans; Immunotherapy, Adoptive - methods; Infusions, Intra-Arterial; Liver; Liver - blood supply; Liver - immunology; Liver - pathology; Liver - radiation effects; Liver Neoplasms - immunology; Liver Neoplasms - mortality; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Lymphocytes T; Male; Metastases; Metastasis; Middle Aged; Neurotoxicity; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; PD-L1 protein; Radiation therapy; Receptors, Chimeric Antigen - immunology; Rectal Neoplasms - immunology; Rectal Neoplasms - mortality; Rectal Neoplasms - pathology; Rectal Neoplasms - therapy; Response Evaluation Criteria in Solid Tumors
• ISSN: 0929-1903; 1476-5500; 1476-5500
• DOI: 10.1038/s41417-019-0104-z

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA +  LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4–31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.