HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery
Steven C Katz, Ashley E Moody, Prajna Guha, John C Hardaway, Ethan Prince, Jason LaPorte, Mirela Stancu, Jill E Slansky, Kimberly R Jordan, Richard D Schulick, Robert Knight, Abdul Saied, Vincent Armenio, Richard P Junghans, Steven C Katz, Ashley E Moody, Prajna Guha, John C Hardaway, Ethan Prince, Jason LaPorte, Mirela Stancu, Jill E Slansky, Kimberly R Jordan, Richard D Schulick, Robert Knight, Abdul Saied, Vincent Armenio, Richard P Junghans
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
References
- Katz SC, Burga RA, McCormack E, et al. . Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res 2015;21:3149–59. 10.1158/1078-0432.CCR-14-1421
- Katz SC GP, Hardaway JC, Prince E, et al. . HITM-SURE: phase Ib CAR-T hepatic artery infusion trial for stage IV adenocarcinoma using Pressure-Enabled drug delivery technology. Washington, D.C: Society of Immunotherapy for Cancer (SITC), 2018.
- Katz SC, Bamboat ZM, Maker AV, et al. . Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 2013;20:946–55. 10.1245/s10434-012-2668-9
- Katz SC, Hardaway J, Prince E, et al. . HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases. Cancer Gene Ther 2020;27:341-355. 10.1038/s41417-019-0104-z
- Guha P, Gardell J, Darpolor J, et al. . Stat3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells. Oncogene 2019;38:533–48. 10.1038/s41388-018-0449-z
- Zarour LR, Anand S, Billingsley KG, et al. . Colorectal cancer liver metastasis: evolving paradigms and future directions. Cell Mol Gastroenterol Hepatol 2017;3:163–73. 10.1016/j.jcmgh.2017.01.006
- Hardaway JC, Prince E, Arepally A, et al. . Regional infusion of chimeric antigen receptor T cells to overcome barriers for solid tumor immunotherapy. J Vasc Interv Radiol 2018;29:1017–21. 10.1016/j.jvir.2018.03.001
- Ali AI, Oliver AJ, Samiei T, et al. . Genetic redirection of T cells for the treatment of pancreatic cancer. Front Oncol 2019;9:56. 10.3389/fonc.2019.00056
Source: PubMed