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


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.

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  1. 1.

    Cantor HM, Dumont AE. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature. 1967;215(5102):744–5.

  2. 2.

    Katz SC, Pillarisetty VG, Bleier JI, Kingham TP, Chaudhry UI, Shah AB, et al. Conventional liver CD4 T cells are functionally distinct and suppressed by environmental factors. Hepatology. 2005;42(2):293–300.

  3. 3.

    Katz SC, Pillarisetty VG, Bleier JI, Shah AB, DeMatteo RP. Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol. 2004;173(1):230–5.

  4. 4.

    Katz SC, Ryan K, Ahmed N, Plitas G, Chaudhry UI, Kingham TP, et al. Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J Immunol. 2011;187(3):1150–6.

  5. 5.

    Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80.

  6. 6.

    Katz SC, Bamboat ZM, Maker AV, Shia J, Pillarisetty VG, Yopp AC, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20(3):946–55.

  7. 7.

    Katz SC, Donkor C, Glasgow K, Pillarisetty VG, Gonen M, Espat NJ, et al. T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases. HPB (Oxf). 2010;12(10):674–83.

  8. 8.

    Katz SC, Pillarisetty V, Bamboat ZM, Shia J, Hedvat C, Gonen M, et al. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16(9):2524–30.

  9. 9.

    Wagner P, Koch M, Nummer D, Palm S, Galindo L, Autenrieth D, et al. Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer. Ann Surg Oncol. 2008;15(8):2310–7.

  10. 10.

    Turcotte S, Katz SC, Shia J, Jarnagin WR, Kingham TP, Allen PJ, et al. Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol Res. 2014;2(6):530–7.

  11. 11.

    Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood. 2006;107(4):1325–31.

  12. 12.

    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. New Engl J Med. 2011;365(8):725–33.

  13. 13.

    Hardaway JC, Prince E, Arepally A, Katz SC. Regional infusion of chimeric antigen receptor T cells to overcome barriers for solid tumor immunotherapy. J Vasc Inter Radio. 2018;29(7):1017–21 e1.

  14. 14.

    Archer SG, Gray BN. Vascularization of small liver metastases. Br J Surg. 1989;76(6):545–8.

  15. 15.

    Katz SC ME, Burga R, Wang L, Mooring W, Davies R, Stainken BF, et al. Hepatic immunotherapy for metastases (HITM) – A phase I trial of anti-CEA genetically modified T cells for unresectable adenocarcinoma SSO's 67th Annual Cancer Symposium; Phoenix, AZ: Society of Surgical Oncology. 2014.

  16. 16.

    Saied A, Licata L, Burga RA, Thorn M, McCormack E, Stainken BF, et al. Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. Cancer gene Ther. 2014;21(11):457–62.

  17. 17.

    Gray B, Van Hazel G, Hope M, Burton M, Moroz P, Anderson J, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol : Off J Eur Soc Med Oncol/ESMO. 2001;12(12):1711–20.

  18. 18.

    Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256–65.

  19. 19.

    Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015;64(7):817–29.

  20. 20.

    Thorn M, Point GR, Burga RA, Nguyen CT, Joseph Espat N, Katz SC. Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+ CD11b+ myeloid cells. J Leukoc Biol. 2014;96(5):883–94.

  21. 21.

    Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, 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(14):3149–59.

  22. 22.

    Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.

  23. 23.

    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60.

  24. 24.

    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

  25. 25.

    Beaudoin EL, Bais AJ, Junghans RP. Sorting vector producer cells for high transgene expression increases retroviral titer. J Virol Methods. 2008;148(1-2):253–9.

  26. 26.

    Quintas-Cardama A, Yeh RK, Hollyman D, Stefanski J, Taylor C, Nikhamin Y, et al. Multifactorial optimization of gammaretroviral gene transfer into human T lymphocytes for clinical application. Hum Gene Ther. 2007;18(12):1253–60.

  27. 27.

    Ma Q, DeMarte L, Wang Y, Stanners CP, Junghans RP. Carcinoembryonic antigen-immunoglobulin Fc fusion protein (CEA-Fc) for identification and activation of anti-CEA immunoglobulin-T-cell receptor-modified T cells, representative of a new class of Ig fusion proteins. Cancer Gene Ther. 2004;11(4):297–306.

  28. 28.

    Guha P, Cunetta M, Somasundar P, Espat NJ, Junghans RP, Katz SC. Frontline science: functionally impaired geriatric CAR-T cells rescued by increased alpha5beta1 integrin expression. J Leukoc Biol. 2017;102(2):201–8.

  29. 29.

    Thorn M, Guha P, Cunetta M, Espat NJ, Miller G, Junghans RP, et al. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther. 2016;23(6):188–98.

  30. 30.

    Junghans RP, Manning W, Safar M, Quist W. Biventricular cardiac thrombosis during interleukin-2 infusion. New Engl J Med. 2001;344(11):859–60.

  31. 31.

    Sridhar P, Petrocca F. Regional delivery of chimeric antigen receptor (CAR) T-cells for cancer therapy. Cancers (Basel). 2017;9(7):E92.

  32. 32.

    Reha J, Katz SC. Regional immunotherapy for liver and peritoneal metastases. J Surg Oncol. 2017;116(1):46–54.

  33. 33.

    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.

  34. 34.

    Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423–9.

  35. 35.

    Titano JJ, Fischman AM, Cherian A, Tully M, Stein LL, Jacobs L, et al. End-hole versus microvalve infusion catheters in patients undergoing drug-eluting microspheres-TACE for solitary hepatocellular carcinoma tumors: a retrospective analysis. Cardiovasc Interv Radio. 2019;42:560–8.

  36. 36.

    Chae YK, Wang S, Nimeiri H, Kalyan A, Giles FJ. Pseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review. Oncotarget. 2017;8(34):57889–97.

  37. 37.

    Wong AS, Thian YL, Kapur J, Leong CN, Kee P, Lee CT, et al. Pushing the limits of immune-related response: a case of “extreme pseudoprogression”. Cancer Immunol Immunother. 2018;67(7):1105–11.

  38. 38.

    Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–50S.

  39. 39.

    Barabasch A, Kraemer NA, Ciritsis A, Hansen NL, Lierfeld M, Heinzel A, et al. Diagnostic accuracy of diffusion-weighted magnetic resonance imaging versus positron emission tomography/computed tomography for early response assessment of liver metastases to Y90-radioembolization. Invest Radiol. 2015;50(6):409–15.

  40. 40.

    Carter CA, Schmitz B, Peterson PG, Quinn M, Degesys A, Jenkins J, et al. Immune reactivity and pseudoprogression or tumor flare in a serially biopsied neuroendocrine patient treated with the epigenetic agent RRx-001. Case Rep Oncol. 2016;9(1):164–70.

  41. 41.

    Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–e52.

  42. 42.

    Larimer BM, Wehrenberg-Klee E, Dubois F, Mehta A, Kalomeris T, Flaherty K, et al. Granzyme B PET imaging as a predictive biomarker of immunotherapy response. Cancer Res. 2017;77(9):2318–27.

  43. 43.

    Hege KM, Bergsland EK, Fisher GA, Nemunaitis JJ, Warren RS, McArthur JG, et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer. 2017;5:22.

  44. 44.

    Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31(17):2205–18.

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We thank TNK therapeutics, a subsidiary of Sorrento Therapeutics, for providing the anti-CEA CAR-T-cell vector, which was obtained from the National Gene Vector Laboratory. We are grateful to Jason LaPorte and Jillian Gardell for their assistance with the correlative studies.


SirTex Medical provided the funding for study related costs. The Roger Williams Medical Center funded personnel who executed the production and clinical aspects of the study. Prometheus provided the Proleukin for infusion and CAR-T production.

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Conflict of interest

Dr. Katz receives research support from and previously served as a scientific advisor for TNK Therapeutics, in addition to once serving on an advisory panel for Prometheus. Dr. Espat has served as an advisor for Sirtex.

Correspondence to Steven C. Katz.

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