Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer.
BACKGROUND
The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports.


METHODS
Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes.


RESULTS
A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease.


CONCLUSIONS
We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option.


BACKGROUND
NCT00558051, registered Nov. 13, 2007.
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Michal
M
Radomski
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Herbert J
HJ
Zeh
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Howard D
HD
Edington
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
James F
JF
Pingpank
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Medicine, Hillman Cancer Center, UPCI Research Pavilion, Suite 137, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Immunology, Hillman Cancer Center, UPCI Research Pavilion, Suite 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Lisa H
LH
Butterfield
University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Immunology, Hillman Cancer Center, UPCI Research Pavilion, Suite 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Pathology, Hillman Cancer Center, UPCI Research Pavilion, Suite 132, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Otolaryngology, Hillman Cancer Center, UPCI Research Pavilion, Suite 132, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Theresa L
TL
Whiteside
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Eva
E
Wieckowski
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
David L
DL
Bartlett
Department of Surgery, Division of Surgical Oncology, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 400, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center, UPCI Cancer Pavilion, Suite 500, 5150 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Immunology, Hillman Cancer Center, UPCI Research Pavilion, Suite 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Infectious Diseases and Microbiology, Hillman Cancer Center, UPCI Research Pavilion, Suite 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA ; Department of Bioengineering University of Pittsburgh, Hillman Cancer Center, UPCI Research Pavilion, Suite 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 USA.
Pawel
P
Kalinski
Adoptive cell therapies; Cannulation; Colorectal cancer; Dendritic cells; Human T cells; Immunotherapy; Intralymphatic port; Lymphatic vessels