TY - JOUR
T1 - Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity
AU - Miller, Jeffrey S.
AU - Tessmer-Tuck, Jennifer
AU - Pierson, Bryce A.
AU - Weisdorf, Daniel
AU - McGlave, Philip
AU - Blazar, Bruce R.
AU - Katsanis, Emmanuel
AU - Verfaillie, Catherine
AU - Lebkowski, Jane
AU - Radford, James
AU - Burns, Linda J.
PY - 1997/4
Y1 - 1997/4
N2 - Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lyric activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 × 106 (n=6) or 0.5 × 106 (n=6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 × 106 U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n=2 at 0.25 × 106 U/m2/day, n=4 at 0.5 × 106 U/m2/day) consisting of decreased performance status (n=2), thrombocytopenia (n=3, 1 at the lower dose), and mild neutropenia (n=1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 × 106/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.
AB - Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lyric activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 × 106 (n=6) or 0.5 × 106 (n=6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 × 106 U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n=2 at 0.25 × 106 U/m2/day, n=4 at 0.5 × 106 U/m2/day) consisting of decreased performance status (n=2), thrombocytopenia (n=3, 1 at the lower dose), and mild neutropenia (n=1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 × 106/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.
UR - http://www.scopus.com/inward/record.url?scp=0031113474&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031113474&partnerID=8YFLogxK
M3 - Article
C2 - 9209739
AN - SCOPUS:0031113474
SN - 1083-8791
VL - 3
SP - 34
EP - 44
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 1
ER -