Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro.
Because the requirement for long-term cell culture can make adoptive cellular immunotherapy cumbersome, experiments were designed to determine whether smaller numbers of tumor-sensitized T cells activated briefly with bryostatin 1 and ionomycin (B/I) could be returned immediately to recipient mice without in vitro expansion and still have an anti-tumor effect in vivo. Popliteal tumor-draining lymph nodes (DLNs) from mice bearing progressive MCA-105 and MCA-203 footpad sarcomas were harvested and treated for 18 h with B/I. These cells were then washed and transferred immediately to naive C57B1/6 mice. In some experiments, these mice were irradiated (500 rads) before adoptive transfer and were given interleukin-2 (IL-2, 7,500 IU i.p., b.i.d. for 3 days) after receiving the activated lymphocytes. Recipient mice were challenged with sarcoma cells (4 x 10(5) i.v.) 6 to 32 days after receiving the activated lymphocytes. Mice receiving 10(6) B/I-activated lymphocytes before tumor challenge had significantly fewer metastases than did controls. This protective effect did not require exogenous IL-2 or host irradiation. Using Thy-1 congenic donors, it was shown that B/I-activated T cells expanded in recipients when IL-2 was also given, and these cells were a prominent component (15% of total cells) in the infiltrates found in the lungs of mice 7 days after i.v. tumor challenge. Combining these B/I-"pulsed" cells with cyclophosphamide (CYP) and IL-2 to treat mice with established (3-day) metastases resulted in significant reduction in pulmonary nodules, with complete regression in many of the treated mice, which was rarely seen with CYP alone or with CYP + IL-2. Thus, adoptive transfer of tumor-sensitized, B/I-activated DLN cells confers protection against i.v. tumor challenge, without prior in vitro expansion of the effector cells. Phenotyping studies demonstrate that donor cells activated with B/I do expand in recipient mice after adoptive transfer and can move to sites of tumor. Moreover, these cells can mediate a therapeutic effect on established tumor metastases, when combined with chemotherapy.
Fleming
M D
MD
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Bear
H D
HD
Lipshy
K
K
Kostuchenko
P J
PJ
Portocarero
D
D
McFadden
A W
AW
Barrett
S K
SK
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D054713:Bryostatins; D002455:Cell Division; D002465:Cell Movement; D003520:Cyclophosphamide / Q000008:administration & dosage; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000008:administration & dosage; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D018942:Macrolides; D051379:Mice; D008810:Mice, Inbred C57BL; D012513:Sarcoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D013154:Spleen / Q000276:immunology / Q000473:pathology
D000276:Adjuvants, Immunologic; D054713:Bryostatins; D007376:Interleukin-2; D007476:Ionophores; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D015759:Ionomycin; D003520:Cyclophosphamide