Adoptive transfer of anti-CD3-activated CD4+ T cells plus cyclophosphamide and liposome-encapsulated interleukin-2 cure murine MC-38 and 3LL tumors and establish tumor-specific immunity.
The infusion of anti-CD3-activated murine T cells plus interleukin-2 (IL-2) exerts antitumor effects against several tumors in murine immunotherapy models. This study compares the therapeutic efficacy of anti-CD3-activated CD4+ or CD8+ T-cell subsets, when given with cyclophosphamide (Cy) and liposome-encapsulated IL-2 (L-IL2) in a murine model. C57BL/6 mice bearing subcutaneous (S.C.) MC-38 colon adenocarcinoma, 3LL Lewis lung carcinoma, or 38C13 lymphoma for 7 to 14 days were pretreated with low-dose intraperitoneal (I.P.) Cy before intravenous (I.V.) injection of anti-CD3-activated T cells or T-cell subsets. Cell administration was followed by I.P. administration of L-IL2 for 5 days. Mice receiving activated CD4+ T cells showed significantly reduced tumor growth or complete remissions with prolonged disease-free survival in MC-38, 3LL, and 38C13. The timing of Cy doses in relation to adoptive transfer was critical in obtaining the optimal antitumor effect by CD4+ cells. Injecting Cy 4 days before the infusion of CD4+ cells greatly enhanced the antitumor effect of the CD4+ cells and improved survival of the mice compared with other Cy regimens. C57BL/6 mice cured of MC-38 after treatment with CD4+ T cells developed tumor-type immunologic memory as demonstrated by their ability to reject rechallenges with MC-38, but not 3LL. Similarly, mice cured of 3LL tumors rejected rechallenges of 3LL, but not MC-38. The immunologic memory could be transferred with an I.V. injection of splenocytes from mice cured of MC-38 or 3LL. No cytotoxic T-lymphocyte activity was detected in T cells or T-cell subsets from mice cured of MC-38 or 3LL. Increased IL-2 and interferon-gamma (IFN-gamma) production was observed from CD4+ subsets in cured animals when stimulated in vitro with the original tumor, but not with an unrelated syngeneic tumor. These results suggest that tumor-specific immunity can be achieved in vivo with anti-CD3-stimulated CD4+ T cells in this cellular therapy model.
Saxton
M L
ML
Biological Response Modifiers Program, National Cancer Institute, Frederick Cancer Research and Development Center, MD, USA.
Longo
D L
DL
Wetzel
H E
HE
Tribble
H
H
Alvord
W G
WG
Kwak
L W
LW
Leonard
A S
AS
Ullmann
C D
CD
Curti
B D
BD
Ochoa
A C
AC
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008081:Liposomes; D003520:Cyclophosphamide