Adoptive cellular therapy of human breast and colorectal tumor targets using ex vivo activated memory T lymphocytes with potentiation by cis-diamminedichloroplatinum(II).
Autolymphocyte therapy (ALT) is adoptive cellular therapy of cancer using ex vivo activation of autologous peripheral blood lymphocytes (PBL). Memory T cells are the principal effector population in ALT, with in vivo activity in patients with metastatic renal cell carcinoma (RCC) and melanoma, and ex vivo cytotoxicity against autologous tumor targets. However, the noncytolytic lymphocyte portion of ex vivo-activated memory T cells (ALT cells) may also contribute as antitumor effectors. Pretreatment of murine and human tumor cells ex vivo with chemotherapeutic agents can enhance their susceptibility to antitumor lymphocytes ex vivo and in vivo. To determine whether cis-diamminedichloroplatinum(II) (DDP) could enhance ex vivo antitumor effects of ALT cells by immunomodulation, human breast and colorectal carcinoma target cells were derived from both primary and metastatic surgical specimens and incubated in complete medium (CM) with DDP or in CM alone (control group). Viability of each group was confirmed by trypan blue-dye exclusion test. ALT cells were prepared from autologous PBL at surgery. Primary and metastatic tumor cells from each group were used as targets for ALT cells and levels of interferon-gamma (IFN-gamma) release were measured as a determination of antitumor effect and recognition. Primary tumor target cells incubated in DDP showed enhanced antitumor effects and recognition by autologous ALT cells, as measured by the IFN-gamma assay compared to non-DDP-treated controls. Metastatic autologous tumor target cells demonstrated less IFN-gamma release than did the primary targets, although this was enhanced by pre-treating metastatic tumor targets with DDP. ALT cells demonstrated minimal IFN-gamma release when incubated with allogeneic tumor targets. These data suggest that autotumor recognition of metastatic tumor targets is comparable to that of primary lesions following ex vivo pretreatment of metastatic cells with nonlethal doses of certain chemotherapeutic agents. DDP may somehow alter the physical properties of target cells, rendering them susceptible to immune-mediated attack and the combination of ALT and DDP may lead to increased therapeutic efficacy in patients with metastatic breast and colon cancer.
Gold
J E
JE
Department of Medicine, Mount Sinai Hospital, New York.
Bleiweiss
I J
IJ
Goldfarb
A B
AB
Bauer
J J
JJ
Gelernt
I M
IM
Schwartz
M E
ME
Reiner
M A
MA
Miller
C M
CM
Weiss
M F
MF
Brower
S T
ST
D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D002945:Cisplatin / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D007371:Interferon-gamma; D002945:Cisplatin