The effect of leukocyte interleukin injection (Multikine) treatment on the peritumoral and intratumoral subpopulation of mononuclear cells and on tumor epithelia: a possible new approach to augmenting sensitivity to radiation therapy and chemotherapy in oral cancer--a multicenter phase I/II clinical Trial.
OBJECTIVE
The main objective of this study was to investigate the effect of the administration of a novel immunoadjuvant, leukocyte interleukin injection, as part of an immuno-augmenting treatment regimen on the peritumoral and intratumoral subpopulations of the tumor infiltrating mononuclear cells and on the epithelial and stromal components, when administered to patients with advanced primary oral squamous cell carcinoma classified as T2-3N0-2M0, as compared with disease-matched control patients (not treated with leukocyte interleukin injection).


METHODS
Multicenter Phase I/II clinical trial. Fifty-four patients from four clinical centers were included in the dose-escalating study (27 in each group [leukocyte interleukin injection-treated and control groups]). Cumulative leukocyte inter-leukin injection doses were 2400, 4800, and 8000 IU (as interleukin-2 equivalent).


METHODS
Paraffin-embedded tumor samples obtained at surgical resection of the residual tumor (between days 21 and 28 after treatment initiation) were used. Histological analysis, necrosis evaluation, and American Joint Committee on Cancer grading were performed from H&E-stained sections. Immunohistochemical analysis was performed on three different tumor regions (surface, zone 1; center, zone 2; and tumor-stroma interface, zone 3). Trichrome staining was used to evaluate connective tissue, and morphometric measurements were made using ImagePro analysis software. Cell cycling was determined by the use of Ki-67 marker.


RESULTS
Leukocyte interleukin injection treatment induced a shift from stromal infiltrating T cells toward intraepithelial T cells and posted a significant (P <.05) increase in intraepithelial CD3-positive T cells independent of the leukocyte interleukin injection dose, whereas the increase in CD25 (interleukin-2 receptor alpha [IL-2Ralpha])-positive lymphoid cells was significant only at the lowest leukocyte interleukin injection dose (P <.05). Furthermore, both low- and medium-dose leukocyte interleukin injection treatment induced a significant (P <.05) increase in the number of cycling tumor cells, as compared with control values.


CONCLUSIONS
The results could be highly beneficial for patients with oral squamous cell carcinoma. First, leukocyte interleukin injection treatment induces T-cell migration into cancer nests and, second, noncycling cancer cells may enter cell cycling on administration of leukocyte interleukin injection. This latter effect may modulate the susceptibility of cancer cells to radiation therapy and chemotherapy. The findings may indicate a need to re-evaluate the way in which follow-up treatment (with radiation therapy and chemotherapy) of patients with head and neck cancer is currently approached.
Tímár
József
J
National Institute of Oncology, Semmelweis University, Budapest, Hungary.
Forster-Horváth
C
C
Lukits
J
J
Döme
B
B
Ladányi
A
A
Remenár
E
E
Kásler
M
M
Bencsik
M
M
Répássy
G
G
Szabó
G
G
Velich
N
N
Suba
Z
Z
Elõ
J
J
Balatoni
Z
Z
Bajtai
A
A
Chretien
P
P
Talor
Eyal
E
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D017252:CD3 Complex / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007267:Injections; D007271:Injections, Intradermal; D007378:Interleukins / Q000008:administration & dosage*; D019394:Ki-67 Antigen / Q000032:analysis; D007694:Killer Cells, Natural / Q000473:pathology; D007962:Leukocytes; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009336:Necrosis; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D019287:Zinc Sulfate / Q000008:administration & dosage
D000276:Adjuvants, Immunologic; D018906:Antineoplastic Agents, Alkylating; D017252:CD3 Complex; D007378:Interleukins; D019394:Ki-67 Antigen; D015375:Receptors, Interleukin-2; D019287:Zinc Sulfate; D003520:Cyclophosphamide; D007213:Indomethacin