Adjuvant, adoptive immunotherapy with tumor infiltrating lymphocytes plus interleukin-2 after radical hepatic resection for colorectal liver metastases: 5-year analysis.
OBJECTIVE
Conventional chemotherapy has not proven effective in improving long-term results of surgery for liver metastases from colorectal cancer. We assessed the usefulness of immunotherapy with tumor infiltrating lymphocytes (TIL) plus Interleukin-2 (IL-2) as adjuvant treatment.


METHODS
Between 1995 and 1998, 47 patients were enrolled onto a prospective protocol; 25 entered the treatment group (A) and 22 entered the control group (B). All patients had undergone radical liver resection. TIL obtained from surgical specimens from group A patients were cultured and activated in vitro with IL-2, then reinfused into the patients with IL-2. We investigated pre- and post-IL-2 stimulation expression of T cell receptor (TCR) zeta- and epsilon-chains, p56(lck), Fas, and Fas-L by TIL immunostaining.


RESULTS
Fourteen patients from group A (56%) received immunotherapy; 14 from group B (60%) underwent conventional chemotherapy, and the remaining 19 patients did not receive any treatment. No significant differences between the two groups were found in the actuarial and disease-free survival (DSF) rates after 1, 3, and 5 years. After IL-2 exposure, TCR zeta-chain expression significantly increased (P = 0.001); An increase in TCR epsilon-chain expression (P = 0.04), and p56(lck) (P = 0.03) was detected; TCR epsilon-chain expression was significantly increased in disease-free patients compared to those who relapsed (P = 0.04). Fas-L expression was correlated with the TCR epsilon-chain and p56(lck) levels (P = 0.05).


CONCLUSIONS
Our data suggest that we are still a long way from being able to propose TIL + IL-2 treatment as an effective adjuvant therapy. However, the results confirm that the biological indicators examined could play an important role in modulating immunitary response against tumor cells.
Gardini
Andrea
A
Department of Surgery and Transplantation, University of Bologna, Bologna, Italy. andrea.gardini@writeme.com
Ercolani
Giorgio
G
Riccobon
Angela
A
Ravaioli
Matteo
M
Ridolfi
Laura
L
Flamini
Emanuela
E
Ridolfi
Ruggero
R
Grazi
Gian Luca
GL
Cavallari
Antonino
A
Amadori
Dino
D
D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006498:Hepatectomy; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000637:transplantation*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008875:Middle Aged; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)