Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients.
OBJECTIVE
Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability. Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients. The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.


METHODS
Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.


RESULTS
Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.


CONCLUSIONS
We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer.
Besser
Michal J
MJ
Ella Institute of Melanoma, Sheba Medical Center, Tel-Hashomer, Israel. michal.besser@sheba.health.gov.il
Shapira-Frommer
Ronnie
R
Treves
Avraham J
AJ
Zippel
Dov
D
Itzhaki
Orit
O
Hershkovitz
Liat
L
Levy
Daphna
D
Kubi
Adva
A
Hovav
Einat
E
Chermoshniuk
Natalia
N
Shalmon
Bruria
B
Hardan
Izhar
I
Catane
Raphael
R
Markel
Gal
G
Apter
Sara
S
Ben-Nun
Alon
A
Kuchuk
Iryna
I
Shimoni
Avichai
A
Nagler
Arnon
A
Schachter
Jacob
J
D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000276:immunology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use; D007902:Length of Stay; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D007376:Interleukin-2