Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer.
Cytotoxic chemotherapy is ineffective in metastatic renal cancer. However, systemic administration of interleukin 2 (IL-2) or infusion of dendritic cells (DCs) loaded with tumor extracts can lead to some response rates with concomitant survival improvements. We report the results of a phase I-II pilot study combining DCs and IL-2 where six patients were included. DCs were derived from bone marrow CD34+ cells and loaded with autologous tumor extracts. CD34-DC vaccines were infused subcutaneously at day 45, 52, 59, 90 and 120 following surgery in combination with IL-2, that was subsequently administrated after the 3rd and 4th DC vaccinations. Preparation of tumor extracts and CD34-DCs were satisfactory in all patients but one. Due to rapid tumor progression, one patient was excluded before vaccination. In the 4 remaining patients, two received 3 vaccinations, while the 2 others received 5 vaccinations and the full IL-2 treatment. No adverse effect due to the vaccinations was observed. A specific immune response against autologous tumor cells was observed in the 2 patients who completed the treatment. Interestingly, these 2 patients had a more prolonged survival than the patients receiving 3 vaccinations. Importantly, a transient and massive increase of circulating natural regulatory T-cells (nTregs) was evidenced in 3 patients following IL-2 administration. Overall, the use of CD34-DC vaccines is feasible, safe and non-toxic. A specific anti-tumor immune response can be detected. However, our data highlights that IL-2 is a potent inducer of nTregs in vivo and as such may have a negative impact on cancer immunotherapy.
Lemoine
François M
FM
Department of Biotherapies, Bâtiment CERVI, 83 Boulevard de L'Hôpital, Paris Cedex, France. francois.lemoine@upmc.fr
Cherai
Mustapha
M
Giverne
Camille
C
Dimitri
Dalia
D
Rosenzwajg
Michelle
M
Trebeden-Negre
Helene
H
Chaput
Nathalie
N
Barrou
Benoit
B
Thioun
Nicolas
N
Gattegnio
Bernard
B
Selles
Frederic
F
Six
Alain
A
Azar
Nabih
N
Lotz
Jean Pierre
JP
Buzyn
Agnes
A
Sibony
Mathilde
M
Delcourt
Annick
A
Boyer
Olivier
O
Herson
Serge
S
Klatzmann
David
D
Lacave
Roger
R
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D007376:Interleukin-2