TY - JOUR
T1 - MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion
T2 - Results of a Phase I trial
AU - Romano, Emanuela
AU - Michielin, Olivier
AU - Voelter, Verena
AU - Laurent, Julien
AU - Bichat, Hélène
AU - Stravodimou, Athina
AU - Romero, Pedro
AU - Speiser, Daniel E.
AU - Triebel, Frédéric
AU - Leyvraz, Serge
AU - Harari, Alexandre
N1 - Funding Information:
This clinical trial was supported by a grant from Fond’Action Contre le Cancer to ER and SL. We appreciate the support and assistance of the CHUV physicians, nurses, and staff of the Medical Oncology Service, the Clinical Investigation Unit, and the Blood Bank Donor Room in obtaining patient samples. We also thank the clinical trial participants and healthy volunteers, who provided samples for research.
PY - 2014/4/12
Y1 - 2014/4/12
N2 - Background: Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.Methods: We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.Results: After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7- CD45RA+/-) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1-CD160-TIM3-LAG3-2B4+/-). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.
AB - Background: Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.Methods: We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.Results: After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7- CD45RA+/-) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1-CD160-TIM3-LAG3-2B4+/-). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.
KW - Adjuvant
KW - Adoptive cell therapy
KW - Immunization
KW - Immunogenicity
KW - Immunotherapy
KW - LAG-3Ig
KW - Melanoma
KW - Tumor-specific CD8 T cells
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U2 - 10.1186/1479-5876-12-97
DO - 10.1186/1479-5876-12-97
M3 - Article
C2 - 24726012
AN - SCOPUS:84899083535
SN - 1479-5876
VL - 12
JO - Journal of Translational Medicine
JF - Journal of Translational Medicine
IS - 1
M1 - 97
ER -
