MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial

Journal of Translational Medicine

Alexandre Harari⁵  Serge Leyvraz²  Frédéric Triebel¹  Daniel E Speiser⁴  Pedro Romero⁴  Athina Stravodimou⁶  Hélène Bichat²  Julien Laurent³  Verena Voelter⁶  Olivier Michielin⁴  Emanuela Romano⁴ 

[1] Immutep, SA, Orsay, France;Laboratory of tumor immunobiology, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland;Current address: Merck-Serono, Darmstadt, Germany;Ludwig Center for Cancer Research at the University of Lausanne, Lausanne, Switzerland;Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland;Department of Oncology, Service of Medical Oncology, CHUV BH-06 1011 Lausanne, Switzerland

关键词: Adoptive cell therapy;    Tumor-specific CD8 T cells;    LAG-3Ig;    Immunogenicity;    Adjuvant;    Immunization;    Immunotherapy;    Melanoma;   

Others  :  815046
DOI  :  10.1186/1479-5876-12-97

 received in 2013-12-17, accepted in 2014-03-31,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Romano et al.; licensee BioMed Central Ltd.

【 图 表 】

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