IMP321 and weekly paclitaxel as first-line chemo-immunotherapy in metastatic breast cancer (MBC)


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Frédéric Triebel

Immutep SA, Paris, France

Abstract

IMP321 and weekly paclitaxel as first-line chemo-immunotherapy in metastatic breast cancer (MBC)

Background

IMP321 (hLAG-3Ig), a novel immunomodulator:

1. derived from the natural human protein LAG-3 (CD223), a ligand for MHC class II molecules, in the form of a soluble fusion protein

2. acts indirectly on T cell responses by MHC class II+ APC activation

3- two intended clinical settings:

a) low dose (250 µg) as T-cell adjuvant for therapeutic vaccines

b) high dose (> 6 mg) as monotherapy (i.e. without antigen) combined with standard chemotherapy

4- pharmacokinetics study on patient’s plasma shows systemic exposure to IMP321 for at least 24 hr following s.c. injection of doses above 1 mg

5- more than 500 s.c. injections of IMP321 have been administered since 2005 and the product has a good local and systemic tolerability profile

6- chemo-immunotherapy protocol rationale: boosting the DC network when it is loaded with tumour antigens for the several days following chemotherapy (secondary to tumour cell apoptosis) with repeated s.c. injections of the APC-specific activator IMP321 may increase cytotoxic CD8 T cell responses. Direct and prolonged activation of APC such as blood monocytes/DCs may also occur.

Method

This is an open label fixed dose-escalation phase I study, performed in ambulatory setting in patients receiving, as a first-line chemotherapy for MBC, the standard 6 cycles of weekly paclitaxel (80 mg/m² at D1, D8 and D15 of a 4-week cycle). Three IMP321 doses, 0.25, 1.25 and 6.25 mg given s.c., are being tested, given at D2 and D16 of this 4-week cycle, for 6 courses.

Results

IMP321 was very well tolerated. Sixteen pts have been treated to date (12 injections) with no grade III or IV adverse events related to the product. A three-fold increase in MHC class II+ monocyte blood counts was observed two weeks after the last injection in patients injected with the lowest dose (0.25 mg). In addition, a two-fold increase in activated circulating CD8+ T cells was observed in these pts that mimics in vivo the in vitro effect of IMP321 on human PBMCs.

Conclusion

IMP321 at 0.25 mg in MBC patients treated with first-line chemotherapy was well-tolerated when given s.c. over 6 months and this low IMP321 dose (i.e. for systemic exposure) was already efficacious in some patients at enhancing significantly the number of effector cytotoxic cells in vivo.