NANOIMMUNO:
IMMUNOMODULATING PROPERTIES OF 3D GENERATION NANOPARTICLES: ASSOCIATION WITH ANTIANGIOGENICS AND ANTI-PDL1 IN HER2+ BREAST CANCER MODELS
P.I.: R. Fanciullino, A. Rodallec
COMPO members involved: J. Ciccolini, G. Sicard
Partners: Industrials: C. Borchier (Institut Roche), S. Nadir (Institut Roche), Institutional: Inserm, CNRS, AMU.
Clinical need:
Immune check point inhibitors are considered as ground-breaking innovations in oncology, limited however to a small subset of patients in a small subset of tumors. Immune desert with lack of infiltrating lymphocytes in the tumor micro-environment, overexpression of Tregs and MDSCs downregulating immune response or limited immunogenicity of cancer cells are common reasons explaining why immunotherapy fails in several settings. As consequence, combinatorial therapy is seen as the future of immunotherapy, because associated treatments, all aim at turning once cold tumors into hot ones. Among the most promising entities likely to harness tumor immunity, nanoparticles display unique and attractive features. Modalities of combinaition remain to be investigated.
Objectives:
To determine whether our nanoparticles (i.e, ANC-1 = immunoliposome encapsulating docetaxel and tagged with anti-Her2 trastuzumab) displays immunomodulating properties in breast cancer models, and to determine the optimal modalities of a future combination between ANC-1, anti-VEGF (bevacizumab) and anti-PDL1 (atezolizumab) in breast cancer.
Data
All data will be generated at our benchtop.
Methodology,
1. ANC-1’s immunomodulating properties on LTCD8, LTCD4, Treg, NK, LB and MDSC will be investigated on immunocompetent mice
2. Development of a pharmacometric models to determine optimal administration of the combination
3. Animal efficacy studies to evaluate the antiproliferative action of the combination and pharmacodynamic endpoints to decipher the mechanisms underlying the synergism between the three drugs and to validate/optimize our model
Funding
Institut Roche (until march 2023) and Genentech.
SMART Project:
Sensitivity-based Multi-ARm Trials (SMART): modelling the synergic combination of radiotherapy & chemotherapy with ICIs in recurrent cancers.
P.I.: F. Barlési, J.Ciccolini,
COMPO members involved: R. Fanciullino, A.Rodallec, G. Sicard
Partners: AMU, APHM, A*MIDEX
Clinical need:
As of today immunecheckpoint inhibitors such as anti-PD1 drugs are used concomitandly to cytotoxics doublet (i.e., pemetrexed + cisplatin combo) and anti-angiogenics in NSCLC cancers. To what extent sequencing these treatments would yield higher anticancer efficacy is yet to be elucidated.
Objectives:
To determine whether the standard concomitant association between the pemetrexed + cisplatin doublet, bevacizumab and pemetrexed used at beside could be outperformed by a sequential association of these drugs on a syngeneic mice model of NSCLC.
Data
All data will be generated at our benchtop.
Methodology,
1. Drugs will be cytotoxics (pemetrexed, CDDP), murine clone of bevacizumab (anti- murine VEGF) and murine clone of pemetrexed (anti-murine PD1).
2. Experiments will be performed in murine NSCLC cells in immunocompetent mice (i.e., BalbC and C57/Bl-6 mice).
3. Different regimen varying in dosing and scheduling will be performed with full immunomonitoring in the spleen, tumor and blood.
4. Semi-mechanistic modeling will be performed to identify the best modality of combination between chemo, anti-angiogenics and anti-PD1.
4. Efficacy studies will test and compare model-informed dosing with standard combiantion.
Funding
A*MIDEX
