Platinum-based therapy (PL) remains the standard of care in MPM, despite encouraging emerging data from immunotherapy (IO) trials. Recently, prognostic MPM clusters with potential implications for targeted-treatments were identified by multiplatform profiling but we are still far from translating these data in therapeutic opportunities for pts. In this scenario, we are leading an international multicenter projecton new biomarkers in MPM.
We used preclinical models to compare PL-naïve and PL-resistant MPM. Protein expression of biomarkers of interest from cells were analyzed by FACS and Western blot at Università degli Studi della Campania Luigi Vanvitelli (Naples, IT). Further, specimens of MPM pts treated with PL and IO will be used for an IHC-based pivotal analysis on known and emerging biomarkers as BAP1, AURKA and CDKN2A. VISTA and PD-L1 will be also analyzed and correlated to other results.
In PL-resistant MPM H2452 cells, generated treating parental cell line with PL dose-escalation, FACS analysis revealed an increased PD-L1 expression (1% in PL-naïve vs 39.1% in PL-resistant). Western blot protein expression analysis confirmed this result, suggesting a PL-driven increased IO-sensitivity, independent from response, as shown in other cancer types. Sixty-two MPM pts treated at Hospital Clínico Universitario de Valencia (Valencia, ES) from 2001 to 2020 were selected for the translational part of the project so far. Mean age was 67.5 years (36-89), 90% (n=56) of pts were male, 80% (n=50) exposed to asbestos and 61% (n=38) ECOG PS<2. The majority (69%, n=43) with epithelioid MPM; 52% (n=33) stage III-IV at diagnosis. Of 58 pts included in the analysis, 4 were exposed to IO and 45 (77%) to PL. 62% (n=28) PL-sensitive and 38% (n=17) PL-resistant. IHC analysis on tissue specimens is ongoing.
Our preliminary results confirmed the activation of PD-L1 by PL, also in resistant setting, showing a biological rationale for IO in these pts. Ongoing analysis will validate on a proteomic level other proposed biomarkers as BAP1, AURKA, CDKN2A and VISTA, to build a cost-effective IHC-based MPM classification, useful for future targeted-treatment strategies.
The authors.
Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.
F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Servier; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: Lilly; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ipsen. F. Morgillo: Advisory/Consultancy: MSD; Advisory/Consultancy: Lilly; Research grant/Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.