Novel immunotherapy investigation and characterization of immune escape mechanisms to Natural Killer cells in Multiple Myeloma

Description

Despite the significant improvement in multiple myeloma (MM) survival owing to novel treatments, 15-20% of MM patients experience relapse or a refractory disease, thus novel therapeutic options are needed. Natural killer (NK) cells an emerging promising option, especially in patients resistant to T-cell based immunotherapies. However, our recently published data on cell lines show that MM is relatively resistant to NK cell attack and fails to elicit a strong NK cell activation, posing a major question about the feasibility of translating NK cells as an effective therapy in MM. As the proposed model didn’t encompass all the clinical cytogenetic risk categories found in patients and didn’t include other cellular components of the microenvironment, in this project I propose to explore those aspects, to have a better understanding of the patterns of NK cell activation to primary MM and identify other mechanisms of immune evasion or markers of response to adoptive NK cell therapies. The next step towards applied adoptive treatment will be arming the NK cells with a chimeric antigen receptor (CAR) against a MM-expressed antigen (BCMA), to overcome the MM intrinsic resistance to NK cells, and even allow activity against those tumors that escaped the current novel T-cell immunotherapies. I thus propose to evaluate CAR-NK efficacy and transcriptional phenotype upon engaging MM cells in vitro and ex vivo. Finally, building on our CRISPR data pointing at the druggable core-fucosylation pathway as one of the mechanisms of NK cell evasion in MM, l will conduct extensive studies to validate this observation on a wide range of cell lines with diverse cytogenetic backgrounds. I will also study the transcriptomic response of NK cells to FUT8 deficient cells to identify possible underlying mechanisms. Subsequently, I will seek to identify core-fucosylated candidate surface proteins that are relevant to the MM escape to NK cell engagement, using cutting edge high-throughput glycoproteomic analyses. This study will be a resource for advancement of NK cell response prediction and rational application in MM, will generate a proof of concept for CAR-NK products to inform clinical trials, and improve the understanding of the role of core-fucosylation in the complex dialogue between MM and NK cells. This could lead to potentially uncover novel immune checkpoints or resistance pathways to target and inspire the development of similar strategies in other blood cancers.