Next, the researchers demonstrated that exposing the T cells of patients with early RA to Pim kinase inhibitors reduced T cell activation. Pim kinase inhibitors were also effective in a mouse model of RA. Importantly, it didn’t matter if a specific Pim-1 inhibitor or a non-specific, pan-Pim inhibitor was used—both approaches seemed effective. However, pan-Pim inhibition led to increased regulatory T cells. This finding is significant, because previous studies favored Pim-1 as the main driver of cytokine-induced proliferation and inflammation.2
Finally, the researchers demonstrated that a novel flow cytometry approach, PrimeFlow, may identify Pim kinase overexpression in CD4+ T cells just as well as the more complicated gold standard of PCR of purified CD4+ T cells. This method may accelerate Pim kinase research and open the door for precision medicine with Pim kinase inhibitors.
Implications
We need more oral targeted therapies for patients with refractory RA, and Pim kinase inhibition is a promising candidate to achieve that goal. Although IL-6 and Janus kinase (JAK) inhibitors target the same inflammatory pathway, Pim kinases act further downstream. Thus, their inhibition may avoid some of the off-target effects of currently available therapies, such as the increased cardiac, thromboembolic and malignancy risk with tofacitinib suggested by the ORAL Surveillance study.3 At the very least, Pim kinase inhibitors do not interfere with markers of the acute phase response, such as C-reactive protein (CRP).1
Additionally, although it remains to be seen if elevated Pim kinase expression influences the therapeutic efficacy of Pim kinase inhibitors in RA, it’s exciting to think of the possibility of using a blood test to identify patients who may benefit from the flow cytometry techniques detailed in this study.1
This type of precision medicine would certainly be easier than the synovial biopsy strategy used in the R4RA study highlighted in last year’s RheumMadness tournament, and much easier than the machine learning strategy to predict tumor necrosis factor inhibitor (TNFi) response in the Machines Region of this year’s tournament.4,5
Chances in the Tournament
We think Pim Kinase is a heavy favorite to win its first-round matchup with CAR-T cells. Although Pim kinase inhibitors are a newcomer to rheumatology and still early in their development, CAR-T cell therapy is highly labor intensive compared with the promise of oral Pim kinase inhibitors. If the Blue Ribbon Panel recognizes Pim Kinases’ amazing scientific basis and therapeutic potential, this team may make it all the way to the championship. If they do, we hope they face Artificial Intelligence and TNFi Response from the Machines Region because both teams highlight the potential for precision medicine to optimize RA treatment.
