ASH 2024 | Combining JAK inhibition and immune checkpoint blockade for the treatment of 9p amplified lymphomas

I’m very excited that we will have an oral presentation here at ASH with my mentee, Sadaa Tolu, who will be presenting her work and our work in the laboratory combining JAK inhibition with immune checkpoint blockade with pembrolizumab. This work started from the recognition that in 9P-amplified lymphomas, we see both increased expression of PD-L1 expression on tumors as well as increased JAK/STAT pathway expression. And the JAK/STAT pathway also activates PD-L1, so it’s sort of like a combined pathway leading to T-cell exhaustion and decreased recognition of tumors. So there’s increased immune evasion by tumors. So Dr Tolu really elegantly evaluated the role of ruxolitinib as a JAK inhibitor in increasing MHC1 and 2 expression and CIITA expression in primary mediastinal B-cell lymphoma and other non-9P-amplified lymphomas and found that this can sort of increase immune activation and recognition in the B-cell compartment. She also found that there was activation of T-cells, increased NK-cell activity, and decreased Treg activity in peripheral blood, healthy peripheral blood, following exposure to ruxolitinib. Dr Tolu then, to better examine how these drugs work in combination to help kill primary mediastinal B-cell lymphoma, which is a 9P-amplified lymphoma, developed an organoid strategy to prime both the peripheral blood with ruxolitinib and pembrolizumab and then combine these in organoids to examine how the T cells could then attack the lymphoma and very elegantly shows that there’s increased apoptosis with the combination of these drugs when T-cells are combined with the primary mediastinal B cell lymphoma and there’s also increased infiltration of T-cells. And then finally, she evaluated very early on in humanized mouse model, the combination of ruxolitinib and pembrolizumab. And we found that the combination is safe and well tolerated. There is decreased tumor growth with the combination compared to either drug alone or the controls. And in fact, we do see increased infiltrating activated CD8 T-cells into the lymphoma tumors of these humanized mouse models. So we’re really excited about this combination. We’ll be opening a clinical trial at Columbia University looking at the combination of ruxolitinib plus pembrolizumab in both 9P-amplified lymphomas as well as JAK/STAT-driven T-cell lymphomas such as mycosis fungoides and PTCL. So please look forward to that clinical trial opening soon.

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