Abstract A046: Dynamic changes in peripheral blood immune cells are associated with response to targeted therapies in relapsed/refractory T-cell lymphoma
Gonca Ozcan, Logan Cook, Rahul Lakhotia, Wyndham H. Wilson, Samuel Ng, Christopher Melani, Joseph Rocco, Max J. GordonAbstract
Introduction:
Targeted agents romidepsin and lenalidomide induce direct tumor cell killing in patients with relapsed/refractory T cell lymphoma (r/r TCL). These drugs also activate and expand effector CD8 and NK cells which could contribute to their clinical activity, for example, by enhancing tumor clearance by antibody dependent cellular cytotoxicity (ADCC). We hypothesized that both treatment type and response to targeted agents would be associated with divergent immunologic states in r/r TCL.
Methods:
Peripheral blood samples were prospectively collected from patients with r/r TCL treated on two clinical trials: romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR; Gordon et al Blood Adv 2026) and VIP152, venetoclax, and prednisone (VVIP; Gordon et al BJH 2025). Multi-color flow cytometry was performed for immune profiling at baseline and during treatment.
Results:
15 patients were included. Median age was 61 years (range 28-79). Median prior lines were 3 (range 1-6). Diagnoses included PTCL NOS (47%), AITL (27%), MF (13%), ALCL (7%), and ENKTL (7%). Unsupervised clustering identified 10 immune cell clusters. In the RAdR cohort (n=10, 64 samples), responders (CR/PR, n=6) had higher baseline levels of intermediate cytotoxic NK cells and terminally differentiated effector CD8 T cells, while non-responders (n=4) had higher classical monocytes and immature cytokine-producing NK cells (p<0.05). Baseline activated NKG2D+CD8 T cells (p=0.019), CD38+NK cells (p=0.0095), and NKG2D+NK cells (p=0.0095) were enriched in non-responders. Among RAdR responders, activated CD8 T cells increased following a single agent lenalidomide lead-in (p<0.05). After 3 cycles of RAdR, effector CD8 T cells, intermediate and mature cytotoxic NK cells, monocytes, and cytokine-producing NK cells were increased (all p<0.05). During treatment, activated CD8 T and NK cells decreased in non-responders and increased in responders to RAdR. In contrast, in the VVIP cohort (n=5, 34 samples), there were no significant changes in immune cell clusters in responding patients during treatment.
Conclusions:
Effector CD8 and NK cell populations increased, along with markers of activation, in responding patients treated with RadR, whereas non-responders demonstrated higher baseline activation markers without further expansion. In contrast, no significant immune changes were observed in responding patients treated with VVIP. These preliminary results require further validation. If confirmed, it would be rationale to combine a RAdR like regimen with tumor directed antibodies for the treatment of r/r TCL as the increased activated CD8 and NK cell populations observed with RAdR could synergistically enhance tumor clearance by ADCC with antibodies.
Citation Format:
Gonca Ozcan, Logan Cook, Rahul Lakhotia, Wyndham H. Wilson, Samuel Ng, Christopher Melani, Joseph Rocco, Max J. Gordon. Dynamic changes in peripheral blood immune cells are associated with response to targeted therapies in relapsed/refractory T-cell lymphoma [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A046.