Immunomodulatory AVM0703 enhances R-CHOP anti-lymphoma effect with reduced toxicity: Immune-resistant, aggressive A20 lymphoma model.

Abstract

e14583 Background: Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (RCHOP) is the standard of care for most aggressive B-cell lymphomas. RCHOP requires numerous treatment cycles, typically 6, with challenging side effects, including toxicity and long-term secondary malignancies. Trials have demonstrated that 4 cycles of RCHOP was non-inferior to 6 with similar secondary malignancies, however, real world experience has demonstrated that long term outcomes are superior when patients achieve minimal residual disease negative (MRD-) status after the 3rd cycle (1,2). Addition of a novel agent to RCHOP that could reduce the number of cycles to 3 while maintaining response, could overcome the long-term side-effects and allow frail and elderly patients to receive full dose RCHOP in each cycle to improve outcomes. For example, addition of Lenalidomide with RCHOP improved outcomes in ABC-DLBCL patients (3), but leads to therapy related myeloid neoplasm in recent studies (4). AVM0703, an immunomodulatory drug, mobilizes bispecific and i-TCR double-positive NKT cells (AVM_NKT). In the aggressive, immune resistant A20 mouse lymphoma model, neoadjuvant AVM0703 was additive/synergistic, when cyclophosphamide/fludarabine (CyFlu) was dosed 3 + 24 hours later, with no additional toxicities. Therefore, we hypothesized that combining AVM0703 with RCHOP would be an effective and well tolerated treatment of DLBCL. Methods: Tumor-bearing mice were made by sc flank injection of 2x106 murine A20 B-cells in 10-week-old Balb/c mice. When tumor size reached established ~100 mm3, 48 mice (1:1 male: female) were randomized (12 mice each cohort) 1) Placebo 2) 1 cycle RCHOP 3) AVM0703 (18mg/kg HED) 4) AVM0703+1 cycle RCHOP combination treated as described previously (5,6). When Placebo tumors reached ~ 2000 mm3, all mice were sacrificed and tumors, blood, spleen, bone marrow were analyzed for the presence of remnant A20, and immune cell state by flow cytometer. Results: One RCHOP only mouse died from the chemo. There were no deaths in AVM0703+RCHOP group. Tumor remnant live A20 were significantly reduced in all 3 treatment groups compared to Placebo. Interestingly, AVM0703+RCHOP significantly increased the number of MRD- A20 tumors compared to RCHOP alone. Conclusions: Based on this study we plan to determine whether 3 cycles of AVM0703+RCHOP can induce long term CR and if AVM0703 could replace R and reduce long term side effects. 1) Poeschel Lancet 2019. 2) Spurgeon J Natl Canc Inst 2016. 3) Nowakowski JCO 2021. 4) Sperling Blood 2022. 5) Bascuas J Transl Med 2016. 6) Bongard PLoS Pathog 2019. [Table: see text]