Immunomodulatory AVM0703 lacks the association between anti-cancer activity and immune-mediated side-effects of the checkpoint Inhibitors.
Authors: Mittal Sandeep , Deisher Theresa , Sawas Spencer , Patterson Elizabeth , Michiels McKenzie , Nakamura Evan , Jarzyna Peter , Wasserfall Clive , McGrail Sean 
Published: June 2023

e14585

Background: Immune checkpoint inhibitors are approved to treat a variety of solid tumors and Hodgkin’s Lymphoma. However, they have not been shown to be effective against Non-Hodgkin’s Lymphoma (NHL). Unfortunately, their use is associated with induction of autoimmune reactions, termed immune mediated side-effects (irAEs) (1-3). AVM0703 is an immunomodulatory drug which mobilizes bispecific gd and invariant TCR double-positive NKT-like cells (AVM_NKT), currently enrolling a Phase 2 clinical trial to treat R/R NHL of all subtypes based on strong activity against the aggressive, immune-resistant mouse A20 lymphoma. Unlike the checkpoint inhibitors which trigger irAEs, gdTCR expression of the AVM0703 mobilized AVM_NKT, suggests that AVM0703 should not trigger irAEs, and in fact might be a treatment for autoimmune diseases such as type 1 diabetes (T1D). As monotherapy in the A20 lymphoma model, AVM0703 completely eradicates ~20% of flank tumors, and used as a neoadjuvant prior to cyclophosphamide/fludarabine (CyFlu) it provided additive/synergistic A20 killing. As a single dosed monotherapy, AVM0703 prevented T1D onset in the gold standard NOD model. Reversal of already established T1D has proven difficult, and monotherapy approaches abandoned for lack of efficacy. Based on its activity in combination with CyFlu, and since teplizumab anti-CD3 has been approved to prevent progression to grade 3 T1D in at risk people (4), we investigated the combination with AVM0703 to reverse recent onset T1D in the NOD mouse. Methods: One hundred twenty hyperglycemic non-obese diabetic (NOD) mice were randomized to receive an insulin pellet followed by 1) Oral Placebo (18 mg/kg HED) 2) 5 µg anti-CD3 (for 5 days) i.p. 2) Oral AVM0703 (18 mg/kg HED) – weekly/biweekly/tri-weekly 3) AVM0703 (18 mg/kg HED) followed by 5 µg anti-CD3 (for 5 days) and then AVM0703 – weekly/bi-weekly/tri-weekly. Mice were monitored for body weight, body condition and hyperglycemia. Results: Timing between 18 mg/kg AVM0703 and 5 ug anti-CD3 dosing was taken from lymphoma studies that demonstrated that chemotherapy 3 and 24 hours after AVM0703 dosing maximally eradicated lymphoma. The combinations of AVM0703 (day 1) and anti-CD3 (day 2-6) were able to reverse diabetes in 26 mice for 0-9 weeks, with six mice in ongoing normoglycemia at the time of this report. The combination group that received weekly AVM0703 dosing was more effective than the bi-weekly or tri-weekly AVM0703 groups. Monotherapy with AVM0703 did not reverse diabetes, in contrast to its profound ability to prevent or delay diabetes onset in the NOD model. Conclusions: We hypothesize that the combination of AVM0703 and anti-CD3 will be more effective when anti-CD3 is added 5 days after AVM0703. 1) Tocut, Autoimmun Rev 2018. 2) Sakowska, Front Immunol 2022. 3) Sherry, Lancet. 2011. 4) Hagopian, Diabetes 2013.