IMMU-18. IL-7 MEDIATED UPREGULATION OF VLA-4 INCREASES ACCUMULATION OF ADOPTIVELY TRANSFERRED T LYMPHOCYTES IN MURINE GLIOMA

We have previously described the development of a novel brain bi-specific T cell engager (BRiTE) targeting EGFRvIII in Glioma. Despite BRiTEs impressive potency, efficacy in solid tumors is dependent on tumor-infiltrating lymphocytes (TILs). We evaluated if peripheral adoptive lymphocyte transfer (ALT) increases TILs in immunocompetent mice, even during glioma-induced sequestration. C57/Bl6 mice were implanted with 3 x 10^4 cells syngeneic glioma (CT-2AvIII) and treated with 1 x 10^7 IV CD45.1+ ALT on Day 15. The brain was divided into tumor and non-tumor bearing hemispheres and analyzed each day for exogenous (CD45.1+) CD3/4/8 counts. We observed that IL-7-expanded ALT accumulated at a higher rate within tumor versus IL-2 ALT (72-hours IL-7 median 26.66x vs IL-2 median 4.291x, p=0.0159*). Exogenous T cell entry into tumor-bearing CNS overwhelmingly consisted of CD8+ T cells, and CD45.1+ IL-7 ALT cells made up ~20% of the CD3+ population in tumor 72-hours following administration (mean 19.4%, SD ±4.53%, n=5). Survival experiments used combination ALT and anti-4-1BB therapy in the same model. Mice were treated with IV ALT on Day 5, along with 200µg of IP anti-4-1BB. IP mAb Injections were given every 3 days for 4 total cycles (D5, D8, D11 & D14). Evaluation at these time points was selected as this correlated with peak sequestration of immune cells as evidenced by splenic involution. For survival studies, only combination ALT and anti-4-1BB produced significantly increased survival benefit in our CT-2AvIII model compared to ALT alone (median survival 45.5 days for combination versus 25 days in ALT only group, p=0.0134, chi-square test). These findings demonstrate the feasibility of combination ALT/antibody-based therapy in pre-clinical glioma, as well as outlining a novel approach for delivering both immune cells and antibody-based immunotherapy. Combination therapy with BRiTE and ALT will be explored in an upcoming clinical trial (NCT04903795).

Duke Scholars

Author Mustafa Khasraw Neurosurgery

Author Beth H. Shaz Pathology