Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 1010 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 1010 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 1010 BATs/infusion over 4 weeks for a total of 8 x 1010 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3rd infusion, and IFN-γ EliSpots increased from < 20 to 1000 IFN-γ EliSpots/106 PBMC (p < 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/106 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p < 0.04). Levels of IP-10 increased significantly (p < 0.04), and levels of IL-8 decreased but not significantly (p < 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.