Abstract PO2-04-08: Translational insights from a phase 1, first-in-human (FIH) clinical trial of the anti-HER2 CAR macrophage CT-0508 in participants with HER2 positive metastatic breast cancer and other HER2 overexpressing solid tumors
Authors: Abdou Yara , Mortimer Joanne , Pohlmann Paula , Johnson Melissa , Maziarz Richard , Specht Jennifer M. , Dees Claire , Ueno Naoto , Yuan Yuan , Angelos Mathew , Gill Saar , Shestova Olga , Serody Jonathon , Priceman Saul , Qureshi Rehman , Sonawane Poonam , Pierini Stefano , Oliveira-Nunes Maria Cecilia , Cushing Daniel , Klichinsky Michael , Condamine Thomas , Swaby Ramona , Reiss Kim 
Published: May 2024

Abstract
Background: In pre-clinical studies, CAR macrophages (CAR-M) phagocytose tumor cells, activate the tumor microenvironment (TME), recruit T cells, and induce anti-tumor T cell immunity. CT-0508 is a first-in-class CAR-M product comprised of autologous monocyte-derived macrophages expressing an anti-HER2 CAR. In pre-clinical models, anti-HER2 CAR-M was able to control the growth of syngeneic metastatic HER2+ breast cancer. Here we present preliminary clinical results and translational data from Group 1 of the CT-0508 Phase 1 FIH study.
Methods: This multi-center, open-label study is evaluating CT-0508’s safety, tolerability, and manufacturing feasibility in 18 participants with advanced solid tumors overexpressing HER2 with progression on prior therapies. Monocytes are isolated from mobilized apheresis products, differentiated into macrophages, and engineered with an anti-HER2 CAR. Group 1 participants (n = 9) receive a fractionated dose on days 1, 3, 5 and Group 2 participants (n = 9) receive the full dose on day 1. CT-0508 is administered without preparative chemotherapy. Serial blood samples and biopsies (baseline and 2 post-treatment) are collected to investigate safety, pharmacokinetics, and mechanism of action. AU565 and 4T1-HER2 cell lines were utilized to model human and murine breast cancer, respectively, in vitro and in vivo.
Results: Nine participants (6F/3M) have been treated in Group 1, comprising breast (4), esophageal (2), cholangiocarcinoma, ovarian, and parotid gland cancers, with a median age of 58. Participants had received a median of 3 (range, 2-11) prior lines of therapy; 8 had received prior anti-HER2 therapy. CT-0508 was successfully manufactured and well tolerated with no dose-limiting toxicities. Three related SAEs occurred in 2 participants: grade 1 CRS with hospitalization for monitoring and grade 2 infusion reaction that resolved within 1 hour were reported in one participant. Grade 2 CRS with fever and hypoxia occurred in another participant and resolved within ~ 72 hours. Five additional participants experienced Grade 1-2 CRS and/or infusion reactions with rapid resolution. There were no cases of Grade 3 or 4 CRS. There were no major organ toxicities. Post-infusion cytokines were transiently elevated in most participants enrolled in group 1 and were self-limiting. Four of the 7 participants evaluated had stable disease. CT-0508 was transiently detectable in the blood and was detected in the TME of 8/9 participants. CT-0508 modulated the TME, leading to myeloid cell activation, effector T cell infiltration, activation, and proliferation. TCR sequencing demonstrated newly expanding T cell clones in the blood post-treatment that accumulated within the TME, suggesting expansion of tumor-reactive T cells upon CT-0508 infusion. Data from participants enrolled in Group 1 will be presented. Most of these patients were breast cancer patients with HER2 overexpressing metastatic disease.
Conclusions: CT-0508 was feasible to manufacture and had acceptable safety and tolerability. Early correlative data demonstrate trafficking, TME modulation, and induction of anti-tumor T cell immunity in participants with HER2 overexpressing solid tumors including metastatic breast cancer. The study is actively enrolling (NCT04660929).
Citation Format: Yara Abdou, Joanne Mortimer, Paula Pohlmann, Melissa Johnson, Richard Maziarz, Jennifer M. Specht, Claire Dees, Naoto Ueno, Yuan Yuan, Mathew Angelos, Saar Gill, Olga Shestova, Jonathon Serody, Saul Priceman, Rehman Qureshi, Poonam Sonawane, Stefano Pierini, Maria Cecilia Oliveira-Nunes, Daniel Cushing, Michael Klichinsky, Thomas Condamine, Ramona Swaby, Kim Reiss. Translational insights from a phase 1, first-in-human (FIH) clinical trial of the anti-HER2 CAR macrophage CT-0508 in participants with HER2 positive metastatic breast cancer and other HER2 overexpressing solid tumors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-08.