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H - Clinical Translation of Gene and Cell Therapies -> Cell Therapy Product Engineering, Development and Manufacturing

751: Pre-Clinical Development of CT-1119, a Mesothelin-Targeting Chimeric Antigen Receptor Macrophage

Type: Poster Session

Poster Board Number: 751
Presentation Details
Session Title: Wednesday Poster Session
Start Time: 5/17/2023 12:00
End Time: 5/17/2023 14:00

The immunosuppressive characteristics of the tumor microenvironment (TME) include the exclusion of T cells from the tumor and the surrounding stroma. Myeloid cells such as monocytes and macrophages, however, are actively recruited to the TME. Chimeric antigen macrophages (CAR-M) infiltrate the TME and exert targeted effector function, including phagocytosing tumor cells, activating the TME, and priming a broad anti-tumor adaptive immune response via T cell recruitment and antigen presentation. Previously, we developed CT-0508, a HER2-targeted CAR-M, which showed efficacy in a variety of pre-clinical models and is currently in a Phase I clinical trial for patients with HER2+ solid tumors. Mesothelin is a tumor associated antigen which is overexpressed in a wide variety of solid tumors, including lung, pancreatic, and ovarian cancers. CT-1119 was generated using the chimeric adenoviral vector Ad5f35 to express a CAR containing a fully human scFv targeting an epitope on the tumor associated antigen mesothelin. We evaluated its activity using both in vitro cell-based assays and in vivo xenograft tumor models. CT-1119 was highly viable with durable expression of the CAR. Importantly, the Ad5f35 vector yielded macrophages which were M1 (pro-inflammatory) polarized and resistant to re-polarization by M2 (pro-tumor) cytokines. Exposure to antigen amplified this effect with further down-regulation of M2 markers following stimulation. CT-1119 phagocytosed the A549 lung adenocarcinoma and MES-OV ovarian cystadenocarcinoma cell lines in an antigen-dependent manner and killed these cell lines in vitro in an antigen dependent manner. Engagement of the CAR yielded the release of pro-inflammatory cytokines such as TNFα in a dose-dependent manner in both cell-free and cell-based assays. CT-1119 significantly reduced tumor burden as measured by bioluminescent imaging in a murine xenograft model of lung cancer. In addition, Ad5f35 was utilized to generate functional anti-mesothelin CAR monocytes in a rapid single day process, yielding a population of myeloid progenitors restricted to M1-macrophage differentiation. In summary, these results show that the autologous human anti-mesothelin CAR-M are a targeted cell therapy capable of inducing a multi-modal anti-tumor mechanism of action.

Nicholas R. Anderson, Brinda Shah, Alison Worth, Rashid Gabbasov, Brett Menchel, Kerri Ciccaglione, Daniel Blumenthal, Stefano Pierini, Sabrina Ceeraz DeLong, Sascha Abramson, Thomas Condamine, Michael Klichinsky

Carisma Therapeutics, Philadelphia, PA
  N.R. Anderson: 1; Commercial Interest i.e. Company X; Carisma Therapeutics. 1; What was received? i.e. Honorarium; Salary/stock options. 1; For what role? i.e. Speaker; Employment.

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