Abstract B015: A non-genetic engineering platform for rapidly generating and expanding cancer-specific armed T cells

Abstract

Abstract Genetically engineered T cell technology, especially the chimeric antigen receptor (CAR) T cell, has successfully treated hematological tumors in clinical practice. However, the gene transfer technology used in current CAR-T cells is still mainly based on lentivirus systems, which poses a potential carcinogenic risk. Additionally, the laborious protocols for manufacturing and quality control of CAR-T cell products take over 20 days and delay treating patients. Our team presents a non-genetic engineering technology for rapidly manufacturing cancer-specific T cells. Using an anti-cancer/anti-CD3 bispecific antibody (BsAb) with a high-affinity CD3-binding arm to culture patients’ peripheral blood mononuclear cells (PBMCs), a large amount of cancer-specific BsAb-armed T cells can be rapidly generated with a purity of over 90% in 7 days. The BsAb-armed T cells efficiently accumulated at tumor sites in vitro and in vivo. The release of cytotoxins (perforin and granzyme) and cytokines (TNF-α and IFN-γ) from the BsAb-armed T cells dramatically increased after they contacted cancer cells, resulting in a remarkable anti-cancer efficacy. Preclinical animal studies have shown that the BsAb-armed T cells can effectively treat blood cancers, various solid tumors, and malignant metastatic tumors without severe cellular cytokine release syndrome (CRS) and tissue toxicity. Our first candidate (anti-EGFR/anti-CD3 BsAb armed T cell product) is ready to initiate an investigator-initiated clinical trial in EGFR expressed Kras, Braf, and Nras mutations in end-stage untreatable metastatic colorectal cancer. The technical schematic and representative results of the BsAb-armed T cell technology present in this linked video: https://youtu.be/TlDos-vPg3o According to the results mentioned above, we conclude that the BsAb-armed T cell technology has the following essential advantages: 1. The BsAb armed T cell technology is a non-viral method for rapidly producing cancer-specific T cells with more than 90% purity. 2. Easily controlling the surface amounts of BsAb on T cells allows us to generate customized BsAb-armed T cells with higher therapeutic efficacy and lower CRS risk for individual patients 3. The T cells armed with 10% to 100% of the maximum BsAb loading amount exhibited similar tumor-killing ability. 4. During the T cell culturing process, the BsAbs could bind directly to the surfaces of ex vivo amplified effector T cells but not pro-inflammatory Th17 or immunosuppressive Treg cells, which were able to provide the cancer-targeting ability for these effector T cells. 5. This strategy provides flexibility to choose the appropriate cancer target by simply changing the anti-cancer portion of BsAbs. The BsAb-armed T cell technology, as compared to current genetically engineered T cell technology, represents a simple, time-saving, highly safe, and cost-effective method to generate highly pure cancer-specific effector T cells, thereby providing a better T cell immunotherapy to patients. Citation Format: Kuo-Hsiang Chuang. A non-genetic engineering platform for rapidly generating and expanding cancer-specific armed T cells [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B015.