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Phase I Study of Autologous CD8+ and CD4+ Engineered T Cell Receptor T Cells in Subjects With Advanced or Metastatic Solid Tumor

ABSTRACT: This study is open to adult patients with solid tumors who have a KRAS G12V mutation. This mutation is often found in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and other cancers. The study is for patients whose cancer has spread through the body and for whom previous treatments were not successful or treatment does not exist. Patients need to be positive for HLA-A*11:01. The purpose of this study is to find the best dose of AFNT 211 that is safe and can shrink tumors in patients. AFNT-211 is an investigational therapy and this is the first time that AFNT-211 is administered to patients. AFNT-211 is an autologous T cell product which means that it is made from a patient’s own T cells. These cells are engineered and grown to recognize the KRAS G12V protein on the cell surface of cancer cells. AFNT-211 is infused into patients after a short course of chemotherapy. Patients will frequently visit the study site. The doctors there will regularly check the size of the cancer and the patient’s health. They will also take note of any unwanted effects. Patients may continue in this study for as long as they benefit from the treatment.

DISEASE(S): Adenocarcinoma,Solid Tumor,Nsclc,Kras G12v,Non-small Cell Lung Cancer,Colorectal Cancer,Pancreatic Ductal Adenocarcinoma

PROVIDER: 115042 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:This study aims to elucidate the cellular mechanisms underlying the secretion of factor B (CFB), recognized for its dual role as an early biomarker of pancreatic ductal adenocarcinoma (PDAC) and as the initiating substrate for the alternative complement pathway (ACP), a crucial component of the innate immune system. Employing parallel reaction monitoring analysis, we substantiated CFB's consistent ~2-fold elevated expression in PDAC patients compared to both healthy donors (HD) and chronic pancreatitis (CP) patients, thereby affirming its status as a cancer biomarker, as previously established through ELISA methods. In contrast to CFB expression, we observed heightened ACP activity in the patients of CP and other benign cancer compared to both HD and PDAC patients, prompting further exploration of a potential functional link between ACP and PDAC. To investigate the cellular secretion mechanism of CFB, we conducted protein-protein interaction analyses involving key complement proteins and their regulatory factors within the ACP cascade. These analyses encompassed blood samples from PDAC patients spanning various disease stages, alongside cancer cell lines. Our findings unveiled an intricate control system governing the ACP and its regulatory factors, including KRAS mutation, adrenomedullin (AM), and factor H (CFH). Notably, AM emerged as a pivotal player in CFB secretion, activating CFH and thereby promoting its predominant binding to C3b over CFB. Mechanistically, our data propose that KRAS mutation stimulates AM expression, subsequently enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction evidently conferred a greater affinity for C3b over CFB, potentially leading to suppression of the ACP cascade. This sequence of events likely culminated in the release of ductal CFB into plasma during the early stages of PDAC. Thus, our findings illuminate an intriguing trade-off between suppressed ACP activity and the early detection of PDAC.

Dataset Information

Phase I Study of Autologous CD8+ and CD4+ Engineered T Cell Receptor T Cells in Subjects With Advanced or Metastatic Solid Tumor

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