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Dose Escalation and Dose Expansion Phase I Study to Assess the Safety and Clinical Activity of Multiple Doses of NKR-2 Administered Concurrently With FOLFOX in Colorectal Cancer With Potentially Resectable Liver Metastases

ABSTRACT: SHRINK (Standard cHemotherapy Regimen and Immunotherapy with NKR-2) is an open-label Phase I study to assess the safety and clinical activity of multiple administrations of autologous NKR-2 cells administered concurrently with a standard chemotherapy treatment (FOLFOX) in potentially resectable liver metastases from colorectal cancer. The trial will test three dose levels. At each dose, the patients will receive three successive administrations, two weeks apart, NKR-2 cells. The study will enroll up to 36 patients (dose escalation and expansion phases).

DISEASE(S): Neoplasm Metastasis,Colon Cancer Liver Metastasis,Liver Neoplasms

PROVIDER: 2256420 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:More than 70 million people worldwide are still infected with the hepatitis C virus 30 years after its discovery, underscoring the need for a vaccine. To develop an effective prophylactic vaccine, detailed knowledge of the correlates of protection and an immunocompetent surrogate model are needed. In this study, we describe the minimum dose required for robust equine hepacivirus (EqHV) infection in equids and examined how this relates to duration of infection, seroconversion, and transcriptomic responses. To investigate mechanisms of hepaciviral persistence, immune response, and immune- mediated pathology, we inoculated eight EqHV naive horses with doses ranging from 1 to 2 to 1.3 106 RNA copies per inoculation. We characterized infection kinetics, pathology, and transcriptomic responses via new generation sequencing. The minimal infec- tious dose of EqHV in horses was estimated at 13 RNA copies, whereas 6 to 7 copies were insufficient to cause infection. Peak viremia did not correlate with infectious dose, while seroconversion and duration of infection appeared to be affected. Notably, sero- conversion was undetectable in the low-dose infections within the surveillance period (40 to 50 days). In addition, transcriptomic analysis revealed a nearly dose dependent effect, with greater immune activation and inflammatory response observed in high-dose infections than in low-dose infections. Interestingly, inoculation with 6 to 7 copies of RNA that did not result in productive infection was associated with a strong immune response, similar to that observed in the high-dose infections. IMPORTANCE We demonstrated that the EqHV dose of infection plays an important role for inducing immune responses, possibly linked to early clearance in high-dose and prolonged viremia in low-dose infections. In particular, pathways associated with innate and adaptive immune responses, as well as inflammatory responses, were more strongly upregulated in high-dose infections than in lower doses. Hence, inoculation with low doses may enable EqHV to evade strong immune responses in the early phase and therefore promote robust, long-lasting infection.

Dataset Information

Dose Escalation and Dose Expansion Phase I Study to Assess the Safety and Clinical Activity of Multiple Doses of NKR-2 Administered Concurrently With FOLFOX in Colorectal Cancer With Potentially Resectable Liver Metastases

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