1457 Phase IB study of immunotherapy combining ex-vivo pre-activated and expanded cord blood NK cells with cetuximab in colorectal cancer patients with minimal residual disease: an interim report
Year: 2024
Type: conference-abstract
Abstract: Background Colorectal cancer (CRC) ranks as the second most prevalent cancer type. Despite successful initial treatment, patients frequently experience relapse, potentially due to undetected micro-metastatic lesions. The advent of tumor-informed ctDNA testing has enabled the identification of these patients before radiographic evidence emerges, leading to the concept of minimal residual disease (MRD). No standard treatment options are available for CRC MRD patients. We designed a Phase IB trial evaluating the combination of in vitro pre-activated and expanded cord blood natural killer (pre-A+E CBNK) cells with cetuximab. We hypothesize that CAR-like efficacy can be achieved without genetic modification by pre-activating NK cells with inflammatory cytokines and utilizing antibodies to direct NK cell specificity and enhance antibody-dependent cellular cytotoxicity. The highly immunosuppressive CRC tumor microenvironment remains underexplored, and novel NK-cell therapies may offer significant potential for MRD clearance. Methods 15 CRC-MRD patients completed the treatment protocol. Each patient underwent lymphodepletion treatment prior to receiving up to 1x10^8/kg of pre-A+E CBNK CBNK cells. Patients were monitored inpatient for 24 hours for infusion-related reactions and subsequently followed for toxicity in the outpatient clinic twice weekly for four weeks (DLT window). Correlative analysis samples were collected at various time points. Results Of the 15 patients enrolled, 8 were female and 7 were male, aged 26–69. All patients presented with no measurable radiographic disease but had positive ctDNA Signatera tests at baseline. 11 patients had a history of metastatic disease, including liver (7), lymph nodal (2), and peritoneal (2) metastases. All patients had previously received 5-FU-based chemotherapy. Genotypically, 7 were RAS/RAF wild-type, 4 were KRAS mutated, 1 had a BRAF mutation, and 1 had HER2 amplification. All patients were pMMR (table 1). No dose-limiting toxicities (DLTs) were observed; however, one patient experienced Grade 2 cytokine release syndrome (CRS) (table 2), managed with tocilizumab. 7/15 patients achieved ctDNA clearance at some point during the study. Specifically, 1 patient had negative ctDNA at 3 and 6 months, 3 patients were ctDNA-negative at day 28, and 6 at day 14 (two have yet to reach the next time point) (table 3). 10/12 patients analyzed up to the primary endpoint demonstrated decreased ctDNA levels compared to baseline. CBNK cells in the bloodstream peaked three hours post-infusion and remained detectable for three days. Ongoing analyses include phenotyping of pre- and post-infusion CBNK cells, donor NK cells, and other immune cell types. Conclusions The combination of cetuximab with pre-A+E CBNK cells is safe and demonstrates promising efficacy for treating MRD in CRC.
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4404068205