One of the ways that cancer grows and spreads is by avoiding the immune system.NK cells are immune cells that kill cancer cells, but are often malfunctioning in people with colorectal cancer and blood cancers. A safe way to give people with colorectal cancer and blood cancers fresh NK cells from a healthy donor has recently been discovered. The purpose of this study is to show that using two medicines (vactosertib and IL-2) with NK cells will be safe and will activate the donor NK cells. NK cells and vactosertib are experimental because they are not approved by the Food and Drug Administration (FDA). IL-2 (Proleukin®) has been approved by the FDA for treating other cancers, but the doses used in this study are lower than the approved doses and it is not approved to treat colorectal cancer or blood cancers.
The goal of our study is to demonstrate that natural killer (NK) cells from non- HLA-matched donors can be safely infused into patients with colorectal cancer, patients with gastric or esophageal cancer, and patients with relapsed/refractory hematologic malignancies in combination with IL-2 and the oral TGFβ receptor I inhibitor vactosertib to improve the persistence of donor NK cells.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Vactosertib is a highly selective, potent inhibitor of the protein serine/threonine kinase activity of transforming growth factor (TGF)-β receptor type 1 (TGFBR1; also known as activin receptor-like kinase 5 \[ALK5\]). Vactosertib inhibits the phosphorylation of the ALK5 substrates Smad2 and Smad3, as well as the intracellular signaling of TGF-β.
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoroara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis.
Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity.
Proleukin® (aldesleukin) has been shown to possess the biological activities of human native interleukin-2. In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of Proleukin, including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production. The in vivo administration of Proleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. In vivo experiments in murine tumor models have shown inhibition of tumor growth
Adoptive NK cell therapy has demonstrated the potential for cancer immunotherapy in various malignancies with particular potential in hematologic malignancies including acute myeloid leukemia (AML), and colon cancer \[14, 19-23\]. This therapeutic approach is extremely well tolerated in patients even when massive numbers of cells are utilized (\~109 NK cells/kg). In fact, studies suggest that high doses of NK cells are not only well tolerated but have potential to lead to higher levels of efficacy.
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
This will be defined as the incidence of Grade ≥ 2 treatment-related adverse events
Time frame: Within 28 days of NK cell infusion
Persistence of donor NK cells
This will be defined as the presence of donor NK cells in recipient blood as determined by next-generation sequencing-chimerism at a frequency of \>10%.
Time frame: 7 days post-treatment
Persistence of donor NK cells
This will be defined as the presence of donor NK cells in recipient blood as determined by next-generation sequencing-chimerism at a frequency of \>10%.
Time frame: 14 days post-treatment
Persistence of donor NK cells
This will be defined as the presence of donor NK cells in recipient blood as determined by next-generation sequencing-chimerism at a frequency of \>10%.
Time frame: 21 days post-treatment
Persistence of donor NK cells
This will be defined as the presence of donor NK cells in recipient blood as determined by next-generation sequencing-chimerism at a frequency of \>10%.
Time frame: 28 days post-treatment
Clinical Response
This will be defined as a change in size of measurable disease on CT scans (colorectal cancer) or by standard methods for hematologic malignancies (e.g. bone marrow biopsy for AML)
Time frame: 28 days post-treatment
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