Treating prostate cancer animal models with modified immune cells that were isolated from bone marrow led to a significant reduction in tumor growth, a study in mice reports.
These findings support a novel strategy called adoptive cell therapy, in which a patient’s immune cells are taken, modified (to remove NF-κB p50, a protein important for immune regulation, in this study’s case), and then re-infused to activate the immune system to fight cancer.
The study, “NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma,” was published in the Journal for ImmunoTherapy of Cancer.
Cancers such as melanoma, colon cancer, fibrosarcoma, and glioblastoma have been shown to grow slower in mice that lack NF-κB p50, compared with normal mice.
Further investigations have suggested that myeloid immune cells such as macrophages and dendritic cells that lack this protein are more likely to mount a pro-inflammatory response that attacks cancer cells by activating killer T-cells.
These findings led researchers at the Johns Hopkins University School of Medicine, in Baltimore, to wonder if treating mice with their own isolated immune cells — then modified to remove NF-κB p50 — would protect those with prostate cancer tumors.
“Building on these mouse studies, this approach may offer a unique method to activate patient immune systems, including T cells, against cancer,” Alan Friedman, MD, study co-author and professor at the Johns Hopkins Kimmel Cancer Center, said in a press release.
The team first confirmed that tumors initiated by the injection of prostate cancer cells into mice without NF-κB p50 were three to 16 times smaller compared to those in normal mice with NF-κB p50.
Immature macrophages and dendritic cell precursors were then isolated from the bone marrow of these NF-κB p50-deficient mice. Previous studies have confirmed that immature cells, called immature myeloid cells (IMC), increased the likelihood of an anti-tumor response.
These cells were then injected in mice with prostate cancer following treatment with 5-fluorouracil (5FU), a common anti-cancer medication known to reduce the number of normal myeloid blood cells, reducing competition with injected cells. As controls, additional groups of mice received 5FU alone, IMCs from p50-deficient mice alone, normal IMCs plus 5FU, or neither.
After 19 to 35 days, tumor size in the mice treated with both chemo and IMC p50-deficient cells was three to 10 times smaller than tumors seen in controls receiving the normal myeloid cells plus chemo or chemo alone.
Notably, mice receiving this combo had a significant increase in a particular type of immune cell known as CD8+ T-cells — also known as cytotoxic T-cells or killer T-cells. As the name suggests, these cells target and kill damaged cells such as cancer cells or those infected with viruses.
A final experiment showed that depleting CD8+ T-cells using anti-CD8 antibodies eliminated the effectiveness of the cell transfer, demonstrating that killer T-cell activation was needed to decrease tumor growth.
Similar results were reported in a pancreatic cancer mouse model that showed 5FU and p50-negative IMC triggered cancer regression and up to a 10-fold reduction in tumor size.
“5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+ T cell activation,” the scientists wrote.
“Deletion of p50 in patient-derived marrow CD34+ cells [immature human immune cells] and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers,” they said.
To illustrate the promise of cancer treatments that focus on NF-κB p50, Friedman added, “Seven different cancers — prostate cancer, pancreatic cancer, brain cancer, melanoma, colon cancer, sarcoma and neuroblastoma — tested by us and others grew slower in mice lacking NF-κB p50.”