In a study to be published on April 1 in the Journal of Experimental MedicineResearchers at Institut Pasteur and INSERM reveal that chimeric antigen receptor (CAR) T cells can induce tumor regression by directly targeting and killing cancer cells, discovering new details of how these immune cells work and how their effectiveness can be improved in the treatment of non-Hodgkin's lymphoma and other B-cell cancers.
CAR T cells are genetically engineered immune cells that can be tailored to attack a patient's tumor cells. For example, CAR T cells targeting a protein called CD19, which is found in many lymphoma cells and leukemia, are an FDA approved treatment for various B cell neoplasms, including non-Hodgkin's lymphoma and acute lymphoblastic leukemia.
However, some patients do not respond to anti-CD19 CAR T cells, while others, after initial improvement, relapse and develop therapy-resistant tumors that no longer express CD19. Philippe Bousso and colleagues at the Institut Pasteur believe that the key to improving treatment is to learn more about how CAR T cells work. For example, it has not been clear whether TCA cells kill the cancer cells themselves or induce other immune cells to attack the tumor.
For the study, researchers tracked the activity of anti-CD19 CART T cells injected into mice with B-cell lymphoma. Using a microscopy technique known as intravital two-photon imaging, Bousso and his colleagues were able to view individual CAR T-cells killing lymphoma cells in the bone marrow of animals. Some CARs T cells appeared to be more active than others, but in most cases, lymphoma cells died within minutes of coming into direct contact with a T-cell CAR. This suggested that CAR T cells primarily kill their targets directly.
"Computational simulations based on our experimental data supported the idea that T-cell CARs depend on their direct cytotoxic activity, rather than the recruitment and activation of other cells to eliminate most of the B-cell lymphoma in the bone marrow," says Bousso.
The simulations also suggested that relatively small differences in the infiltration of CAR T cells into the bone marrow can substantially affect the outcome of the treatment. One reason why CAR T cells may not infiltrate the bone marrow is if they find lymphoma cells, or healthy B cells that also express CD19, circulating in the blood. Bousso and colleagues found that CAR T cells can aggregate with these circulating cells and become trapped in the lungs, preventing them from reaching the bone marrow. Reducing these encounters – for example, by temporarily reducing the number of circulating B cells – increased the ability of T-cells to infiltrate bone marrow and kill tumor cells, prolonging the survival of mice with B-cell lymphoma.
"Purging circulating tumor and normal B cells prior to transfer of CAR T cells may therefore offer a clinical benefit by improving the graft and persistence of CAR T cells," Bousso says.
Still, the researchers found that tumor relapse and the onset of non-CD19 tumors occur in the bone marrow, not in other organs affected by B-cell lymphoma, such as lymph nodes. This appears to be because CAR T cells are not as active in these other organs, reducing the incentive for tumor cells to lose CD19 protein.
"In short, our results reveal the great diversity of behavior of CAR T cells in distinct anatomical sites, impacting the graft, antitumor activity and tumor recurrence," says Bousso. "Understanding these differences is an important step in developing strategies to optimize treatments based on CAR T cells."
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Cazaux et al. 2019 J. Exp. Med. jem.rupress.org/cgi/doi/10.1084/jem.20182375
Rockefeller University Press
Researchers discover how immune cells that kill tumors attack lymphomas in living mice (2019, April 1)
recovered on April 1, 2019
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