14 August 2019

A new combination therapy could help tackle treatment-resistant non-Hodgkin’s lymphoma, researchers have reported.

A team at Mount Sinai School of Medicine, New York, USA, has combined the use of immunotherapy drugs with stem cell transplantation. This combination enhances the ability of T cells to fight lymphoma cells by removing a mechanism that tumours use to evade the immune system.

‘Checkpoint blockade’ immunotherapy is effective in several tumour types, but not in non-Hodgkin's lymphomas. However, this new work shows it can succeed when combined with stem cell transplant, which the researchers have called ‘immunotransplant’.

Dr Joshua Brody and colleagues report that immunotransplant improves the effectiveness of T cells 10‑fold, so can work well against non-Hodgkin's lymphoma, as well melanoma and lung cancer.

During the process of bone marrow transplant, the patient’s original immune system is cleared out. This ‘makes space’ for re-infused immune T cells to proliferate, which activates the T cells. But at the same time, the re-infused T cells naturally increase production of checkpoint molecules PD1 and CTLA4. The presence of these molecules provides tumour cells with the opportunity to suppress the T cells’ activity. Adding checkpoint inhibitors – drugs which bind to PD1 and CTLA4 – prevents this suppression of the T cells, unleashing their full effect against cancer cells.

The results of their study appeared recently in the journal Cancer Discovery. Following this work, a clinical trial has been launched to test this immunotransplant approach on patients with aggressive non-Hodgkin’s lymphoma. The team believe this could eventually lead to effective therapies for several cancer types.

Dr Brody says: “Using immunotransplant to enhance the efficacy of checkpoint blockade therapy could be broadly significant as these immunotherapies are a standard therapy for melanoma, kidney cancer, lung cancer, and others.

“Even for settings in which checkpoint blockade therapy proves ineffective, our data suggest that its efficacy may be ‘rescued’ by immunotransplant. This research also suggests that the addition of checkpoint blockade may improve other T cell therapies, such as CAR-T therapy.”

Source: Marshall, N., Hutchinson, K., Marron, T.U., Aleynick, M., Hammerich, L., Upadhyay, R., Svensson-Arvelund, J., Brown, B.D., Merad. M., Brody, J.D. (2019) “Anti-tumor T-cell homeostatic activation is uncoupled from homeostatic inhibition by checkpoint blockade”, Cancer Discovery, available from doi: 10.1158/2159-8290.CD-19-0391


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