Researchers have reported new insights into the mechanisms of how B-cell cancers become resistant to CD20-targeting immunotherapies, offering hopes of improving survival.
Therapies such as rituximab target the CD20 protein found on healthy and cancerous B cells. These are given alone or with chemotherapy for diffuse large B-cell lymphoma, follicular lymphoma, Burkitt’s lymphoma, and others.
Resistance can develop against these immunotherapies, due to the loss of the CD20 antigen on the surface of the cancer cells. But this cannot be fully explained by reduced expression of the gene that codes for CD20 in B cells, or the emergence of genetic variants.
Dr Andrei Thomas-Tikhonenko of the University of Pennsylvania, USA, and colleagues looked at the underlying mechanisms behind this resistance to CD20-targeting therapies. Their work was published in the journal Blood.
They examined CD20 dysregulation with a focus on alternative gene splicing: a process where a single gene produces different forms of mRNA molecules, which can create more than one version of the same protein.
They found that CD20 splicing is indeed involved in immunotherapy resistance and lymphoma relapses. Some CD20 mRNA isoforms can’t be effectively translated into proteins, which reduces the amount of CD20 protein on the cell surface.
They confirmed that this ‘switching’ – from mRNA isoforms that can be translated into CD20 protein to those than can’t – does happen in some patients with relapsed follicular lymphoma.
Dr Thomas-Tikhonenko said: “In this study, we found that certain isoforms of the mRNA responsible for producing CD20 were impacted by splicing in a way that the proteins were not being made at the levels necessary for these immunotherapies to do their job.”
The team also demonstrated that cancer cells with very low levels of CD20 may still be responsive to CAR-T therapy, even if they can’t be targeted with the anti-CD20 antibody mosunetuzumab.
First author Dr Zhiwei Ang said: “If a patient has relapsed because CD20 levels are downregulated, CAR T-cell therapy may still be an option, as it requires a lower threshold of the protein in order to be effective.
“These findings may help clinical staff offer more precise options when treating these hematologic malignancies.”
Source:
Ang Z, Paruzzo L, Hayer KE, Schmidt C, Torres Diz M, Xu F, Zankharia U, Zhang Y, Soldan S, Zheng S, Falkenstein CD, Loftus JP, Yang SY, Asnani M, King Sainos P, Pillai V, Chong E, Li MM, Tasian SK, Barash Y, Lieberman PM, Ruella M, Schuster SJ, Thomas-Tikhonenko A. (2023) “Alternative splicing of its 5’-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies.” Blood, doi: 10.1182/blood.2023020400
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