Inhibiting mTORC1 with rapamycin or temsirolimus may increase CD20 expression on leukaemic cells and improve responses to anti-CD20 antibodies, according to new preclinical research.

A study published in Leukemia has identified a potential strategy for improving CD20-directed immunotherapy in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), including genetically high-risk disease characterised by IKZF1 deletion.

The researchers found that inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) increased surface expression of CD20 on BCP-ALL cells and enhanced the anti-leukaemic activity of anti-CD20 monoclonal antibodies in experimental models.

Low or heterogeneous CD20 expression can limit the effectiveness of CD20- directed therapies in BCP-ALL. The investigators therefore explored whether the expression of the antigen could be therapeutically manipulated.

Their initial experiments focused on IKZF1, a transcriptional regulator involved in B-cell development that is frequently altered in high-risk BCP-ALL.

Restoring wild-type IKZF1 expression increased CD20 levels and promoted features associated with a more mature B-cell phenotype.

Using gene-expression profiling to identify pharmacological interventions that could reproduce aspects of this IKZF1-associated programme, the researchers identified mTORC1 inhibition as a promising candidate.

Further experiments using BCP-ALL cell lines and patient-derived models showed that mTORC1 inhibition increased CD20 expression both in vitro and in vivo. The treatment also altered the expression of other B-lineage markers, consistent with a partial shift towards a more mature cellular phenotype.

Mechanistic studies implicated the AKT–FOXO1 signalling pathway in the response. Notably, the increase in CD20 expression was also observed in models harbouring IKZF1 deletions, suggesting that the approach could potentially overcome at least some of the biological consequences of this high-risk genetic abnormality.

The mTORC1 inhibitors rapamycin and temsirolimus enhanced the activity of anti-CD20 antibodies, including rituximab and obinutuzumab, in vitro. In a mouse model of BCP-ALL, combining temsirolimus with rituximab significantly reduced leukaemia burden and prolonged survival compared with either drug alone.

The findings raise the possibility of using mTORC1 inhibitors to increase the density of a therapeutic target before or alongside CD20-directed immunotherapy, rather than relying on the level of CD20 already present on leukaemic blasts. Both mTORC1 inhibitors and anti-CD20 antibodies are already used in clinical practice.

If validated clinically, combining these established medicines could offer a more accessible way to improve immunotherapy for BCP-ALL, potentially allowing a broader group of patients to benefit from CD20-directed treatment.

The approach could have broader implications for immunotherapy development in BCP-ALL. The authors suggest that future studies should investigate whether mTORC1 inhibition can similarly enhance other CD20-directed strategies, including bispecific antibodies and cellular therapies.

However, the findings remain preclinical and should not yet be considered practice-changing. Clinical studies will be required to establish whether increased CD20 expression translates into improved patient outcomes, and to determine appropriate dosing and treatment schedules.

The potential effects of mTOR inhibition on immune-cell function will also need careful consideration when developing combinations with immunotherapies.

Nevertheless, the study provides a mechanistic rationale for targeting the mTORC1 pathway to modify antigen expression and sensitise BCP-ALL cells to immunotherapy, offering a potentially actionable strategy for overcoming one of the limitations of CD20-directed treatment.

Article: Leukemia