Chimeric Antigen Receptor T-Cell Therapy in Hematological Malignancies

Chimeric antigen receptor (CAR) T-cell therapy represents a paradigm shift in the treatment of relapsed or refractory haematological cancers by harnessing patients’ own immune cells to target surface antigens on malignant cells. Following leukapheresis, T cells are genetically modified to express a synthetic receptor composed of an antigen-binding domain linked to T-cell activation and co-stimulatory signalling modules. After expansion in vitro and lymphodepletive conditioning, these engineered cells are reinfused, where they recognise and eliminate tumour cells expressing the target antigen. Clinical application has yielded high rates of complete remission in B-cell acute lymphoblastic leukaemia, large B-cell lymphoma and multiple myeloma. Durable responses in heavily pretreated patients have underscored global interest and spurred regulatory approvals. Nevertheless, challenges persist, including severe inflammatory toxicities, antigen loss by tumour cells, limited persistence and manufacturing complexity. Advances in multispecific CAR designs, precise genome editing of checkpoint molecules and novel antigen discovery are now guiding next-generation strategies to enhance efficacy, overcome resistance and broaden the therapeutic reach beyond current indications.

Research from Nature Portfolio

Innovative genome-engineering approaches have been applied to augment CAR T-cell function. One foundational study demonstrated that CRISPR/Cas9-mediated disruption of the PD-1 gene in CD19-directed CAR T cells enhances tumour clearance in preclinical models by preventing inhibitory signalling within the tumour microenvironment. Building on this, bispecific CAR T cells targeting both CD19 and CD22 have been evaluated in adults with B-cell acute lymphoblastic leukaemia and large B-cell lymphoma. These dual-targeted cells met manufacturing and safety endpoints and produced high remission rates, illustrating a viable strategy to circumvent antigen escape and reduce relapse driven by loss of a single target antigen.

Chimeric Antigen Receptor T-Cell Therapy in Hematological Malignancies publication trend

The graph below shows the total number of articles in chimeric antigen receptor t-cell therapy in hematological malignancies across all publications each year (not limited to Nature Index journals).

Technical terms

Chimeric antigen receptor (CAR): A synthetic fusion receptor that combines an antigen-recognition domain with T-cell signalling modules to direct T-cell cytotoxicity against specific cell-surface molecules.

Cytokine release syndrome (CRS): A systemic inflammatory response caused by massive cytokine secretion from activated CAR T cells and bystander immune cells, ranging from mild flu-like symptoms to life-threatening multiorgan dysfunction.

Antigen escape: A mechanism of tumour resistance in which malignant cells downregulate or lose expression of the target antigen, rendering CAR T cells unable to recognise and kill them.

Lymphodepletion: A conditioning regimen, often using chemotherapy, administered before CAR T-cell infusion to reduce regulatory and competing immune cells, thereby promoting CAR T-cell expansion and persistence.

References

1. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific Reports (2017).
2. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature Medicine (2021).
3. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal (2021).
4. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia (2020).
5. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. Journal of Hematology & Oncology (2018).