CAR-T (chimeric antigen receptor T-cell) therapy represents a revolutionary advance in treating hematologic cancers, offering promising outcomes for lymphoma patients, especially those with relapsed or refractory disease. Initially approved for diffuse large B-cell lymphoma (DLBCL), CAR-T therapy is expanding to address a broader range of lymphomas, including other B-cell and T-cell subtypes. As CAR-T technology evolves, researchers are exploring innovative delivery strategies and engineering methods to enhance efficacy and address the unique challenges of treating different lymphoma types.

CAR-T cell therapy works by genetically modifying a patient's T cells to express a receptor targeting specific cancer cell antigens. In B-cell lymphomas, CD19 has proven an effective target, with CAR-T therapies such as axicabtagene ciloleucel and tisagenlecleucel demonstrating remarkable responses. Recent studies reveal high remission rates in DLBCL, mantle cell lymphoma, and follicular lymphoma when using CD19-targeted CAR-T therapy, even in patients who have exhausted other treatment options. The success of these therapies has catalyzed research into additional lymphoma subtypes and new antigen targets, allowing CAR-T cell therapy to benefit an expanding patient population (Denlinger et al., 2022).

One notable development is the investigation of CAR-T cell therapy in T-cell lymphomas. T-cell lymphomas pose unique challenges due to their antigen overlap with healthy T cells, leading to risks like T-cell fratricide, where CAR-T cells inadvertently destroy each other. To address this, researchers are designing CAR-T cells targeting less common antigens, such as CD30, which is often overexpressed in Hodgkin lymphoma and some T-cell lymphomas, but not in normal T cells. CD30-directed CAR-T therapies have shown early success in clinical trials, offering hope for relapsed Hodgkin lymphoma patients who lack other viable options (Brudno et al., 2024, Ramos et al., 2020).

Localized CAR-T cell therapy is another emerging strategy, particularly for lymphomas affecting the central nervous system (CNS). CNS lymphomas present an additional barrier because CAR-T cells administered intravenously may struggle to cross the blood-brain barrier (BBB) and reach tumor cells. Direct intrathecal CAR-T administration, which bypasses the BBB, has shown promising early results for CNS lymphoma, providing high CAR-T cell concentrations directly within the CNS and improving patient outcomes. This approach may reduce systemic side effects like cytokine release syndrome (CRS) and neurotoxicity, although localized neurotoxicity remains a concern (Sagnella et al., 2022).

Engineering advancements are also helping address antigen escape, where cancer cells evade CAR-T cells by losing the targeted antigen. Dual-target CAR-T cells can recognize multiple antigens, reducing the risk of relapse due to antigen loss. For example, dual CD19/CD22 CAR-T therapies are being studied for their ability to sustain long-term remission by targeting two markers common to B-cell lymphomas, thus enhancing durability and reducing escape mutations. Also combining CAR-T with immune checkpoint inhibitors improve CAR-T cell efficacy. (Roddie et al., 2023).

In summary, CAR-T cell therapy has transformed the lymphoma treatment landscape, extending beyond DLBCL to address Hodgkin lymphoma, follicular lymphoma, and other challenging subtypes. As new approaches evolve—such as local delivery for CNS lymphoma, dual-target CAR-T constructs, and novel T-cell lymphoma strategies—CAR-T therapy's role continues to expand, offering new hope to patients with previously untreatable lymphomas. Continued innovation will be crucial for refining CAR-T technology, overcoming barriers, and realizing its full potential across diverse lymphoma types.