How can CD4 T “helper” T cells be leveraged for advanced therapeutics for cancer treatment?
In a recent study, researchers from the University of Geneva (UNIGE; Switzerland) have demonstrated that CD4 T lymphocytes, a type of helper T cell, have strong cytotoxic capabilities that can be leveraged for therapeutic applications. By modifying a specific subtype of CD4 T cells, the researchers were able to target an antigen found in many cancer types, including melanoma, lung, ovarian and brain cancer. Their findings may offer an alternative immunotherapy strategy for treating a broad range of tumor types and demonstrate the strong potential for gene transfer of T-cell receptors (TCR) in CD4 T cells for cytotoxic applications.
T cells play a crucial role in the body’s immune system, helping to protect the body from infection and disease. Immunotherapies have leveraged the functionality of T cells, primarily CD8 T “killer” cells – cytotoxic cells that target and eliminate diseased and cancerous cells. By modifying these naturally occurring cytotoxic T cells, researchers have harnessed patients’ own immune systems to provide an alternative approach in cancer treatment for many patients.
CD8 T cell-based immunotherapy has been a promising strategy in cancer treatment, but growing interest in CD4 T “helper” cells is opening new avenues. As interest in their role grows, researchers are exploring how they could strengthen the fight against cancer. According to the study’s paper, “…emerging evidence suggests that the polyfunctional and cytotoxic subsets of CD4 T cells may be crucial in the immune response against cancer.” From being considered as helper cells – supporting the function, migration and proliferation of other immune cells – the researchers, led by Camilla Jandus, have revealed that CD4 T cells can also be cytotoxic.
Cellular ‘barrier’ discovered in CAR-T-resistant lymphomas
New hope for lymphoma patients as scientists uncover why CAR-T therapy fails for some patients with aggressive B-cell lymphoma, and how to fix it.
A key barrier to translating CD4 T cells into effective therapies has been the complexity of their antigen recognition. Unlike CD8 T cells, which recognize peptides presented by HLA class I molecules, CD4 T cells interact with peptides bound to HLA class II molecules – structures that are both polymorphic and expressed in different variations. Moreover, on-target off-tumor toxicity remains a concern, as some target antigens are also expressed in healthy tissues, risking autoimmune responses from CD4 cell-based therapies.
To mitigate these challenges, the researchers focused on NY-ESO-1, an antigen with limited expression in normal tissues (primarily testis and ovary) but abundantly expressed in multiple tumor types such as melanoma, lung and ovarian cancer.
First, they isolated CD4 T cells from the blood, tumor tissue and lymph nodes of melanoma patients with the HLA-DRB3*02:02 allele and from healthy donors and studied their molecular characteristics. The researchers selected this HLA type due to is prevalence in 50% of the Caucasian population. This enabled them to assess the anti-tumor potential of CD4 T cells in a broader population group, avoiding the challenges associated with the polymorphic nature of CD4 T cells. From this, they identified and isolated a subset if these CD4 T cells (dominant alpha and beta chains) that possessed a TCR that was able to recognize the NY-ESO-1 antigen. Next, these specific TCRs were cloned into lentiviral vectors and transduced into human CD4 T cells and expanded in vitro. Analysis against positive and negative tumor cell-lines revealed that these modified CD4 T cells were able to eliminate NY-ESO-1–positive tumor cells and produced cytotoxic molecules like granzyme B (a protease that induces apoptosis). Additionally, the researchers assessed the modified CD4 T cells in human samples of lung, ovarian and neuroblastoma tumors, and the analysis revealed that the modified T cells could be applied to other tumor types.
Following this, the team evaluated these CD4 T cells modified with the relevant TCRs in both in vitro and in vivo systems using immunodeficient mice with NY-ESO-1 tumors. Encouragingly, analysis revealed significant tumor regression, with no off-target cytotoxicity observed.
The findings from this study suggest that modified CD4 T cells can potentially efficiently target cancer cells in an addition to their “helper” role. “This dramatically expands the pool of patients who could benefit, especially since the targeted antigen is expressed in many types of cancer,” according Jandus.
Looking ahead, the team is preparing a clinical trial involving patients with confirmed HLA-DRB3*02:02 expression and NY-ESO-1–positive tumors. A personalized workflow will involve isolating CD4 T cells from patients, modifying to express the NY-ESO-1 TCR, expanding them ex vivo and reintroducing them as a therapeutic product.
Additionally, the team is exploring the development of allogeneic TCR-modified CD4 T cell banks from healthy donors, matched by HLA typing. They hope this off-the-shelf approach could accelerate treatment initiation, particularly for patients with rapidly progressing or pediatric cancers.