As antigen-specific T cells eradicate cancerous cells, those lacking the expression of target antigens are favored to evade the immune response in a process known as antigen-negative tumor escape. Researchers from the Peter MacCallum Cancer Centre at the University of Melbourne in Australia have shown that this important obstacle to the broader clinical application of T cell-based immunotherapies including CAR T cells and adoptive transfer could be overcome by boosting the activity of dendritic cells, a type of antigen presenting cell that influences the behavior of T cells.
The team demonstrated that the expression of the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) by T cells could program the immune response to target additional cancer antigens (“epitope spreading”), leading to an improved anti-tumor immune response with implications for the treatment of solid tumors.
“Chimeric Antigen Receptor (CAR) T cells that target the CD19 antigen are highly effective (>90% response rates) and FDA approved for haematological malignancies. In solid tumors, CAR T cells targeting more than 20 different antigens have been evaluated, but none have been as effective as anti-CD19 CAR T cells in B cell malignancies,” stated Dr. Paul Beavis, PhD, co-senior author of the study.
“A major barrier to the success of CAR T cells in solid tumors is antigen heterogeneity; clinical observations indicate that the antigen targeted by the CAR is typically expressed on only 20-80% of tumor cells. This heterogeneity in tumor antigen expression contrasts with the application of anti-CD19 CAR T cells, where >99.9% of cancerous B cells express CD19. As such, treatment of solid tumors with CAR T cells leads to relapse associated with the emergence of antigen-negative tumors.”
“Therefore, development of strategies for CAR T cells to engage host immunity and overcome tumor antigen heterogeneity is of high clinical importance. Given recent data indicating the importance of conventional type 1 dendritic cell (cDC1s) in anti-tumor immunity we hypothesized that engineering chimeric antigen receptor (CAR) T cells to promote the function of cDC1 dendritic cells would allow effective treatment of heterogeneous solid tumors.”
“The differentiation of both murine and human cDC1s is driven by FMS-like tyrosine kinase 3 ligand (Flt3L) and so we engineered CAR T cells to secrete Flt3L to enable them to promote cDC1 expansion. We observed that this strategy significantly expanded cDC1s and enhanced therapeutic efficacy, particularly when combined with the immune adjuvants poly IC and anti-41BB. Through flow cytometry and TCR-sequencing based approaches we discovered that, crucially, therapeutic effects were mediated by endogenous CD8+ T cells against antigens not targeted by the CAR, a process known as epitope spreading.”
“Ultimately, we tested this approach in a more stringent model where 50% of the tumor cells did not express the tumor antigen, thus more closely replicating the clinical situation. In this setting Flt3L-secreting CAR T cells were able to eliminate heterogeneous tumors, leading to long-lasting memory responses against parental tumors. This represents one of the first descriptions of CAR T cells effectively eliminating tumor cells that are negative for the CAR antigen.”
The scientists recently published their findings in the journal Nature Immunology under the title, “Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity.” Junyun Lai and Sherly Mardiana were the co-first authors and Dr. Paul Beavis and Prof. Philip Darcy, PhD were co-senior authors of the study.
“Our study provides a method to overcome a major barrier to the success of CAR T cells in solid tumours, tumour antigen heterogeneity. The major advantage of our approach is that it engages host immunity and allows CAR T cells to indirectly target antigen-negative tumours. Specifically, our study shows that engagement of cDC1s is a viable approach to achieve effective activation of de novo immune responses against tumor cells that do not express the CAR antigen, thus allowing for the successful treatment of heterogeneous solid tumors. We hope that eventually, such approaches can be used clinically to bring success rates for CAR T cell therapy of solid tumors towards those achieved with anti-CD19 CAR T cells.”
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Moving forwards, the team plans to continue studying methods for improving the efficacy of T cell-based immunotherapies in the treatment of solid tumors. “Building upon these findings, we are pursuing avenues for clinical translation of this approach. More broadly we believe that further engineering of the CAR T cells can be made to further leverage this axis for more effective treatment of solid tumors.”
“The take home messages from our study are that engagement of host endogenous immunity is a critical requirement for CAR T cells in the treatment of solid tumors and that the expansion of cDC1s is an effective method to achieve this.”