Researchers at Rutgers University have identified a factor that may help explain why chimeric antigen receptor (CAR) T-cell therapy fails in a majority cancer patients. In a study published in Cell Reports, the investigators found that the poor initial quality of a patient’s harvested CD8+ T cells that are used to manufacture CAR T-cells lack the ability to mount a robust immune response.
“Many of their T-cells are in a defective state called senescence, which means they can’t proliferate in the lab, they can’t migrate to tissue effectively, and they can’t kill very well,” said senor author Ricardo Iván Martínez-Zamudio, PhD, an assistant professor at Rutgers Robert Wood Johnson Medical School.
Building a CAR T-cell therapy depends on successfully harvesting a patient’s own T cells, then modifying to target tumor cells, growing a robust population of these engineered cells in the lab, then reinfusing them into the patient. But, as the new research shows, the efficacy of this process depends on the inherent capacity of the harvested cells to both proliferate in the lab and to retain their immune function.
The Rutgers study showed that in patients where CAR T therapy is ineffective, a large proportion of a patient’s harvested cells are senescent. Their research demonstrated that CD8+ T cells from donors with higher levels of senescence expanded less under standard CAR T culture conditions than cells from donors with lower senescence levels.
Further, a retrospective look at clinical outcomes of published datasets from lymphoma patients treated with CAR T-cell therapy found that patients whose starting cells and final CAR T-cell products had strong senescence signatures were more likely to fail treatment, while those with lower senescent profiles were more likely to respond. This indicated that the state of CD8+ T cells prior to engineering could be influencing the efficacy of CAR T treatments.
To better understand the molecular basis of CD8+ T cell senescence, the researchers collected blood from both younger and older donors, isolated CD8+ T cells, and used a fluorescent marker to identify senescent cells. They then performed multi-omics profiling, including gene expression and chromatin analysis, to map the regulatory networks controlling senescence.
The resulting data showed that T cell senescence, rather than chronological age of the donor, drives most of the molecular differences in CD8+ T cells. “The senescence program is essentially precoded,” Martínez-Zamudio said. “It’s not that older people develop some new dysfunctional program. The capacity is there from the beginning.”
The study identified a number of transcription factors, including AP1, KLF5, and RUNX2, that regulate this dysfunctional program. When the research altered these to effect gene expression patterns in senescent cells, they were able to partially restore aspects of T cell responsiveness. Their ability to proliferate, however, remained limited.
The implications of this research extend beyond cancer therapy. While it is known that senescent CD8+ T cells accumulate with age and contribute to declines in immune function and chronic inflammation, the study also found that senescence gene signatures were enriched in patients with lupus, suggesting this may also play a role to autoimmune diseases.
“Our study defines the gene-regulatory mechanisms underlying human CD8+ T cell senescence, highlights [transcription factor] network perturbation as a viable strategy to manipulate the senescence state, and identifies senescent CD8+ T cell gene signatures as prognostic tools for immunotherapy outcome,” the researchers wrote.
Based on this, the investigators think that T cell senescence profiling could be used to help determine which patients would benefit from CAR T therapy and those that wouldn’t and could help guide alternative treatments. Because the current findings were a retrospective analysis of patient data, the Rutgers team now plan to test this approach in prospective clinical studies through collaborations with Rutgers Cancer Institute.
The study also indicates the potential to improve CAR T-cell therapy by target the senescence program, by altering transcription factor activity to modify gene expression. But restoring the proliferative capability of these cells using this approach will require more research. Another route for improvement suggested by the research is to develop method to reprogram, or selectively eliminate, senescent cells during the CAR T-cell manufacturing process.
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