Researchers have demonstrated the ability to reprogram and revitalize exhausted antigen-specific memory CD8+ T cells using induced pluripotent stem cell (iPSC) technology in the laboratory. The innovative method, which targets multiple myeloma (MM), might be an important adaptive T-cell therapeutic strategy for MM — and potentially other cancers — that maintains anti-tumor activity and has the potential to circumvent long-term T-cell exhaustion. The laboratory results were published in Blood.
Using MM as a model and targeting B-cell maturation antigen (BCMA), researcher Jooeun Bae, PhD, of the Department of Medical Oncology at Dana-Farber Cancer Institute in Boston, and her colleagues generated a BCMA-targeted T-cell therapy candidate by using an iPSC strategy followed by cellular reprogramming technology.
Currently, chimeric antigen receptor (CAR) T-cell or other adoptive T-cell therapies are cell immunotherapies generated from a patient’s own T cells that are transduced and expanded before being infused back into the patient. Two of these CAR-T therapies targeted to BCMA, ciltacabtagene autoleucel and idecabtagene vicleucel, were approved by the U.S. Food and Drug Administration (FDA) as a therapy for patients with MM who have undergone at least four lines of therapy, and both have recently been approved by the FDA to treat patients earlier in the disease course.
While CAR T-cell therapies can be effective for certain patients with MM and other blood cancers, that can be hindered by T-cell exhaustion and senescence. One potential method to provide more efficacious and long-lived cancer-targeting T cells to patients is the generation of T-cell therapy using iPSCs.
“One potential therapeutic approach is to provide ‘rejuvenated’ antigen-specific T cells, which are highly effective and long-lived cancer-targeting memory T cells, to patients with cancer using iPSC technology as a mechanism for overcoming T-cell exhaustion,” Dr. Bae said.
In the current study, Dr. Bae and her colleagues provided a strategy to generate iPSC-derived T-cell therapies that have potential as an MM therapy. First, the team induced BCMA-targeted CD8+ memory cytotoxic T lymphocytes (CTLs) ex vivo specific to MM. Next, they reprogrammed the BCMA-specific CTLs into iPSCs using key transcription factors, formed embryoid body to efficiently develop hematopoietic progenitor cells (HPC), and then re-differentiated the reprogrammed iPSC-HPC to BCMA-specific CD8ab+ memory T cells. The differentiation process from the HPC to mature T cell took 21 days.
The researchers noted that unlike the parental BCMA-specific memory T cells that express immune checkpoint markers such as PD1, LAG3, CTLA4, and TIM3 characteristic of exhausted T cells, the rejuvenated BCMA CD8ab+ memory T cells differentiated from iPSCs had no such detectable inhibitory markers. “The cells had the characteristics of high T-cell expansion ex vivo without further antigen stimulation,” Dr. Bae said. “Our strategy can be applied as a next generation of therapeutic T-cell product.”
Importantly, the team demonstrated that these iPSC-derived BCMA CD8ab+ memory T cells had effective poly-functional anti-tumor activities against MM, which were enhanced compared to the parental BCMA CD8+ memory T cells. Additionally, these iPSC-derived BCMA CD8ab+ memory T cells were able to divide efficiently to expand their numbers, suggesting their utility as a potential adoptive cell therapy, Dr. Bae noted.
The authors also identified genes active in the iPSCs-derived HPC that could serve as specific biomarkers to identify appropriate iPSC clones that can effectively commit and be re-differentiated into CD8ab+ T cells.
“A key to our process is the capacity to differentiate the cells into antigen-specific CD8ab+ T cells that specifically recognize the specific target antigen,” Dr. Bae said. “We were also able to select appropriate iPSC clones committed to differentiate to the desired CD8ab+ T-cell population and characterize their transcriptional profile.
“In our future studies, we plan to reduce the overall time required for the process from iPSC establishment to T-cell differentiation to make it more feasible and clinically applicable,” Dr. Bae added.
Using the current study as a proof of concept, Dr. Bae and her colleagues plan to develop a more efficient process to generate iPSC-derived longer-lived antigen-specific memory CD8ab+ T cells as a next generation of adoptive T-cell therapy to overcome limitations and prolong responses to current T-cell therapy.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Bae J, Kitayama S, Herbert Z, et al. Differentiation of BCMA-specific induced pluripotent stem cells into rejuvenated CD8ab+ T cells targeting multiple myeloma. Blood. 2024;143(10):895-911.
