Waking up exhausted BCMA-specific T cells in myeloma

In this issue of Blood, Bae et al¹ have elegantly shown that an induced pluripotent stem cell strategy may epigenetically reprogram precursor exhausted B-cell maturation antigen (BCMA)–specific cytotoxic T lymphocytes into hematopoietic progenitor cells, which, in turn, differentiate into functional cognate antigen-specific CD8αβ⁺ memory T cells that exert an antitumor effect in multiple myeloma (MM). Overall, these novel studies pave the path to novel strategies for targeting MM cells via an effective antitumor immunity-based approach.

Adoptive cell therapy with the use of tumor cell–targeting chimeric antigen receptor T (CAR-T) cells has certainly shown significant clinical benefits in certain cancers, leading to prolonged remissions, and is probably curative in a subset of cases.^2-8 Within the field of MM, antitumor activity of BCMA-targeting CAR-T cells has been shown.^2-4 

However, the challenge of T-cell exhaustion and impaired immune function remain hurdles for the persistence of the antitumor activity of CAR-T cells. One of the main drivers of T-cell exhaustion is persistent antigen stimulation. This study, led by Bae et al, has implemented an induced pluripotent stem cell (iPSC) approach to revitalize and reprogram BCMA-specific T cells.

BCMA-specific CD8⁺ memory cytotoxic T lymphocytes (CTLs) were epigenetically successfully reprogrammed, returning them to a pluripotent state that then developed into hematopoietic progenitor cells and differentiated into the T-cell lineage. These T cells were fully characterized, confirming the mature CD8ab⁺ memory phenotype; coupled with a robust expression of costimulatory molecules, including CD38, CD28, and 41BB; and lack immune checkpoint or senescence markers, such as CTLA4, PD1, LAG3, TIM3, or CD57. These same markers were enriched within the parental precursor, exhausted BCMA-CTL.

Next, the authors investigated the functional status of the iPSC T cells, demonstrating their ability to proliferate and to exert an antitumor effect. In addition, the use of RNA sequencing showed specific transcriptional signatures mirroring the successful differentiation of iPSC clones into CD8⁺ memory T cells. This sequencing approach is an important tool to facilitate the identification and selection of the most appropriate iPSC clones to be destined to CD8⁺ T-cell lineage differentiation, especially when thinking about clinical application.

Overall, Bae et al have developed a well-defined, robust, and scientifically sound proof-of-principle platform to epigenetically reprogram BCMA-specific CD8⁺ memory cytotoxic T lymphocytes as a promising strategy to promote an efficacious and long-term anti-MM immunity. More important, the findings of these studies may apply to a wider spectrum of cancers, thus covering solid tumors and hematologic malignancies.

We now anxiously await the translation of these exciting data to the clinical setting.

Conflict-of-interest disclosure: A.M.R. has received research funding from AstraZeneca, European Hematology Association, Transcan2-ERANET, and Italian Association for Cancer Research (Fondazione AIRC); and honoraria from Amgen, Celgene, Janssen, and Takeda. A.S. declares no competing financial interests.