Deconvolution of the mechanisms of T cell drug response in multiple myeloma induction therapy
- 1Allen Institute
Abstract
Lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, are used alone or in combination (RVd therapy) as first-line therapies for hematologic malignancies including the plasma cell dyscrasia, Multiple Myeloma (MM). The effects of RVd treatment on tumor cells have been documented, but little is known about their impacts on "healthy" immune cells. New therapeutics, including chimeric antigen receptor T cell (CAR-T) and bispecific T-cell engagers (BiTEs) depend on robust T cell function but these are often harvested for cellular therapies after or in tandem with RVd therapy. Understanding the molecular effects of these drugs on healthy T cells is therefore of particular importance. Since the molecular effects of each drug includes regulation of key transcription factors, we used a tri-modal, single-cell assay (TEA-seq), simultaneously profiling mRNA transcripts, cell surface proteins, and chromatin accessibility in primary human peripheral blood T cells treated for 4, 24, or 72 hours in vitro. Synergies and conflicts potentially arising from combinatorial therapy were identified and validated by flow cytometry. Doublet and triplet drug combinations were used to assess effects on cell-surface marker expression and on T cell activation. Our results suggest that T cell function can be optimized by the administration of these drugs individually and that sequential administration may offer an opportunity to enhance T cell function by affecting localization and altering T cell states. This work provides those interested in immunology, oncology, and cell therapies an opportunity to explore molecular pathways that could be manipulated by these commonly used drugs to modify T cell function.
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BibTeX
@misc{graybuck2026deconvolution,
title = {{Deconvolution of the mechanisms of T cell drug response in multiple myeloma induction therapy}},
author = {L. T. Graybuck and L. Y. Okada and W.-L. Chang and J. Garber and C. Sakai and M. D. A. Weiss and S. Rachid Zaim and V. Hernandez and Z. He and U. Krishnan and P. Ravisankar and J. Reading and E. M. Coffey and T. F. Bumol and J. Meladze and M. S. Kopp and S. B. Munro and G. L. Szeto and E. W. Newell and X.-j. Li and P. J. Skene and T. R. Torgerson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751861},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751861v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Deconvolution of the mechanisms of T cell drug response in multiple myeloma induction therapy
AU - L. T. Graybuck
AU - L. Y. Okada
AU - W.-L. Chang
AU - J. Garber
AU - C. Sakai
AU - M. D. A. Weiss
AU - S. Rachid Zaim
AU - V. Hernandez
AU - Z. He
AU - U. Krishnan
AU - P. Ravisankar
AU - J. Reading
AU - E. M. Coffey
AU - T. F. Bumol
AU - J. Meladze
AU - M. S. Kopp
AU - S. B. Munro
AU - G. L. Szeto
AU - E. W. Newell
AU - X.-j. Li
AU - P. J. Skene
AU - T. R. Torgerson
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751861
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751861v1
AB - Lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, are used alone or in combination (RVd therapy) as first-line therapies for hematologic malignancies including the plasma cell dyscrasia, Multiple Myeloma (MM). The effects of RVd treatment on tumor cells have been documented, but little is known about their impacts on "healthy" immune cells. New therapeutics, including chimeric antigen receptor T cell (CAR-T) and bispecific T-cell engagers (BiTEs) depend on robust T cell function but these are often harvested for cellular therapies after or in tandem with RVd therapy. Understanding the molecular effects of these drugs on healthy T cells is therefore of particular importance. Since the molecular effects of each drug includes regulation of key transcription factors, we used a tri-modal, single-cell assay (TEA-seq), simultaneously profiling mRNA transcripts, cell surface proteins, and chromatin accessibility in primary human peripheral blood T cells treated for 4, 24, or 72 hours in vitro. Synergies and conflicts potentially arising from combinatorial therapy were identified and validated by flow cytometry. Doublet and triplet drug combinations were used to assess effects on cell-surface marker expression and on T cell activation. Our results suggest that T cell function can be optimized by the administration of these drugs individually and that sequential administration may offer an opportunity to enhance T cell function by affecting localization and altering T cell states. This work provides those interested in immunology, oncology, and cell therapies an opportunity to explore molecular pathways that could be manipulated by these commonly used drugs to modify T cell function.
ER -