Development of mRNA-generated CD8+ CAR T: Toward more accessible CAR-T therapy in multiple myeloma treatment

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Chimeric antigen receptor T cell (CAR-T) therapy targeting B-cell maturation (BCMA) has become the major driving force to revolutionize immunotherapies for patient with relapsed and refractory multiple myeloma (RRMM) [1-3].  Multiple early phase clinical trials using conventional CAR-T cells transfected by viral method demonstrated highly anti-MM activity of anti-BCMA CAR-T cell therapy with high minimal residual negativity rate with prolonged survival [4, 5].  However, proliferation and activation of T cells are also associated with increased risk of potentially life-threatening cytokine releasing syndrome (CRS) or neurotoxicity that require substantial intensive care for many patients.  Since a significant proportion of MM patients are elderly or not physically fit, they may not tolerate the potential side effect of powerful CAR-T cell therapy.  It is thus urgently needed to optimize CAR-T cell production or infusion protocol to minimize fetal toxicity and achieve treatment efficacy.  Using messenger RNA (mRNA) transfection, relatively short-lived CAR T-cells can be generated quickly and with restrictive persistence, thereby providing a potentially faster and safer treatment intervention.

 

In our study, a novel mRNA-generated anti-BCMA CAR T cells (Descartes-08) was constructed and evaluated.  Highly activated cytotoxic CD8+ T cells were made with a CAR targeting BCMA by electroporation of in vitro transcribed mRNA.  The high expression of BCMA CAR and high post-cryopreservation viability of Descartes-08 cells lasted for approximately 1 week after generation.  The degranulation CD107a and key cytotoxic cytokines (IFN-γ, TNFα) on Descartes-08 cells were shown in all co-cultures with BCMA+ MM cell lines and patient cells, which were decreased to baseline at Day 7.  These findings indicated Descartes-08 has a limited duration of action.

Significantly, Descartes-08 induced dose- and time- dependent lysis of MM cells at suboptimal test conditions including low effector-to-target cell ratios, incubated with drug-resistant MM cells (lenalidomide and pomalidomide resistant), or the presence of MM-supporting bone marrow stromal cells.  Importantly, Descartes-08 were highly active in primary MM cells from newly diagnosed or RRMM patients.  In a murine model of disseminated human MM, Descartes-08 further exhibited CAR-specific dose-dependent growth suppression of MM cells throughout the duration of treatment and prolonged overall survival.  Excitingly, the preliminary result of an elderly patient with plasma cell leukemia achieved stringent complete response at 12 weeks after three infusion of Descartes-08.  Notably, there was no significant associated side effect related to the Descartes-08 CAR T-cell infusion.  These findings strongly support further clinical investigation of Descartes-08 and its derivative Descartes-11.

The novel mRNA-generated anti-BCMA CAR-T cell Descartes-08 may reduce the risk of inevitable CRS and neurotoxicity, thereby improving safety and readiness of this powerful novel therapy in MM.  Its unique pharmacodynamic characteristics could improve therapeutic accessibility and flexibility in terms of new protocol design for repeat dosing with higher cell number in patients who may not tolerate single infusion of conventional CAR-T cells or even patients refractory to prior BCMA-targeted therapies [6].  Moreover, such mRNA-generated CD8+ CAR-T cell could be potentially applied in different clinical settings in MM to first deepen minimal residual disease negativity and further prevent the progression to active MM in patients.

  1. Cho SF, Lin L, Xing L, Li Y, Yu T, Anderson KC, et al. BCMA-targeting therapy: driving a new era of immunotherapy in multiple myeloma. Cancers (Basel). 2020;12:1473.
  2. D'Agostino M, Raje N. Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better? Leukemia. 2020;34:21-34.
  3. Gagelmann N, Riecken K, Wolschke C, Berger C, Ayuk FA, Fehse B, et al. Development of CAR-T cell therapies for multiple myeloma. Leukemia. 2020.
  4. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380:1726-37.
  5. Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129:2210-21.
  6. Cohen AD, Garfall AL, Dogan A, Lacey SF, Martin C, Lendvai N, et al. Serial treatment of relapsed/refractory multiple myeloma with different BCMA-targeting therapies. Blood Adv. 2019;3:2487-90.

This post was co-written by Yu-Tzu Tai and Shih-Feng Cho 

Go to the profile of YU-TZU TAI

YU-TZU TAI

Principal Scientist, Dana Farber Cancer Institute

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