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Resistance mechanisms to CAR T-cell therapy

May 5, 2023
Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM

The introduction of chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed/refractory multiple myeloma has resulted in increased complete response and measurable residual disease-negativity rates for some patients with multiple previous lines of therapy.1 However, recent data on progression-free survival have not demonstrated any clear curve plateaus, highlighting the need to better understand therapy failure and resistance mechanisms to CAR T-cell therapy.1

Resistance can occur from multiple sources, including multiple myeloma microenvironments, tumor-related factors, the patient’s T-cell characteristics, and CAR T-cell characteristics (Figure 1). Here, we summarize a lecture by Van de Donk1 on the resistance mechanisms to CAR T-cell therapy presented at the International Myeloma Society 4th Immune Effector Cell Therapies in Multiple Myeloma Workshop.

Figure 1. Mechanisms of resistance to CAR T-cell therapy* 

BM, bone marrow; CAR, chimeric antigen receptor; MM, multiple myeloma; Treg, regulatory T cell.
*Adapted from Van de Donk.8 Created with

Antigen escape

For CAR T-cell activity, a minimum antigen expression is required; therefore, when there is a loss of antigens, the efficacy of CAR T-cell therapy is reduced.2 Following B-cell maturation antigen (BCMA) CAR T-cell therapy, there can be a reduction or even a total loss of BCMA expression in a small subset of patients. Multiple options exist to combat this antigen loss, such as using two different CAR T­‑cell products concurrently or a T cell with two different binding domains for two antigens.2 This may also be addressed with the development of novel receptors that require a lower antigen density threshold, such as the chimeric costimulatory receptor CAR T cell.3 Methods to address antigen escape are outlined in Figure 2.

Figure 2. Mechanisms to combat antigen escape in CAR T-cell therapy* 

CAR, chimeric antigen receptor.
*Adapted from Rasche, et al.3 Created with

Lack of persistence of CAR T cells

Multiple factors contribute to the lack of persistence of CAR T cells, one example of this being the therapies to which patients have been previously exposed.1 Patients treated with idecabtagene vicleucel who had been treated with an alkylator, proteasome inhibitors, or topoisomerase inhibitor have been found to have poorer overall progression-free survival.5 Since treatment with CAR T cells is recommended in later lines of therapy, there is a high likelihood that a patient receiving CAR T-cell therapy will have been exposed to a treatment that may negatively impact their outcomes.1

Patients with a smaller proportion of undifferentiated T cells were also found to be less likely to respond to BCMA CAR T-cell therapy.1 Methods to increase the proportion of CAR T cells produced from an immature memory T-cell phenotype may include reducing the production time or adding a phosphoinositide 3-kinase inhibitor in the culture condition. A recent example of this comes from clinical trials where BMS-986354, a less differentiated and faster-to-produce CAR T cell, was compared with its similar orvacabtagene autoleucel and was found to have superior tumor control at the same dose.6

Reduced functionality of CAR T cells

Stromal cells can suppress the efficacy of CAR T cells by upregulating anti-apoptotic molecules in the tumor cells, outlined in Figure 1.1 Designing CAR T cells that can overcome the immune suppression in the tumor environment may overcome this resistance mechanism, for example, by developing CAR T cells that produce pro-inflammatory cytokines such as IL-12. Maintenance strategies, such as lenalidomide treatment, could also be applied to mitigate the negative impacts of the bone marrow microenvironment. Lenalidomide has been shown to have positive effects on regulatory T cells and can improve CAR T-cell function, indicating its use as a maintenance therapy after CAR T-cell infusion.7


Improved understanding of therapy failure in CAR T cells and methods of resistance may allow for the development of more resilient and effective CAR T-cell therapies. The primary issues include the lack of persistence, antigen escape, and reduced functionality of CAR T cells. Methods to address these are being investigated, focusing on optimizing CAR design, culturing conditions during manufacturing, and amending therapy guidelines.

  1. Van de Donk N. Overview of resistance mechanisms. Determinants of response/resistance part I. International Myeloma Society 4th Immune Effector Cell Therapies in Multiple Myeloma Workshop; Mar 25, 2023; Boston, US.
  2. Cohen A D, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210-2221. DOI: 10.1172/JCI126397
  3. Rasche L, Weinhold N, Morgan GJ, et al. Immunologic approaches for the treatment of multiple myeloma. Cancer Treat Rev. 2017;55:190-199. DOI: 10.1016/j.ctrv.2017.03.010
  4. Katsarou A, Sjöstrand M, Naik J, et al. Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence. Sci Transl Med. 2021;13(623). DOI: 10.1126/scitranslmed.abh1962
  5. Paiva B, Manrique I, Rytlewski J A, et al. Early and sustained undetectable measurable residual disease (MRD) after idecabtagene vicleucel (ide-cel) defines a subset of multiple myeloma (MM) patients in Karmma achieving prolonged survival. Blood. 2022;140(1). DOI: 10.1182/blood-2022-166658
  6. Costa L. Results from the first phase I clinical study of the B-cell maturation antigen (BCMA) Nex T chimeric antigen receptor (CAR) T cell therapy CC-98633/BMS-986354 in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Abstract #566. 64th American Society of Hematology Annual Meeting and Exposition; Dec 10−13, 2023; New Orleans, US.
  7. Narayan V, Barber-Rotenberg JS, Jung IY, et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase I trial. Nat Med. 2022;28:724-734. DOI: 10.1038/s41591-022-01726-1
  8. Van de Donk NWCJ, Themeli M, Usmani SZ. Determinants of response and mechanisms of resistance of CAR T-cell therapy in multiple myeloma. Blood Cancer Discov. 2021;2(4):302318. DOI: 10.1158/2643-3230.BCD-20-0227


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