Resistance mechanisms to CAR T-cell therapy

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 BioRender.com.

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 BioRender.com.

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

Conclusion

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.