Brief Report—CAR T Therapy and the Immune Landscape: The Potential Role of CAR T in Earlier Lines of Therapy

Introduction 

The introduction of chimeric antigen receptor T-cell (CAR T) therapy changed the landscape of relapsed/refractory multiple myeloma (RRMM) treatment. Initially approved in the fourth line or greater, CAR T therapy is now available in earlier lines of treatment, with ciltacabtagene autoleucel being available as early as the second line.¹ A subset analysis from the CARTITUDE-1 trial showed that patients with progression-free survival (PFS) of ≥5 years had higher frequencies of CD4-naïve T cells at baseline, as well as higher endogenous T-cell diversity and greater CAR T-cell oligoclonality at Month 1 compared to patients with PFS of <5 years; short-term responders also had a greater proportion of CD8 terminally differentiated effector memory T cells. These findings indicate that the immune landscape plays an important role in patient response to CAR T therapy.² This article explores how the immune landscape impacts CAR T therapy, and how utilizing CAR T in earlier lines of therapy might improve outcomes.

The immune landscape and CAR T therapy

Research indicates that the presence of less differentiated T-cell subsets (eg, naïve, central memory, and stem-like memory T cells) in the leukapheresis and CAR T products can lead to improved patient outcomes, as these subsets have greater proliferative capacity, improve the yield of CAR T product, and promote greater expansion after infusion, compared to more differentiated subsets (eg, effector, terminally differentiated effector memory T cells).^3,4 In a small study of patients treated with anti-B cell maturation antigen (BCMA) CAR T or BCMA-CD3 bispecific T-cell engager therapy, patient responders had a higher proportion of central memory and stem-like memory T cells, while treatment-resistant patients had enrichment of terminally exhausted T cells and senescent cells.⁵

T-cell exhaustion plays an important role in CAR T therapy as well. Exhausted T cells express have high expression of inhibitory receptors, such as lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and mucin domain–containing 3 (TIM-3), and programmed cell death protein 1 (PD-1), which are associated with decreased antitumor activity. These cells also exhibit limited effector function and cannot be activated or proliferate; threfore, CAR T product developed utilizing exhausted T cells would have weak proliferative capacity.^3,4,6 Leblay et al⁵ observed high levels of inhibitory receptors on exhausted T cells and on some memory T cells in treatment-resistant patients.

Both CD4 and CD8 contribute to the effectiveness of CAR T therapy,³ and the CD4:CD8 ratio has been associated with CAR T therapy efficacy. Higher CD4:CD8 ratio in the leukapheresis product has been associated with greater expansion and response.^5,7 In one study, patients with RRMM who responded to BCMA CAR T therapy had a median CD4:CD8 ratio of 1.3 compared to 0.87 for the entire cohort of patients with RRMM.⁸

MM-related factors can contribute to reduced T-cell fitness. MM is linked to an increase in inflammatory cytokines, and inflammatory cytokine signaling pathways are enriched in RRMM, thus contributing to immunosenescence and reduced levels of naïve T cells.^3,4,9 Additionally, aging alters the T-cell landscape, leading to decreased levels of naïve T cells, increased levels of dysfunctional T cells, impaired cytokine production, and immunosenescence.^3,4

MM treatments contribute to immune changes that can negatively affect CAR T therapy. Autologous stem cell transplant (ASCT) can have a large, irreversible impact on T cells. While patients with newly diagnosed MM might have a similar CD4:CD8 ratio to healthy controls, ASCT can lead to a significant decrease in CD4:CD8 ratio, which might not recover to baseline levels even after treatment. Furthermore, the proportion of naïve and central memory CD4 T cells decrease following ASCT, while the proportion of effector CD4 T cells increase.⁹ One study found that compared to patients at diagnosis, treated patients with MM had decreased naïve T cells and patients who received daratumumab showed elevated levels of PD-1 and LAG3.¹⁰ Additionally, treatment with alkylating agents can increase the number of senescent T cells, and bispecific antibody treatment can lead to T-cell exhaustion.⁴

Optimizing treatment: CAR T in earlier lines of therapy

Given the impact of MM treatments and relapsed/refractory disease on the immune landscape, leukapheresis timing is key to optimizing CAR T outcomes. In a study comparing response to anti-BCMA CAR T therapy among 38 patients with MM who underwent leukapheresis after initial response to induction therapy (prior to undergoing ASCT) and were infused post-ASCT (postinduction cohort) and 25 patients with RRMM who underwent leukapheresis after a 2-week washout (median prior lines of therapy: 7; 92% had undergone ASCT), the postinduction cohort had a significantly greater median CD4:CD8 ratio compared to the overall RRMM cohort and a subgroup of responders with RRMM. Furthermore, proliferation capacity during manufacturing was greater  in the postinduction cohort compared to the overall RRMM cohort and the responder subgroup.⁸ In another study, researchers evaluated outcomes of anti-BCMA CAR T cells manufactured at diagnosis, at relapse, upon daratumumab treatment, and at relapse after daratumumab treatment. In vitro analysis demonstrated that anti-BCMA CAR T product developed from patients at relapse and those at relapse after daratumumab treatment had weaker cytotoxic activity against MM cells, with cell viability of 73% and 90% respectively, compared to CAR T from patients at diagnosis and upon daratumumab treatment, with cell viability of 21% and 54%, respectively. Furthermore, in vivo analysis showed that anti-CS1 CAR T from patients at diagnosis controlled MM growth, whereas anti-CS1 CAR T from patients at relapse or upon daratumumab treatment showed intermediate MM growth, indicating that CAR T developed from treated patients is less effective at slowing disease progression.¹⁰ The evidence suggests that CAR T therapy manufactured from patients with earlier-stage, less-treated MM is more clinically effective, and as such, using CAR T therapy in earlier lines of treatment might improve patient outcomes.

Conclusion

T-cell fitness influences the efficacy of CAR T therapy in MM, and research suggests that CAR T product is more effective when manufactured earlier in the disease course. Therefore, it could be more beneficial for patients to receive CAR T therapy in earlier lines of treatment (eg, second- or third-line vs fourth-line or greater).

References

1. CARVYKTI. Prescribing information. Janssen Biotech, Inc.; revised Oct 2025. Accessed 14 Apr 2026. https://www.fda.gov/media/156560/download
2. Vieira Dos Santos J, Melnekoff DT, Aleman A, et al. Long-term remission after cilta-cel in multiple myeloma is linked to diverse T cells and low myeloid suppression. Blood Adv. 2026;10(3):604–607.
3. Mehta PH, Fiorenza S, Koldej RM, et al. T cell fitness and autologous CAR T cell therapy in haematologic malignancy. Front Immunol. 2021;12:780442.
4. Makni-Maalej K, Alotaibi SM, Fernandes Q, et al. Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies. Front Immunol. 2026;17:1762453.
5. Leblay N, Maity R, Barakat E, et al. Cite-seq profiling of T cells in multiple myeloma patients undergoing BCMA targeting CAR-T or BiTEs immunotherapy. Blood. 2020;136(Suppl 1):11–12.
6. Baessler A, Vignali DAA. T cell exhaustion. Annu Rev Immunol. 2024;42(1):179–206.
7. Cohen AD, 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.
8. Garfall AL, Dancy EK, Cohen AD, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3(19):2812–2815.
9. Cooke RE, Quinn KM, Quach H, et al. Conventional treatment for multiple myeloma drives premature aging phenotypes and metabolic dysfunction in T cells. Front Immunol. 2020;11:2153.
10. Abecassis A, Roders N, Fayon M, et al. CAR-T cells derived from multiple myeloma patients at diagnosis have improved cytotoxic functions compared to those produced at relapse or following daratumumab treatment. EJHaem. 2022;3(3):970–974.