Dual-targeting CAR T-cell therapy for refractory multiple myeloma

While most chimeric antigen receptor (CAR) T-cell clinical trials are using CAR T-cell products that target one specific antigen on multiple myeloma (MM) cells, other investigators are trying a different approach: dual-targeting CAR T cells. This article provides a summary of a recently published trial that investigated a dual targeted CAR T-cell approach in patients with refractory MM. The CAR T-cell product in this trial targets the cell surface antigens CD19 and B-cell maturation antigen (BCMA).¹

To date, there has been a clear preference for using BCMA as the target tumor-antigen for CAR-T constructs in MM. However, CAR-T constructs targeting other antigens are also being tested, such as CD19, CD138, and SLAMF7.² CD19 is a surface glycoprotein expressed on B cells that is present during B-cell maturation and expressed by most normal bone marrow plasma cells. However, only a small proportion of patients with MM have CD19 expression (5–10%); it is found on some MM cell subsets that are less differentiated and have a stem cell-like phenotype. CD19-targeted CAR T-cell therapy may therefore have a unique benefit in patients with CD19-expressing plasma cells.^3,4 Following these results and some preliminary clinical data on anti-CD19 CAR T-cell in relapsed MM,⁵ Chinese investigators reported first attempts to treat relapsed/refractory (R/R) MM and high-risk newly diagnosed MM (NDMM) with a dual infusion of CD19- and BCMA-directed CAR T cells.^6-8

Most single and dual-targeted CAR T-cell studies published have tested these new therapies in patients with R/R disease. Commonly, investigators do not differentiate between relapsed or R/R populations when, in fact, they might have very different prognosis. Recently, Tang et al. published the first observational study where only patients diagnosed with refractory MM were included (defined according to National Comprehensive Cancer Network [NCCN] guidelines). These patients were treated with dual CD19/BCMA CAR T cells. The study was published in the Journal of International Medical Research.¹

Study design and patient characteristics

In this publication, Tang et al. report the efficacy and safety results of 16 patients treated between March 2017 and February 2018 at the First Affiliated Hospital of Soochow University (Suzhou, CN). Patients had received two or more prior therapies without complete recovery, or who had recurrence after recovery (refractory). Median patient age was 55.1 years (range, 50–72).¹

Dosing schedule

T-cell collection was undertaken, with cells cultured for 1–2 weeks to generate CAR T cells. Intravenous re-infusion was conducted sequentially after conditioning therapy (100% CD19, 40% BCMA, and 60% BCMA): most patients received fludarabine and cyclophosphamide, but five patients received the infusion immediately following autologous hematopoietic stem cell transplant. The total infused doses ranged between 0.5–1 × 10⁷/kg CD19-targeted CAR T cells and 1.2–6.2 × 10⁷/kg BCMA-targeted CAR T cells. Two patients received 0.5 × 10⁷/kg BCMA CAR T-cell infusion on the surface lesion under B-mode ultrasound guidance.¹

Safety

This study was primarily focused on safety variables, including serum levels of inflammatory factors. All patients experienced cytokine release syndrome (CRS), mainly Grade 1–2 (75.1%), accompanied by a high increase in interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein, peaking at 3–5 days post-infusion and returning to normal levels by Day 10. Thirteen (81.3%) patients with Grade 2–4 CRS also developed persistent hyperthermia that, in some cases, didn’t reverse until 14 days after infusion. Other frequent adverse events (≥ 50%) were muscle pain (68.8%), headache (56.3%), and nausea (50%).¹

Efficacy

Regarding efficacy, 14 out of 16 patients treated responded to treatment (overall response rate, 87.5%), with the majority presenting a good response (12 complete responses and two partial responses), comparable to those observed in previous studies (Table 1).¹

Table 1. BCMA and CD19-targeted CAR T-cell combination trials²

Conclusion

The authors recognize that there is still a need for more significant studies with a higher sample size. Even though all toxicities were managed and patients were stabilized, hospitalization, close monitoring, and symptomatic treatment are still key after CAR T-cell infusion. The efficacy results are encouraging in this difficult-to-treat population, but currently, it’s impossible to confirm the benefit of adding anti-CD19 CAR T cells to anti-BCMA CAR T cells until a comparative, two-arm, randomized study is conducted.¹