Relapsed/refractory patients,   General MM

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

Author and trial site

Patients

Co-stimulatory domain

Conditioning

Total doses

Efficacy

CRS

Registration

Yan L et al. The First Affiliated Hospital of Soochow University, Suzhou, CN6

8 RRMM

Third generation (OX40, CD28)

CP/Flu

1 × 107/kg CD19- targeted CAR-T cells; 2.5–8.2 × 107/kg BCMA-targeted CAR-T cells

ORR, 80% (4/5) with 1 sCR, 1 VGPR, 2 PRs

100%

Grade 1–2: 87.5%

Grade 3: 1 patient

NCT03196414

Shi X et al. The First Affiliated Hospital of Soochow University, Suzhou, CN7

10 high-risk NDMM

Third generation (OX40, CD28)

Bu-CP + ASCT

1 × 107/kg CD19- targeted CAR-T cells; 2.5-8.2 × 107/kg BCMA-targeted CAR-T cells

ORR, 100% (10/10) with 7 sCR, 1 CR, 2 VGPRs

100%

All Grade 1–2

NCT03455972

Yan Z et al. Affiliated Hospital of Xuzhou Medical University, Xuzhou, CN8

21 RRMM

Second generation (4-1BB)

CP/Flu

1 × 106/kg both BCMA and CD19- targeted CAR-T cells

ORR, 95% (20/21) with 9 sCRs, 3 CRs, 5 VGPRs, 3PRs

Grade 1–2: 86%

Grade 3: 5%

ChiCTR-OIC- 17011272

Tang F et al. The First Affiliated Hospital of Soochow University, Suzhou, CN1

16 refractory MM

SSCAR-010 (2nd gen.) SSCAR-030 (3rd gen.)

CP+Flu (11) / ASCT (5)

0.5-1 × 107/kg CD19- targeted CAR T cells; 1.2–6.2 × 107/kg BCMA-targeted CAR T cells

ORR, 87.5% (14/16), with 12 CR, 2 PR

100%

Grade 1–2: 75.1%

Grade 3–4: 25.0%

N/A

ASCT, autologous stem cell transplant; BCMA, B-cell maturation antigen; Bu, busulfan; CAR, chimeric antigen receptor; CP, cyclophosphamide; CR, complete response; CRS, cytokine release syndrome; Flu, fludarabine; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PR, partial response; RRMM, relapsed/refractory multiple myeloma; sCR, stringent complete response; VGPR, very good partial response

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

References
  1. Tang F. et al. Infusion of chimeric antigen receptor T cells against dual targets of CD19 and B- cell maturation antigen for the treatment of refractory multiple myeloma. J Int Med Res. 2020 Jan 15; 48(1):300060519893496. DOI: 10.1177/0300060519893496.
  2. Wu C. et al. Chimeric antigen receptor T cell therapies for multiple myeloma. J Hematol Oncol. 2019 Nov 21; 12:120. DOI: 10.1186/s13045-019-0823-5
  3. Mateo G. et al. Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol. 2008 Jun 1; 26(16):2737–2744. DOI: 10.1200/JCO.2007.15.4120
  4. Paiva B. et al. Differentiation stage of myeloma plasma cells: biological and clinical significance. Leukemia. 2017 Feb; 31:382–392. DOI: 10.1038/leu.2016.211
  5. Garfall A.L. et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight. 2018 Apr 19; 3(8):e120505. DOI: 10.1172/jci.insight.120505
  6. Yan L. et al. Combined infusion of CD19 and BCMA-specific Chimeric Antigen Receptor T cells for RRMM: initial safety and efficacy report from a clinical pilot study. Blood. 2017 Dec 7; 130(Supplement 1):506. DOI: 10.1182/blood.V130.Suppl_1.506.506
  7. Shi X. et al. Tandem auto-SCT and combined infusion of CD19 and BCMA-specific CART cells for high risk MM. 2019 Mar 27. Oral Abstract OS12-1:45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
  8. Yan Z. et al. A combination of humanised anti CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019 Oct 1; 6(10):e521–e529. DOI: 10.1016/S2352-3026(19)30115-2
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