Integrating CAR T-Cell therapy into the treatment of myeloma

Professor Julie Vose (Nebraska, USA) updates us on the current status of BCMA CAR T-cell therapy.

Interviewer: Hannah Chatfield. Article: Maria Dalby.

https://vimeo.com/309636314

Chimeric antigen receptor (CAR) T-cell therapy has recently transformed the treatment of acute lymphoblastic leukaemia (ALL) and some adult B cell lymphomas, and is increasingly discussed as a emerging treatment option for multiple myeloma (MM). CAR T cells targeting BCMA, a TNF receptor super family that is exclusively upregulated in B cells differentiating into plasma cells¹has been shown to achieve substantial treatment responses in patients who have received as many as seven or even more lines of therapy. In a session at ASH 2018, CAR T-cell therapy was highlighted as a promising treatment option for patients with relapsed/refractory MM and also in the frontline setting in patients with high-risk MM. In another session on integrating CAR T-cell therapy into the treatment of lymphoma, myeloma and leukaemia Dr James Kochenderfer (Center for Cancer Research at the National Cancer Institute, MD, USA) summarised the key clinical studies reported to date and outlined ongoing work in the field of CAR T-cell therapy in MM.

The first-in-human clinical study of a CAR T-cell construct targeting BCMA in MM patients was performed by Dr Kochenderfer and his team as a single-centre study initiated in 2014.² In this study 24 patients were included and received a total of 26 cell infusions. The patients in this study had a median of 9.5 prior lines of therapy; 40% of the evaluable patients had high-risk cytogenetics and 33% had del17p. Following a three-day conditioning regimen of cyclophosphamide 300mg/m² and fludarabine 30mg/m² daily patients received anti-BCMA CAR T-cell infusions at dose levels of 0.3×10⁶, 1×10⁶, 3×10⁶ and 9×10⁶ cells/kg, with no further anti-myeloma therapy given until progression.³ The first response on a similar level to those reported for anti-CD19 CAR T cell therapy in ALL occurred in the 3×10⁶ cells/kg dose group, where one patients achieved VGPR for 8 weeks.

The highest dose group of 9×10⁶ cells/kg was found to be highly active against MM with an ORR of 81% and a ≥VGPR rate of 63%. The median event-free survival was 31 weeks. Responses were rapid in most patients; one 65-year-old male patient with extramedullary light-chain myeloma who had received 16 prior lines of therapy including two autologous stem cell transplantations achieved VGPR within less than two weeks which lasted 84 weeks. Of the 16 patients who received the active dose, six patients developed Grade 3 or 4 cytokine release syndrome (CRS). Five patients received tocilizumab for CRS management; one patient required mechanical ventilation and six patients required vasopressor. In the latter part of the study the investigators made a decision to limit the disease burden allowed since Grade 3 and 4 CRS was found to be associated with high plasma cell percentages, and this helped to reduce the rate and severity of CRS in the study.³

The first multicentre study of anti-BCMA CAR T-cell therapy in MM was reported at ASH 2017, and updated at ASCO 2018.^4,5 In this study 21 patients received the same conditioning regimen as in the single-centre study, followed by infusions of the anti-BCMA CAR T-cell construct bb2121 at doses of 50×10⁶, 150×10⁶, 450×10⁶ and 800×10⁶ cells/kg in the initial dose escalation phase of the study. The lowest dose level was found to be inactive; the dose levels ≥150×10⁶cells/kg achieved an ORR of 94%, with more than half of patients (56%) achieving CR. Median PFS was 11.8 months compared with 2.7 months at the inactive dose level. In 16 patients who achieved MRD negativity median PFS was 17.7 months, and the investigators concluded that this data supports bb2121 as a new treatment paradigm in relapsed/refractory MM.⁵

At the National Cancer Institute Dr Kochenderfer and his team are continuing their work to improve CAR T-cell therapy in MM by developing CARs where the antigen recognition domain contains a heavy chain only which allows them to circumvent recipient anti-CAR responses.⁶These CARs have been shown to eradicate tumours in mice⁷ and a phase 1 dose escalation study is currently ongoing.

Another way of improving CAR T-cell therapy may be to target multiple antigens, since BCMA down-regulation is known to occur and correlates with relapse.³ An oral abstract (no. 589) presented by Dr Eric Smith (Memorial Sloan Kettering Cancer Center, NY, USA) investigated the orphan seven transmembrane G protein-coupled receptor GPRC5D as an additional target for CAR T-cell therapy in MM and found that GPRC5D-targeted CAR T-cells proliferated and homed to the tumour site, eradicated MM and increased survival in mice engrafted with a human MM cell line. Studies in mice also indicate that anti-GPRC5D CAR T-cell therapy is capable of salvaging BCMA relapse, and a clinical study is due to open early next year at Memorial Sloan Kettering which will evaluate anti-GPRC5D CAR T-cell therapy in patients with relapsed/refractory MM, including those who have relapsed on anti-BCMA CAR-T-cell therapy.

References

1. Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy 2015;7:1187-99.
2. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 2013;19:2048-60.
3. Brudno JN, Maric I, Hartman SD, et al. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J Clin Oncol 2018;36:2267-2280.
4. Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Blood 2017;130:740-740.
5. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. Journal of Clinical Oncology 2018;36:8007-8007.
6. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med 2016;8:355ra116.
7. Lam N, Alabanza L, Trinklein N, et al. T Cells Expressing Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptors with Antigen Recognition Domains Made up of Only Single Human Heavy Chain Variable Domains Specifically Recognize Bcma and Eradicate Tumors in Mice. Blood 2017;130:504-504.