CAR T-Cell Therapy With CYAD-01 Shows Efficacy in Myeloid Malignancies

A multiple CYAD-01 infusion schedule without preconditioning appears to be well-tolerated and shows anti-leukemic activity in patients with relapsed/refractory acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and multiple myeloma.¹

Phase 1 data from the THINK study (NCT03018405) show that while these data are without durability outside of patients bridged to allogeneic hematopoietic stem-cell transplantation (HSCT), they support the proof-of-concept of targeting natural killer (NK) group 2D (G2D) ligands by chimeric antigen receptor (CAR) T-cell therapy.

Further studies assessing NKG2D-based CAR T cells are warranted to potentially improve anti-tumor activity in these patient populations.

“THINK is one of the first phase 1 completed CAR T-cell studies for myeloid malignancies and one of the only studies to use a multiple infusion regimen without preconditioning or bridging chemotherapy. This differentiated strategy is unusual in the current CAR T-cell therapy space but provides the key advantage of understanding the activity of the therapy in the absence of confounding factors, such as the effect of preconditioning on clinical endpoints or safety parameters,” wrote study authors in findings published in The Lancet Hematology.

"CYAD-01 is a CAR T-cell product where a patient’s T cells are removed from their body and altered to specifically express a novel protein [NKG2D] receptor fused with a T-cell activating domain. NKG2D is over expressed on blood cancers but not normally found on most healthy cells. These NKG2D receptor expressing genetically modified autologous CART now can bind to, recognize, and become activated to destroy cancer cells in patients," Eunice S. Wang, MD, chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, told Targeted Oncology^TM.

Initial clinical studies of a single infusion of CYAD-01 administered to patients at a low dose in those with relapsed/refractory AML, MDS, and multiple myeloma have demonstrated feasibility with the approach. Now, this study aimed to determine the safety and recommended phase 2 dose of CYAD-01 administered without preconditioning or bridging chemotherapy in this patient population.

In the multicenter, open-label, dose-escalation, phase 1 THINK study, patients with relapsed/refractory AML, MDS, and multiple myeloma who had received at least 1 previous line of therapy were enrolled from 5 hospitals throughout the United States and Belgium.

Within the dose-escalation portion of the THINK study, 3 dose levels were evaluated. Dose level 1 consisted of CYAD-01 administered at 3 × 10⁸ total cells per each infusion, dose level 2 was 1 × 10⁹ total cells per each infusion, and dose level 3 was 3 × 10⁹ cells per infusion. The study utilized a 3 + 3 Fibonacci design and used a schedule of 3 infusions at 2-week intervals followed by potential consolidation treatment which included 3 additional infusions.

Those enrolled in the trial were aged 18 years or older, with an ECOG performance status of 2 or lower, relapsed/refractory disease after prior treatment that was AML presenting at least 5% blasts in bone marrow or in peripheral blood after at least 1 previous therapy, MDS with at least 5% blasts in bone marrow, at least 2% blasts in peripheral blood, or TP53 mutation after at least 4 cycles of azacitidine or decitabine, or multiple myeloma after at least 3 previous combination therapies.

The primary end point of the study was the occurrence of dose-limiting toxicities and secondary end points included the occurrence of adverse events (AEs) and serious AEs during study treatment, objective responses, and overall survival and progression-free survival at 2 years.

A total of 2 patients were enrolled into the hematological dose-escalation part of the trial between February 6, 2017, and October 9, 2018. Among those enrolled, 7 patients had manufacturing failure for insufficient yield and 2 had screening failure, and 16 patients were treated with at least 1 CYAD-01 infusion.

Of the 16 patients treated with CYAD-01, 3 had multiple myeloma and 3 had AML at dose level 1, 3 had AML at dose level 2, and 6 had AML and 1 had MDS at dose level 3. No patient received bridging therapy between apheresis and the first CYAD-01 infusion, and no patient had previously had an allogeneic HSCT.

The median age of the patients enrolled was 67 (interquartile range [IQR], 57-76), the median percentage of bone marrow blasts at baseline in patients with AML or MDS was 12% (range, 4%-48%), and 9 (69%) of 13 patients with AML or MDS had 2 or more previous lines of therapy. The median follow-up among patients was 118 days (IQR 46-180).

"This trial examined the safety and preliminary efficacy of NKG2D modified CAR T infusion in patients with relapsed/refractory AML, MDS and multiple myeloma. Sixteen patients were treated with clinically significant cytokine release syndrome occurring in 5 patients and objective responses in 3 of 12 evaluable subjects. Of note, patients treated with these CAR T did not require standard conditioning or bridging chemotherapy prior to infusion. This study demonstrates that NKG2D represents a valid immunotherapeutic target in hematological malignancies and may be worthy of future study. While this CART was plagued by manufacturing issues and low response rates, additional development of NKG2D targeted approaches vis other adaptive cell modalities could be pursued as this antigen was capable of stimulating appropriate cytokine and clinical responses," added Wang.

Of the 12 evaluable patients with relapsed/refractory AML or MDS, 3 (25%) had an objective response. Additionally, 2 responders who were patients with AML proceeded to allogeneic HSCT after receiving treatment with CYAD-01. These patients had durable ongoing remissions at 5 and 61 months.

Three patients had stable disease with a durability of at least 3 months. This included 1 patient who had a 40% marrow blasts decrease. Since there was no preconditioning or other intervention used, investigators believe that this observed clinical activity is directly related to CYAD-01.

Regarding safety, 7 patients (44%) had grade 3 or 4 treatment-related AEs, and 5 patients (31%) had grade 3 or 4 cytokine release syndrome (CRS) across all dose levels. There was 1 CRS dose-limiting toxicity observed at dose level 3, no neurological adverse events observed, nor evidence of on-target off-tumor toxicities following infusion of NKG2D CAR T-cells. Additionally, there were no treatment-related deaths, and the maximum tolerated dose was not reached.

“In conclusion, CYAD-01 is an autologous CAR T-cell therapy that has shown good tolerability but low activity in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes, with additional optimization needed. The results presented here support further development, including the use of preconditioning therapy, and further engineering of NKG2D-based CAR products,” concluded the study authors.

REFERENCE

Sallman DA, Kerre T, Havelange V, et al. CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes or multiple myeloma (THINK): hematological cohorts of the dose escalation segment of a phase 1 trial. Lancet Haematol. 2023;10(3):e191-e202. doi:10.1016/S2352-3026(22)00378-7