One Patient Suggests the Potential for NKG2D-Directed CAR T-Cell Therapy

Early clinical efficacy has already been seen in the form of an objective response achieved by a patient with relapsed/refractory acute myeloid leukemia (AML) receiving NKG2D-directed chimeric antigen receptor (CAR) T-cell therapy, known as CYAD-01, without preconditioning in the phase I/II THINK trial. Preclinical and phase I proof for CYAD-01 as well as preliminary findings from the ongoing THINK trial were presented at the 2018 American Society of Gene and Cell Therapy Annual Meeting.¹

“[There was an] encouraging safety and tolerability profile during dose level 1 and 2 of the THINK trial, now permitting moving into the final dose level,” said Eytan Breman, of Celyad, the company developing the CAR T-cell product, when presenting the findings for CYAD-01.

NKG2D is an activating receptor that is expressed on both natural killer cells and activated CD8-positive T cells. Expression of at least 1 of the NKG2D ligands can be found in many tumor types, including in up to 100% of AMLs, nonsquamous non—small cell lung cancers, bladder cancer metastases, and in up to 93% of triple-negative breast cancers, but with minimal expression in normal tissue, Breman explained. CYAD-01 CAR T-cell therapy comprises of an NKG2D receptor and the co-stimulatory signals DAP10 and CD3ζ. Preclinical studies of CYAD-01 showed long-term survival with the treatment across mouse models with ovarian cancer, lymphoma, and multiple myeloma.

“CYAD-01 can target a wide range of solid and liquid cancers in vitro and in preclinical models,” Breman said.

The first-in-human dose-escalation trial of NKG2D-directed CAR T-cell therapy in patients with AML, myelodysplastic syndrome (MDS), or relapsed/refractory multiple myeloma demonstrated that a single dose without lymphodepletion was safe and feasible to manufacture.²

In results from the phase I study, the investigators found that most observed adverse events (AEs) were not related to treatment. The only 2 grade 4 AEs, 1 case of neutropenia and thrombocytopenia in the 1 x 10⁶CM-CS1 T-cell dose cohort and 1 case of intracochlear bleed in the 1 x 10⁷dose cohort, were related to disease progression.

The ongoing open-label, multicenter THINK trial was designed to assess the safety and activity of 3 administrations of the CAR T-cell therapy in patients with colorectal cancer, ovarian cancer, bladder cancer, triple-negative breast cancer, pancreatic cancer, AML/MDS, and multiple myeloma.

In the dose-escalation portion of the trial, patients were given 3 administrations of the treatment, each 2 weeks apart, at one of 3 doses: 3 x 10⁸, 1 x 10⁹, or 3 x 10⁹. The trial planned to enroll 122 participants.

The first objective response has already been seen in a patient with relapsed/refractory AML.³The 52-year-old male patient had previously received 7+3 induction chemotherapy with daunorubicin and cytarabine (Vyxeos) followed by salvage cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone, at which point he achieved a complete response. After 7 months, he relapsed and was never able to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The patient was enrolled in the THINK trial and received 3 x 10⁸doses of CYAD-01 without preconditioning. He tolerated the NKG2D CAR T-cell therapy with non—treatment-related grade 1 AEs and achieved a morphologic leukemia-free state and resolution of his symptoms, at which point he underwent allo-HSCT and had a complete molecular remission. The response was maintained 9 months after the first CYAD-01 administration.

Breman noted that a significant recovery was seen in his platelets, hemoglobin, and absolute neutrophil count levels. He also pointed to changes in the levels of chemokines SDF1, RANTES, and CCL2, which aligned with administration of CYAD-01. “The mechanisms relating to these observations remain to be elucidated.”

Breman added that stable disease has also been achieved in 2 patients with colorectal cancer and 1 patient with ovarian cancer.

References:

1. Breman E, Sallman DA, Brayer JB, et al. Early signs of clinical activity in Aml patients receiving NKG2D CAR T cell therapy in the absence of pre-conditioning chemotherapy: an alternative strategy to CAR T cell therapy. Presented at: 2018 ASGCT Annual Meeting; May 16-19, 2018; Chicago, IL. Abstract 967. plan.core-apps.com/asgct2018/abstract/493ce7a3-1caa-44a7-a904-32b18fbcf1e5.
2. Nikiforow S, Werner L, Murad J, et al. Safety data from a first-in-human phase I trial of NKG2D chimeric antigen receptor-T cells in AML/MDS and multiple myeloma.Blood.2016;128:4052. bloodjournal.org/content/128/22/4052?sso-checked=true.
3. Sallman DA, Brayer J, Sagatys EM, et al. NKG2D-based chimeric antigen receptor therapy induced remission in a relapsed/refractory acute myeloid leukemia patient [published online April 27, 2018].Haematologica.doi: 10.3324/haematol.2017.186742.