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YTB323, a novel, autologous CD19-directed CAR-T cell therapy, displayed a favorable safety profile and efficacy across multiple dose levels in adult patients with relapsed/refractory diffuse large b-cell lymphoma.
YTB323, a novel, autologous CD19-directed CAR-T cell therapy, displayed a favorable safety profile and efficacy across multiple dose levels in adult patients with relapsed/refractory diffuse large b-cell lymphoma (DLBCL), according to results from a phase 1 trial (NCT03960840) presented at the 2021 ASH Annual Meeting and Exposition.
“YTB323 is manufactured through an innovative process called T-Charge,” said Ian W. Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Research Institute in Nashville, Tennessee. “[This process] preserves the naïve/Tscm cells in the final product.”
T-Charge minimizes the ex vivo culture time and reduces the manufacturing process time to less than 2 days. The process starts from a cryopreserved leukaphresis, T cells are then transduced with a lentviral vector encoding for the same CAR used for tisagenlecleucel (Kymriah) and formulated. Investigators said that data from the trial showed that the process preserved the stemness and memory phenotype of the leukaphresis.
At a median follow-up of 14.01 months, patients treated at dose level 1 (n = 4; DL1) experienced an overall response rate (ORR) of 75%; all responses were complete responses (CRs). One patient had progressive disease (PD). At month 3, 1 patient had a CR and 3 patients had PD.
In the 15-patient dose level 2 (DL2) group, the ORR was 80% and the CR rate was 73%. PD occurred in 2 patients and the median follow-up in this group was 6.23 months. Notably, all of the patients who achieved a CR in DL2 did so at month 3. Two patients had PD at that time.
To be eligible for the trial, adult patients needed to have measurable disease at enrollment and an ECOG performance status of 0 or 1 . Patients also needed to have undergone at least 2 prior lines of therapy, including autologous hematopoietic stem cell transplant.
The lymphodepleting chemotherapy options were intravenous (IV) fludarabine (30 mg/m2 daily for 3 days) plus cyclophosamide (500 mg/m2 IV daily for 3 days) or bendamustine (90 mg/m2 IV daily for 2 days). YTB323 was administered as a single IV dose; DL1 consisted of 2.5 x 106 CAR-positive cells and DL2 was 12.5 x 106 CAR-positive cells. The first efficacy assessment was performed after 28 days.
The primary end point of the trial was to identify the incidence of dose-limiting toxicities and safety in order to determine a recommended dose. Secondary end points included cellular kinetics, ORR, duration of response, and overall survival.
The median age at DL1 was 69 (range, 60-74) and 66 (range, 41-78) at DL2. All patients treated at DL1 had an ECOG performance status of 0; 69% of patients in the DL2 group also had a 0. The median number of prior lines of therapy was 2.5 for DL1 and 2 for DL2. Half of patients in DL1 and 63% of patients in the DL2 cohort had stage IV disease.
All patients at both dose levels experienced an adverse event (AE) of any grade. Grade 3 or greater AEs occurred in 100% and 75% of patients treated at DL1 and DL2, respectively. Two patients treated at DL1
died while on the study and 3 died at DL2. Investigators determined that none of these deaths were related to treatment with YTB323.
Cytokine release syndrome (CRS) of any grade was present in 25% and 31% of patients at DL1 and DL2, respectively. Neurological AEs of any grade were present at a rate of 25% at both dose levels. Half of the patients treated at DL1 experienced infections of any grade; the rate was 19% at DL2. All patients at both dose levels experienced grade 3 or greater cytopenia.
Only 1 patient experienced CRS of grade 3/4; this patient was treated at DL2. The median time to onset of CRS was 9 days (range, 9-9) and 11 days (range, 1-17) at DL1 and DL2, respectively. The median time to resolution was 5 days (95% CI, not evaluable [NE]-NE) and 2 days (1-NE) in the DL1 and DL2 arms, respectively.
Neurological adverse reactions had a median time to onset of 7 days (range, 7-7) and 6.5 days (range, 2-16) at DL1 and DL2, respectively. A single patient experienced aphasia in the DL1 arm and 1 patient each had ICANS, muscular weakness, seizure, and a confused state in the DL2 cohort. The median time to resolution for neurological adverse reactions was 5 days (95% CI, NE-NE) and 14 days (95% CI, 1-NE), respectively.
Investigators noted that the time to peak YTB323 in patients with DLBCL showed a delay compared with tisagenlecleucel (16 days vs 9 days by flow in JULIET). Although long term persistence data are still emerging, CAR expression was detectable by flow for at least 9 months in DL2 and 3 patients showed persistence at 6 months.
“YTB323 is effective with comparable in vivo expansion to tisagenlecleucel in [patients with] DLBCL at a 25-fold lower dose,” said Flinn. “YTB323 merits continued exploration as a therapy for the treatment of adult patients with relapsed/refractory DLBCL.”