Universal CAR-T Therapy Produces CRs in Relapsed/Refractory T-ALL

Sharon Worcester

May 20, 2020

A universal chimeric antigen receptor (CAR) T-cell therapy produced responses in adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), according to initial findings from an ongoing study.

The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.

All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.

Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.

The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.

TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.

Patients and Treatment

The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).

None of the patients received prior allogeneic hematopoietic stem cell transplant.

All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.

Expansion, Response, and Safety

"GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated," Dr. Wang said. "We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14."

All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.

One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.

In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.

However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.

All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.

"The CRS was manageable and reversible," Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.

Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.

"Very Impressive" Early Results

Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.

One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.

Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.

"[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels," Dr. Wang said in closing, noting that further evaluation is warranted.

Indeed, the results of this next-generation CAR T-cell trial are "very impressive," said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.

There have been concerns that "off-the-shelf" CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.

"I think it's also important to note, however, that there's quite a high incidence rate of grade 3 or higher toxicities, including CRS," Dr. Chen said. "I suspect this may have something to do with the fairly high dosing levels used in this trial."

The "big question," however, is durability of the response, Dr. Chen said. "And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today."

Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.

SOURCE: Wang X et al. AACR 2020, Abstract CT052.

This story originally appeared on MDedge.com.


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