Point-of-care manufacturing delivers effective CAR T cells faster
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On-site manufacturing of autologous adoptive cell therapy products resulted in similarly effective treatments in far less time compared with commercially manufactured therapies, according to results of a comparison analysis published in Journal for ImmunoTherapy of Cancer.
The investigators also found that point-of-care manufacturing allowed for successful production of a cell therapy for nearly all patients in the analysis, which included participants in a single-center, phase 1b/phase 2 clinical trial of in-house manufactured CAR T cells for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma.
“There are still obstacles related to the commercial CAR T-cell products, including high costs and a long turnaround time from leukapheresis to infusion,” Orit Itzhaki, PhD, senior scientist and deputy manager of the clinical research lab at Ella Lemelbaum Institute for Immuno Oncology at Sheba Medical Center, and colleagues wrote.
“In-house production of CAR T cells can overcome most of these obstacles, leading to a rising number of clinical centers generating their own CAR-T products today,” they added.
The phase 1b/phase 2 trial evaluated an anti-CD19 CAR T-cell therapy manufactured in house at Sheba Medical Center for patients with B-cell malignancies. The investigators analyzed the manufacturing process of 91 in-house produced CAR T-cell therapies for patients aged 50 years of younger with relapsed or refractory ALL and non-Hodgkin lymphoma (NHL).
The trial enrolled 93 heavily pretreated patients with relapsed or refractory B-cell malignancies between June 2016 and August 2019. Ninety patients (mean age, 33 ± 19 years; 68% men; average previous lines of therapy, n = 3) underwent treatment and received in-house CAR T-cell therapies at Sheba Medical Center in Israel.
Thirty-seven patients had relapsed or refractory ALL and 53 had relapsed or refractory NHL.
Patients underwent lymphodepletion 2 to 4 days before infusion, followed by a CAR T-cell infusion of 1 × 106 cells/kg.
CAR T-cell production feasibility, patient safety and overall response rate, as documented during follow-up assessments 1 to 2 months after infusion, served as the trial’s primary endpoints.
The analysis showed an ORR of 84% (n = 30 of 36) for patients with ALL and 62% (n = 35 of 52) for NHL.
Sixty-seven percent of patients with ALL achieved a minimal residual disease (MRD)-negative complete response to therapy, 17% had an MRD-positive complete response and 14% had disease progression. Sixteen patients with NHL had a complete response to therapy, 16 had a partial response and 20 (38%) had disease progression.
“As a consequence of the high turnaround time of 1 to 2 months from leukapheresis to infusion, many rapidly progressive patients clinically deteriorate during the waiting period,” Itzhaki and colleagues wrote. “The JULIET and ELIANA phase 3 trials with tisagenlecleucel [Kymriah, Novartis] reported an intent-to-treat analysis from screening to treatment of only 47% and 70%, respectively.”
Nearly every patient enrolled in the study underwent treatment. Only two patients failed to receive treatment because of disease progression during the manufacturing period. In addition, in-house production had a 99% success rate, failing to produce a viable cell therapy for only one patient in the study.
Further analysis showed greater cell expansion among patients with ALL compared with NHL. Fold expansion on day 6 compared with day 2 was 8.6 ± 6.3 in patients with ALL compared with 5.7 ± 4.9 in patients with NHL (P = .016). The trend continued 10 days after infusion, with fold expansion of 28.7 ± 24.7 in patients with ALL and 17.8 ± 13.5 in patients with NHL (P = .009).
Notably, CAR T cells from younger patients expanded significantly better than those from patients aged older than 21 years, regardless of disease type (age 20, 32.4 ± 27.5; age > 20, 17 ± 11.2; P = .0003).
“We demonstrated that the short turnaround time of only 9 to 10 days enabled the treatment of almost all enrolled patients,” Itzhaki and colleagues wrote.
“The in-house production of CAR T cells is highly efficient,” they added. “CAR-T cells of [patients with ALL] demonstrated increased proliferation and transduction capacity compared with NHL-derived CAR T cells, which may explain improved clinical remission in these patients.” – by Drew Amorosi
Disclosures: This study was funded by Sheba Medical Center and a donation from the Lemelbaum family. The authors report no relevant financial disclosures.
Perspective
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Joseph Alvarnas, MD
Over the past decade, we have witnessed the advent of innovative, potentially lifesaving, gene-modified therapeutics for patients with cancer. CAR T-cell therapeutics represent some of the most impactful of these advances.
JULIET, ZUMA-1 and other CAR T-cell trials demonstrate the remarkable activity of these therapeutics in the treatment of patients with ALL and diffuse large B-cell lymphoma. Unfortunately, the high product acquisition costs of commercial CAR T-cell products — coupled with complicated logistics and long turnaround times — potentially limit patient access.
Itzhaki and colleagues evaluated the effectiveness of point-of-care manufacturing of CAR T-cell and tumor infiltrating lymphocyte products for 93 patients with relapsed or refractory B-cell ALL and non-Hodgkin lymphoma (including patients with other lymphoma subtypes). CAR T-cell products were successfully manufactured and administered to 90 patients in this heavily pretreated population. Product turnaround time ranged from 9 to 10 days. All products met release criteria for cell viability, sterility, mycoplasma and endotoxin testing.
The challenges of ensuring broadly equitable and effective patient access to CAR T-cell therapeutics has proved more difficult than anticipated. Centers at the vanguard of developing and delivering these therapeutics — such as City of Hope, where I work — are leading fast-paced innovation in the arena of gene-modified and cellular therapeutics in the hope that more patients with more types of cancer may benefit from this approach. Without an effective answer to the challenges of delivering these products at lower cost and with a faster turnaround time, the societal impact of these advances will not be fully realized.
Point-of-care manufacturing may be one solution to some of these challenges. The study by Itzhaki and colleagues provides support for a point-of-care manufacturing model for gene-modified cellular products that may eventually become a key component of a more effective delivery system for these potentially lifesaving treatments.
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