Bicistronic CAR-T effective for children with relapsed B-ALL
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Key takeaways:
- Most children with relapsed or refractory B-lineage acute lymphoblastic leukemia achieved complete remission with bicistronic CAR-T.
- Nearly half of participants had grade 3 or 4 cytokine release syndrome.
SAN DIEGO — A bicistronic chimeric antigen receptor T-cell therapy induced durable response for most children with relapsed or refractory B-lineage acute lymphoblastic leukemia, findings presented at ASH Annual Meeting and Exposition showed.
Nearly all patients treated with the CD19- and CD22-directed CAR-T achieved complete response.
“Our early-stage clinical study data appeared to be encouraging and better than those of real-world experience with tisagenlecleucel [Kymriah, Novartis],” Hua Zhang, MD, PhD, vice president and chief scientific officer at SPH Biotherapeutics (HK) Limited in Hong Kong, told Healio. “We attributed our favorable results partly to the simultaneous expression of two different CARs in the T cells, which enhance early eradication of leukemia clones, thereby impeding the development of resistance.
“In addition, our bicistronic CD19- and CD22-targeted CAR T cells are a safe and effective regimen for children with B-ALL who are refractory and relapse after prior CD19-targeted CAR-T therapy,” he added. “It provides an extra opportunity for bridging to transplantation and long-term survival.”
Background and methods
A prior study published in Journal of Clinical Oncology showed co-infusion of CD19- and CD22-directed CAR T cells produced durable remission for patients aged less than 20 years with relapsed or refractory B-ALL.
“[However], we discovered that the co-infusion of both CD19 and CD22 CAR-T experienced an imbalanced amplification of either CD19 CAR T or CD22 CAR T cells in vivo, which may also [have an] impact on the long-term prognosis,” Zhang said. “Further, the limitation of this co-infusion strategy is the doubling manufacture cost.”
Zhang and colleagues developed a bicistronic CD19/CD22 CAR-T product (B019) and tried to improve upon those results.
They evaluated the product in a trial that included 343 people aged 18 years or younger with relapsed or refractory B-ALL.
EFS, OS and safety served as primary endpoints.
Results and next steps
The clinical trial — ChiCTR2000032211 — took place at Shanghai Children’s Medical Center from December 1, 2021, to April 30 of this year.
Median follow-up was 13.9 months (interquartile range, 9-22.4).
Researchers reported a 99.1% complete response rate. These patients all had negative minimal residual disease.
An analysis of the 343 participants enrolled and treated showed a 12-month EFS of 75.5% and 12-month OS of 93.5%.
Of those 292 patients, 38 received consolidative allogeneic stem cell transplantation.
Those participants had improved 12-month EFS compared with those who did not (89.7% vs. 76.8%; P = .04). However, the OS rate did not differ based on consolidative transplantation.
Of 254 children who did not have transplantation, 55 relapsed, and all of those had a second salvaging bicistronic therapy.
The second bicistronic therapy induced complete remission in 76.4% of patients with CD19-positive/CD22-positive disease (n = 42 of 55) and 24.6% of patients with CD19-/CD22+ disease (n = 13 of 55).
Of those who had complete remission, 85.7% remained alive in remission (range, 1-22.1 months).
Participants who had isolated testicular relapse had a 12-month EFS of 93.8% and 12-month OS of 100%.
Those who had central nervous system relapse had a 12-month EFS of 71.6% and 12-month OS of 100%.
All patients developed cytokine release syndrome. Roughly half of cases were grade 3 or grade 4, with two of those cases leading to death. One of the cases, which didn’t meet inclusion criteria but still received the compassionate use of the therapy, happened during the second salvaging treatment after the relapse.
Participants who had grade 0-2 CRS had a 1-year EFS of 80.9%. Those who had grade 3-4 CRS had a 1-year EFS of 69.9% (P = .0191).
“Severity of CRS was not related to the study dose range of infused cells, whereas it was highly correlated with disease burden and CAR-T cell viability, too,” Zhang said during a press briefing.
Researchers also observed neurotoxicity in approximately 16% of participants and most of them resolved quickly within days or weeks.
A phase 1 trial is currently underway. Researchers plan to enroll 12-18 patients.
“We are all excited about the clinical findings from this study since we rarely see the reports about equal expression of both CARs in such a bicistronic construct,” Zhang told Healio. “The success also validates our construct design.”
References:
- Wan X, et al. Abstract 681. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
- Wang T, et al. J Clin Oncol. 2023;doi:10.1200/JCO.22.01214.
For more information:
Hua Zhang, MD, PhD, can be reached at zhangh@sphchina.com.
Perspective
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Cynthia E. Dunbar, MD
Patients treated with CAR T cells reacting against a singular molecular target, such as CD19 for B-cell lymphomas and ALL, can relapse with tumor cells that have lost expression of this single molecule. To overcome this limitation, multiple groups have developed CAR T-cell products against more than one tumor cell target.
Either the infusion of two distinct CAR products – one for each target – or by engineering CAR T cells to express both CARS simultaneously. However, results to date for these combined approaches have been disappointing.
This abstract reports very encouraging results using a CD19/CD22 dual-targeted CAR product for relapsed refractory ALL, reporting a 99.1% initial response rate, with sustained responses for more than two-thirds of patients at 1 year.
Investigators in this trial put both of the CARs in the same T cells as opposed to giving two different products, which makes it simpler. They also seemed to have very good expression of both CAR molecules on their t cells. Some of the other dual-CAR expression systems had very poor expression of the second CAR — usually the CD22 car — so that may be why the response rate was so good. It really is an amazing feat to have a 99% response rate.
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Wan X, et al. Abstract 681. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
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