No GvHD With Allogeneic CRISPR-edited CAR T for LBCL, PFS Associated With Partial HLA Match

CB-010, a CRISPR-edited allogeneic chimeric antigen receptor (CAR) T-cell therapy was well-tolerated and yielded short responses in patients with aggressive forms of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) but showed a strong correlation with HLA-matched alleles and progression-free survival (PFS).

Patients had an overall response rate of 76.1% and a median duration of response of 5 months. There were no cases of graft versus host disease (GvHD) or grade 3 or higher cytokine release syndrome.

Data from the phase 1, multicenter ANTLER study (NCT04637763) were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31 to June 4, in Chicago, Illinois, by Boyu Hu, MD, director of Lymphoma and Chronic Lymphocytic Leukemia (CLL) in the Division of Hematology and Hematologic Malignancies at the Huntsman Cancer Institute of University of Utah.

“While autologous CAR T-cell therapies targeting CD19 have become the standard of care in the treatment of various R/R B-NHLs, there are numerous issues surrounding their production and efficacy that can limit their use,” Hu said during his presentation.

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CB-010 is manufactured using Cas9 CRISPR hybrid RNA-DNA (chRDNA) technology, which allows precise edits to knockout the TRAC gene to eliminate T-cell receptor expression to reduce the risk of GvHD, insert a CD19-targeted CAR into the TRAC locus, and knockout PDCD1, the gene that encodes PD-1.

The ANTLER study evaluated 40 x 10⁶ (n = 8), 80 x 10⁶ (n = 5), and 120 x 10⁶ (n = 3) CAR T-cell doses in the dose-escalation phase and is now enrolling participants with relapsed/refractory large B-cell lymphoma to receive 80x10⁶ CAR T-cells, the selected recommended phase 2 dose, for the study’s expansion phase. Lymphodepletion began a median of 2 days after eligibility confirmation.

Thirty participants have been dosed so far in the expansion phase. Altogether, 46 participants have received CB-010 with at least 28 days of follow-up as of the data cutoff date, 40 with LBCL that received CB-010 as second-line treatment. Participants had a median of 1 (range, 1-8) prior line of therapy.

As of the data cutoff, 2 participants have completed the study in complete remission at 24 months, 16 are continuing in follow-up, and 28 have discontinued the study, including 5 who died and 23 who experienced disease progression. CR rate was 45.7% with a median duration of 6.7 months and median follow-up time of 12.2 months.

The most common serious (at least grade 3) adverse events (AEs) were cytopenias (n = 28; 82.6%), immune effector cell-associated neurotoxicity syndrome (ICANS; n = 3; 6.5%), and infections (n = 10; 21.7%).

Pharmacokinetic analysis found that CB-010 expansion and persistence were impacted by the number of matched HLA alleles. Participants who received cells from a donor with at least 4 matched HLA alleles had a median PFS of 14.4 months (95% CI, 1.58-not estimable) and participants that received cells with less matching alleles had a median PFS of less than 3 months. This trend was amplified in the 40 participants with LBCL, with participants with at least 4 matched HLA alleles not reaching median PFS and participants with less than 4 matched HLA alleles similarly reaching a median PFS of under 3 months.

“Higher HLA matching was associated with improved PFSsurvival, so based on these findings, the trial will enroll additional patients with a patient to product HLA match of at least 4 alleles to further evaluated the partial HLA matching effect in second-line LBCL patients at the RP2D,” Hu concluded his presentation.

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REFERENCE

Hu B, Nastoupil LJ, Holmes H, et al. A CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knockout (CB-010) in patients with relapsed/refractory B cell non-Hodgkin lymphoma (r/r B-NHL): Updated phase 1 results from the ANTLER trial. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Poster #8