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HD-CAR-1 Treatment Is Safe and Feasible in Heavily Pretreated CLL

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Key Takeaways

  • HD-CAR-1 therapy achieved a 67% complete remission rate in heavily pretreated CLL patients, with 83% showing undetectable minimal residual disease.
  • CD4-positive T cells were more prevalent in responders, while nonresponders had effector memory-like CD8-positive T cells with high CD39/CD197 expression.
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Treatment with the third-generation anti-CD19 CAR T-cell therapy HD-CAR-1 is feasible and safe in heavily pretreated chronic lymphocytic leukemia.

HD-CAR-1 in Heavily Pretreated CLL | Image Credit: © Dr_Microbe - stock.adobe.com

HD-CAR-1 in Heavily Pretreated CLL |

Image Credit: © Dr_Microbe - stock.adobe.com

Treatment with the third-generation anti-CD19 CAR T-cell therapy HD-CAR-1 is feasible and associated with a tolerable toxicity profile in patients with heavily pretreated chronic lymphocytic leukemia (CLL), according to data from a phase 1/2 trial (NCT03676504) published in Leukemia.

In this investigation, 9 patients were treated with HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CAR T cells/m2; in-house manufacturing of HD-CAR-1 was successful for all patients. In total, by day 90, 67% of patients had a complete remission (CR), 83% of whom had undetectable minimal residual disease (MRD). Moreover, at a median follow-up of 27 months, the 2-year progression-free and overall survival rates were 30% and 69%, respectively.

Investigators also noted that HD-CAR-1 products derived from responders contained significantly more CD4-positive T cells compared with those from nonresponders, and that in nonresponders, a strong enrichment of effector memory-like CD8-positive T cells with high expression of CD39 and/or CD197 was observed.

“Treatment of heavily pretreated patients with high-risk CLL having [progressed on] multiple pathway inhibitors with the third-generation CAR T HD-CAR-1 is feasible and associated with only very modest CAR T–specific toxicity. The preliminary efficacy signals obtained suggest that HD-CAR-1 can induce prolonged CRs in otherwise refractory patients and warrant further exploration of this approach,” study authors wrote in a report of the data.

Although the utility of second-generation CD19-directed CAR T-cell therapy has shifted the treatment paradigm for patients with B-cell malignancies, patients with CLL still do not achieve superior response rates or longer durations of response compared with patients with other indolent B-cell lymphomas. Due to a dearth of data [in this area], investigators sought to further investigate findings with third-generation CAR T-cell therapies manufactured academically.

In this basket trial of patients with relapsed/refractory CLL, investigators aimed to assess the feasibility of and identify dose-limiting toxicities of HD-CAR-1 CAR T-cell therapy. Eligible patients included those with CLL who had progressed on 2 or more lines of therapy, including at least 1 pathway inhibitor or allogeneic hematopoietic cell transplantation (alloHCT), and had an ECOG performance score of 0 or 1.

Patients received treatment with HD-CAR-1 at increasing doses of autologous T cells retrovirally transduced with a third-generation CD19-directed CAR in a 3 + 3 design; CARs were manufactured at the institutional Good Manufacturing Practice Core Facility. HD-CAR-1 CAR T-cell therapy was given 2 days following administration of lymphodepletion with fludarabine at 30 mg/m2 per day and cyclophosphamide at 500 mg/m2 per day for 3 days.

Adverse effects, such as cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and immune effector cel­-associated hematotoxicity (ICAHT), were graded according to consensus guidelines and managed according to institutional guidelines. Additionally, during lymphodepletion, CAR T-cell infusion, and monitoring, patients were hospitalized from day −6 through day +14.

In total, 8 patients with relapsed/refractory CLL were enrolled onto the investigator-led trial between October 2018 and May 2023; a ninth patient was treated compliant with the trial but formally off-study in July 2023 after having given fully informed consent.

The median age of patients enrolled was 60 years (range, 45-68). Patients had received a median of 5 (range, 2-10) prior treatment lines, 44% of patients had received prior alloHCT, and 78% of patients harbored TP53 abnormalities. One hundred percent of patients had progressed on Bruton’s tyrosine kinase inhibitors and had received at least 1 venetoclax (Venclexta)–based regimen; 8 patients were refractory to venetoclax-based treatment as well. Moreover, bridging therapy was administered to 100% of patients, mostly with venetoclax-antibody combinations, resulting in CR and partial remission in 3 and 2 patients, respectively. All patients had flow-detectable MRD at lymphodepletion. One patient also had a history of Richter transformation, which was not present at the time of enrollment.

Manufacturing results of HD-CAR-1 were successful in all 9 patients, with a median transduction efficiency of 52.3% (range, 41.7%-67.7%) and a median CAR T viability of 95.2% (range, 86.2%-95.8%). The median duration of manufacturing was 13 days (range, 10-13); in 2 patients, a second leukapheresis had to be performed due to an unfavorable T-cell:B-cell ratio in the first leukapheresis products.

Furthermore, 100% of patients received at least 1 dose of HD-CAR-1 CAR T cells. “Dose levels were DL1 [1 × 106 CAR T cells/m2] in 1 patient, DL2 [5 × 106 CAR T cells/m2] in [1 patient], DL5 [10 × 107 CAR T cells/m2] in 2 patients, and DL6 [20 × 107 CAR T cells/m2] in 5 patients,” the study authors shared.

Overall, HD-CAR-1 CAR T-cell therapy was well tolerated. Regarding safety, higher-grade CRS was observed in 11% of patients, and no ICANS was observed. Early ICAHT occurred in 89% of patients and was grade 4 in 11% of patients. Late ICAHT was observed at grades 1 and 2 in 1 and 2 patients, respectively, without the need for granulocyte colony-stimulating factor support. Hypogammaglobulinemia was observed in 8 patients at lymphodepletion, 1 of which showed recovery of gamma globulin levels following HD-CAR-1 treatment. One patient did not exhibit hypogammaglobulinemia at lymphodepletion or after day 90 post-CAR T infusion. Intravenous immunoglobulins were administered to 3 patients following treatment.

Furthermore, early infections post-CAR T-cell infusion occurred in 1 patient who presented with herpes simplex virus type 1 infection of the lower lip and respiratory infection without pathogen identification. Late infections, classified as those occurring beyond day 30, occurred in 4 patients.

Rapid CAR T expansion in the peripheral blood was observed in 89% of patients with a median CAR T peak level of 82,358 CAR T/µg peripheral blood mononuclear cell (PBMC) DNA (range 37,792-369,756). The study authors noted that, “In all 7 patients evaluated, CAR T cells were persistent at end of study. Five patients were evaluated beyond 100 days after HD-CAR-1 infusion, with detectable CAR T cells in the peripheral blood of all patients. [One] patient still showed 202 CAR T/µg PBMC DNA even at day 994 after HD-CAR-1 infusion, and in [another patient], a particularly high CAR T concentration was observed with 18,199 and 13,521 CAR T/µg PBMC DNA at days 171 and 295, respectively.”

All the patients with a CR as best response presented with B-cell aplasia at end of study on day 90 after CAR T-cell therapy administration; 2 patients showed absolute T-cell counts above the lower limit of normal but presented with counts below the lower limit of normal at day 200 after CAR T-cell therapy administration. B-cell and T-cell recovery took place on day 450 along with ongoing CR with undetectable MRD in 1 patient. B-cell aplasia and lymphopenia were still present in 4 patients at their latest assessment on days 771, 548, 198, and 301, respectively, after CAR T-cell therapy administration.

“This confirms the results of HD-CAR-1 in patients, where a low CD39-expression on effector T cells within the CAR T product was associated with a higher response rate. This clinical confirmation strengthens the role of CD39 within CAR T products as a marker for T-cell exhaustion and possible predictor of response in CAR T,” the authors concluded.

Reference

Derigs P, Schubert ML, Dreger P, et al. Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study. Leukemia. 2024;38:2419–2428. doi:10.1038/s41375-024-02392-7

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