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Anti-CD70 CAR-NKT therapy shows promise in renal cell carcinoma

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Article

Among the 3 CD70-positive patients, the ORR was 66.7%, with 2 patients achieving a partial response.

Preliminary data from a first-in-human trial (NCT06182735) showed that the anti-CD70 CAR-NKT therapy CGC729 demonstrated a manageable safety profile and promising anti-tumor activity in patients with relapsed and refractory metastatic renal cell carcinoma (mRCC).

Study completion is anticipated for January 2025.

Study completion is anticipated for January 2025.

Findings from the phase 1 study were presented at the 27th Annual Meeting of the American Society for Gene & Cell Therapy in Baltimore, Maryland.1

The ongoing study is assessing the safety and efficacy of CGC729 in patients who have relapsed and refractory mRCC following at least 2 lines of prior therapy. Patients included in the trial will receive CGC729 at 3 dose levels: 5 x 106/m2 (DL1), 1.5 x 107/m2 (DL2), and 4.5 x 107/m2 (DL3).

At the time of the interim data report, 5 patients were enrolled in the study and received a single dose of CGC729 following a 3-day lymphodepletion regimen. Of those, 3 patients were from DL1 and 2 patients were from DL2.

Regarding safety, no patients in the study experienced a dose-limiting toxicity. The most common adverse events were neutropenia, thrombocytopenia, and leukopenia, which were related to lymphodepletion. No cytopenia higher than grade 2 was observed by day 28.

A single patient in DL1 cohort developed grade 2 cytokine release syndrome (CRS), which resolved within 24 hours, as well as grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS), which rapidly improved following symptomatic treatment with corticosteroids. No instances of CRS or ICANS was observed in the 2 other patients in DL1 nor the 2 patients in DL2.

Regarding efficacy, the overall response rate (ORR) among 4 eligible patients was 50%. Among the 3 CD70-positive patients, the ORR was 66.7%, with 2 patients achieving a partial response.2 Those 2 patients achieved a deep tumor reduction of 80.4% at week 20 and 57.2% at week 28.

The authors added,1 “Notably, both CD70+ patients had low CD70 expression (H-score < 100) in RCC, indicating CGC729 may have the potential to target CD70-low patients.”

The longest duration of response in the trial has not yet been reached, with the longest ongoing at 9 months following treatment.

Further, among the 5 patients eligible for pharmacokinetic analysis, robust expansion of CGC729 was observed in all patients, regardless of CD70 expression level. CGC729 demonstrated peak expansion between days 14 and 28, with prolonged persistence in the blood up to 20 weeks. The investigators also observed a significant decrease of CD70-positive T cells in the peripheral blood following CGC729 infusion. The levels remained low up to week 20, which indicates durable activity of CGC729, according to the authors.

In total, the open-label trial plan to enroll 9 patients.3 The study is designed in a 3+3 fashion with the goal of determining a maximum tolerated dose.

To be included in the trial, patients must have relapsed or refractory advanced clear cell RCC following at least second-line treatment, at least 1 measurable lesion at baseline per RECIST v1.1, an ECOG score of 0-1, and an expected survival time of more than 12 weeks. Further, patients must have adequate organ function and archival and/or fresh tumor tissue samples.3

The primary outcome measure for the study is the percentage of patients with dose-limiting toxicities. Secondary end points include ORR, duration of response, and safety.

Study completion is anticipated for January 2025.

References

1. Lin Y, Zhang Y, He S, Ye D. Interim Safety and efficacy of AntiCD70 CAR-NKT (CGC729) for patients with refractory metastatic renal cell carcinoma. Presented at: 27th Annual Meeting of the American Society for Gene & Cell Therapy. May 7-11, 2024. Baltimore, Maryland. Abstract LBA10

2. Cure Genetics announced promising safety and efficacy data of CAR-NKT product CGC729 for RCC at ASGCT 2024. News release. Cure Genetics. Published online and accessed May 23, 2024. https://www.prnewswire.com/news-releases/cure-genetics-announced-promising-safety-and-efficacy-data-of-car-nkt-product-cgc729-for-rcc-at-asgct-2024-302153612.html

3. CD70-targeted CAR-NKT Cells (CGC729) Therapy in the Renal Cell Carcinoma. ClinicalTrials.gov. Last updated December 27, 2023. Accessed May 23, 2024. https://clinicaltrials.gov/study/NCT06182735

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