CD30.CAR-T Cells Co-Expressing the CCR4 Chemokine Receptor in Relapsed/Refractory Hodgkin Lymphoma
Year: 2024
Type: conference-abstract
Abstract: Background: Chimeric antigen receptor T cells targeting CD30 (CD30.CAR-Ts) are efficacious in treating patients (pts) with relapsed/refractory (r/r) classical Hodgkin lymphoma (HL), but many pts relapse after treatment. We leveraged the CCL17 chemokine gradient of HL and conducted a phase 1 clinical trial to assess if CD30.CAR-Ts with enhanced tumor homing obtained by co-expressing the CCL17 chemokine receptor CCR4 (CCR4.CD30.CAR-Ts) promotes durable responses. Methods: Subjects on dose levels (DL) 1, 3 and 5 received CCR4.CD30.CAR-Ts only at a dose of 2x107, 5x107, and 1x108 CAR-Ts/m2 respectively, while subjects on DL 2, 4, and 6 received CCR4.CD30.CAR-Ts at the preceding DL plus a fixed dose of 1x108 CD30.CAR-Ts/m2 to compare the kinetics and biodistribution of the 2 products in the same patient. Dose escalation was guided by the 3+3 design. All pts received lymphodepletion (LD) with 3 days of bendamustine 70 mg/m2 and fludarabine 30 mg/m2 followed by CAR-T infusion 2-4 days later. Key eligibility criteria included age ≥ 18 years and diagnosis of r/r HL or cutaneous T cell lymphoma (CTCL) progressed after 2 or more prior lines of therapy, including brentuximab vedotin (BV). Results: Thirty-eight pts were enrolled with CAR-Ts manufactured successfully for 37 pts. Seven pts had product manufactured but were not treated due to ineligibility prior to treatment (n=3), death during the manufacturing period (n=3), or decision to pursue alternative therapy (n=1). Thirty pts were treated on protocol - 6 with CTCL and 24 with HL. This analysis focuses on pts with HL. Out of 24 pts with HL, 5 were treated on DL1, 2 on DL2, 3 on DL3, 3 on DL4, 2 on DL5, and 9 on DL6. The median age was 40 (range 27-75) and pts received a median of 6.5 prior lines of therapy, including BV and checkpoint inhibitor (CPI) in all pts, a prior autologous stem cell transplant in 22 pts and allogeneic stem cell transplant in 6 pts. The median time from collection to LD was 58.5 days (range 33-120). Eleven pts received bridging therapy, most frequently CPI (n=7). One pt had a partial response (PR) to radiation but the other 10 pts had either stable (n=4) or progressive disease (PD) (n=6) post bridging. No dose limiting toxicities were observed. Eight pts had cytokine release syndrome - 5 grade 1 and 3 grade 2 with a median time of onset of 8.5 days and median duration of 3 days. Four pts received tocilizumab. No pts experienced immune effector cell-associated neurotoxicity syndrome. The most common grade ≥ 3 toxicities were cytopenias, primarily attributed to LD, with 37.5% and 29% of pts with grade 3/4 neutropenia and thrombocytopenia, respectively at 4 weeks. Only 1 and 3 pts had persistent neutropenia and thrombocytopenia, respectively at 3 months post treatment. Sixteen pts (67%) had a complete response (CR), 6 (25%) had a PR and 2 (8%) had PD. Five pts are in ongoing CR, which remains durable at 3, 4, and 5 years post treatment in 3 pts. Six pts had biopsies post progression and all had persistent CD30 expression. At a median follow up of 29.6 months, the median progression free survival (PFS) is 6.4 months (95% CI: 3.6-11.5 months) and the median overall survival (OS) has not been reached. The median PFS for pts in CR is 9.3 months (95% CI: 5.8-16.4 months). The 1 year OS is 85% (95% CI: 60-95%). There were 4 deaths - 2 from infection >3 months post treatment and 2 from lymphoma. We observed the expansion of CCR4.CD30.CAR-Ts in the peripheral blood both in pts receiving CCR4.CD30.CAR-Ts alone and co-infused with both CAR-T products. Overall CCR4.CD30.CAR-Ts showed superior persistence to CD30.CAR-Ts (p=0.008, measured as AUC from week 4 after infusion) with CCR4.CD30.CAR signals still detectable 6 months post infusion in 12 of 14 (86%) evaluable pts vs CD30.CAR signals only detectable in 2 of 9 (22%) evaluable pts. Interestingly, these 2 pts were co-infused with both products at the same dose (1x108), suggesting a “helper effect” by CCR4.CD30.CAR-Ts. Plasma levels of CCL17, a biomarker of disease response for HL, were reduced by 86±13% by week 2 post-infusion in patients treated with CCR4.CD30.CAR-Ts as compared to 52±38% in our previous trial with CD30.CAR-Ts lacking CCR4 (p=0.007), suggesting that CCR4.CD30.CAR-Ts show faster antitumor activity. Conclusions: CCR4.CD30.CAR-Ts are safe with high response rates and durable remissions in a subset of pts with r/r HL. We are actively enrolling on a phase 2 clinical trial of CCR4.CD30.CAR-T cells at a dose of 2x108 CAR-Ts/m2 in pts with HL.
Source: Blood
Authors: Natalie Grover, Dominic Moore, Anastasia Ivanova, Anne W Beaven, Christopher Dittus, Catherine Joyce Arago Cheng, Kelly Hoye, Caroline Babinec, Faith Brianne Buchanan, Angela Denise Spruill, Ashley Zanter, John West, J. Kaitlin Morrison, Paul Armistead, Kimberly A. Kasow, Jonathan Serody, Gianpietro Dotti, Barbara Savoldo
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405043254