CD30.CAR-T Cells Co-Expressing the CCR4 Chemokine Receptor in Relapsed/Refractory Hodgkin Lymphoma

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.