Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma

Abstract

Purpose: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).

Methods: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.

Results: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.

Conclusion: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.

FIG 1.

Skin rash and biopsy. (A-B) Examples of the characteristic rash that develops in some patients given CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells). (C-E) Biopsy revealed a spongiotic dermatitis with occasional eosinophils (epidermal edema with few intraepidermal blisters filled with neutrophils and eosinophils, with increased lymphocytes within the papillary dermis and occasional eosinophils within the deeper dermis surrounding skin adnexa). Immunohistochemistry demonstrated a mixed population of lymphocytes with a CD4:CD8 ratio of approximately 1.5:1. Apart from very rare scattered cells, CD30 stain was negative. Quantitative polymerase chain reaction for the CD30.CAR transgene was positive in DNA isolated from biopsy material.

FIG 2.

Clinical outcome. (A) Overall survival (OS) for the 41 patients receiving lymphodepletion with bendamustine alone (benda LD), bendamustine and fludarabine (benda-flu LD), or cyclophosphamide and fludarabine (cy-flu LD). One patient was treated with benda LD before CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells) only at University of North Carolina and then 2 years later received cy-flu LD before CD30.CAR-T cells at Baylor College of Medicine. For the OS analysis, this patient was counted only according to the first treatment. (B) Progression-free survival (PFS) for all 37 patients with measurable disease at the time of treatment. (C) PFS for the 37 patients with measurable disease at the time of treatment and receiving lymphodepletion with bendamustine alone (no flu, red line) or fludarabine containing lymphodepleting regimens (flu, blue line). For the PFS comparison, the patient who received benda before CD30.CAR-T cells only and then cy-flu before CD30.CAR-T cells 2 years later was counted in each treatment group. (D) PFS for the 19 patients with measurable disease at the time of treatment and achieving complete response (CR). The median PFS for these patients was 444 days (95% CI, 260 to infinity). (E) Swimmer plot for all 42 patients (including the one treated at the both institutions). Gray stars indicate patients treated in CR.

FIG 3.

Detection of CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells) and thymus and activation-regulated chemokine (TARC, also known as CCL17) in the peripheral blood. (A) Detection of CD30.CAR-T cell molecular signals by quantitative polymerase chain reaction in patients treated with fludarabine (flu)-based lymphodepletion regimens. Data points represent postinfusion intervals after the administration of CD30.CAR-T cells at different dose levels and type of lymphodepletion. Lines denote mean ± SEM. (B) Percent of CD3⁺ CAR⁺ cells (after gating on CD45⁺ cells) detected in the peripheral blood using flow cytometry for treated patients at the indicated time points. Each dot denotes a single patient, and the line represents the mean value. (C) Detection of TARC in the serum by specific enzyme-linked immunosorbent assay for responding patients (achieving either complete remission [CR] or partial response [PR]) versus nonresponder patients (showing stable disease [SD] or progressive disease [PD]) pre-CAR-T cell infusion versus 6 weeks post–CAR-T cell infusion. P values shown are 2-tailed paired t-test. (D) Detection of interleukin (IL)-2, IL-7, and IL-15 in the plasma after lymphodepletion with bendamustine (benda) and flu in 4 representative patients. cy, cyclophosphamide; ns, nonsignificant; UNC, University of North Carolina.

Fig A1.

Flowchart for CD30-specific chimeric antigen receptor (CAR) T cell (CD30.CAR-T cell) trials including cell procurement and treatment. Dose level (DL) 1, 2 × 10⁷ CAR-T cells/m²; DL2, 1 × 10⁸ CAR-T cells/m²; DL3, 2 × 10⁸ CAR-T cells/m². One patient received bendamustine (benda) lymphodepletion before CD30.CAR-T cells at University of North Carolina (UNC), and 2 years later, received cyclophosphamide-fludarabine (cy-flu) lymphodepletion before CD30.CAR-T cells at Baylor College of Medicine (BCM).

FIG A2.

(A) Detection of biologic markers of cytokine release syndrome (CRS). Fold difference in the plasma levels of (A) interleukin (IL)-6 and (B) IL-1Ra pre–CD30-specific chimeric antigen receptor (CAR) T cell (CD30.CAR-T cell) infusion and 2 weeks post–CD30.CAR-T cell infusion or at the time of grade 1 CRS. Each dot denotes a single patient, and the line represents the mean value. (C) Peak levels of plasma C-reactive protein (CRP) in patients developing grade 1 CRS versus patients who did not develop CRS. Significance determined using 2-tailed unpaired t test.

FIG A3.

Antitumor effects of CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells). Two patients with relapsed Hodgkin lymphoma: (A) one with several bone lesions in the pelvis and elsewhere, and (B) the other with numerous hypermetabolic lymph nodes, including cervical, right axillary, mediastinal, portacaval, and retroperitoneal before treatment. Six weeks after CD30.CAR-T cell infusion, positron emission tomography–computed tomography scan showed complete responses to therapy (Deauville 2).

FIG A4.

(A) Overall survival (OS) and (B) progression-free survival (PFS) of 37 patients receiving lymphodepletion (LD) with bendamustine alone (benda LD; blue line), benda and fludarabine (benda-flu; red line), or cyclophosphamide and flu (cy-flu; black line). For this PFS comparison, the patient who received benda LD before CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells) only and then cy-flu LD before CD30.CAR-T cells 2 years later was counted in each treatment group. BCM, Baylor College of Medicine; UNC, University of North Carolina.

FIG A5.

Detection of CD30-specific chimeric antigen receptor (CAR) T cells (CD30.CAR-T cells) in the peripheral blood. (A) Detection of CD30.CAR-T cell molecular signals by quantitative polymerase chain reaction in patients receiving bendamustine (benda) alone as a lymphodepletion regimen. Data points represent postinfusion intervals after the infusion of CD30.CAR-T cells at different dose levels. Lines denote mean ± SEM for the various dose levels and lymphodepletion regimens. (B) Flow plots of CD30.CAR-T cell detection in the peripheral blood of 2 representative patients using flow cytometry for patients infused with 2 × 10⁸ CAR-T cells/m² post–benda-fludarabine (flu) at the indicated time point. Upper plots for each donor were gated on lymphocytes and on CD45^bright cells. Lower plots were gated on CD3⁺ cells. (C) Fold increase in plasma levels of interleukin (IL)-15 and IL-7 pre- and postlymphodepletion with benda versus lymphodepletion with flu and before CD30.CAR-T cell infusions. Each dot denotes a patient, and the line represents the mean value. P values shown are 2-tailed unpaired t test. CRS, cytokine release syndrome; UNC, University of North Carolina.