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.

The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

“…sCD30 alters Th1/Th17 balance [ 31 ] while CD30-loaded EV can be absorbed on reactive immune cells that become potential targets of anti-CD30-based immunotherapy [ 104 ]. Therefore, brentuximab vedotin and anti-CD30 CAR-T cells [ 105 ] may have yet poorly defined immunomodulatory roles in addition to their direct effects against tumor cells.…”

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

“…Numerous developments are underway with the evaluation of novel tumor targets to treat new categories of diseases such as Hodgkin’s disease [ 38 ], myeloid malignancies [ 39 ] or solid tumors, strategies to overcome resistance, largely due to the loss of the targeted tumor antigen [ 40 ], strategies to mitigate side-effects associated with CAR-T cells administration such as the cytokine release syndrome (CRS) or immune effector cells associated neurological syndromes (ICANS) [ 41 , 42 , 43 ] improved and more complex CAR structures designed to counteract the immune suppressive environment that characterizes many tumor types, support in vivo persistence of CAR-T cells and recruit endogenous immune effectors [ 44 ]. In addition, CAR-technologies are now combined with gene editing as a substitute to retroviral or lentiviral vector transduction [ 45 ] with the use of allogeneic cells that hold the promise of off-the-shelf medicines [ 46 ] and the genetic engineering of other immune cell subsets such as natural killer (NK) cells [ 47 ], γ/δ T cells, or macrophages.…”

Current Immunotherapy Approaches in Non-Hodgkin Lymphomas

“…CD30 is an antigen present exclusively on malignant lymphocytes in patients with Hodgkin lymphoma and some T-NHL subtypes (especially on anaplastic large T-cell lymphomas). However, while results of two parallel phase 1/2 studies (NCT02690545 and NCT02917083) evaluating efficacy of CAR30 T-cells were recently reported in the cohort of patients with Hodgkin lymphoma, results of the cohort of CD30+ NHL were not published so far [ 156 ]. Another experimental approach is engineering of CAR T-cells against constant portions of T-cell receptor (TCR).…”