Helen E. Heslop

Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes

BACKGROUNDnTargeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity.nnnMETHODSnWe conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab.nnnRESULTSnNo toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity.nnnCONCLUSIONnCD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.nnnTRIAL REGISTRATIONnClinicalTrials.gov NCT01316146.nnnFUNDINGnNational Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).

Immunotherapy for Virus-Associated Malignancies

Estimates of the fraction of human malignancies that are associated with viral infections range from 10% to 20% (1). Among viruses and their associated cancers are Epstein-Barr virus (EBV), which is associated with many different malignant diseases including lymphoproliferative disease (LPD) in immunosuppressed patients, Hodgkin’s disease, Burkitt’s lymphoma and nasopharyngeal carcinoma; human papillomaviruses (HPV) types 16 and 18 with cervical cancer; hepatitis B (HBV) and hepatitis C viruses with hepatocellular carcinoma; human T-cell leukemia virus-1 with adult T-cell lymphoma; and human herpes virus-8 with Kaposi’s sarcoma in patients with AIDS.