Evaluating CD30-Targeted CAR T-Cell Therapy in Patients With HL or ALCL

Author’s Perspective

Study co-author Barbara Savoldo, MD, PhD: “Our study demonstrates the tolerability, safety, and potential efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell (CD30 CAR T-cell) therapy in CD30+ lymphoid malignancies. Promising anti-tumor activity was documented in both Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL), with the achievement of complete response in some patients, without significant toxicities. Targeting CD30 with CD30-directed CAR T cells offers the opportunity to rapidly generate tumor-specific T cells in all patients with HL or ALCL.”

Because CD30 is overexpressed in patients with Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL), CD30-targeted monoclonal antibodies are effective in these patients, but treatment-related adverse events (AEs) cause many patients to discontinue treatment. Targeting CD30 with chimeric antigen receptor (CAR) T cells (anti-CD30 CAR T-cell therapy) could limit the toxic effects while maintaining clinical efficacy, according to results from a small phase I study of patients with relapsed/refractory HL or ALCL published in the Journal of Clinical Investigation.

Carlos A. Ramos, MD, from the Center for Cell and Gene Therapy at Baylor College of Medicine at the Houston Methodist Hospital and Texas Children’s Hospital, and co-authors found that anti-CD30 CAR T-cell therapy induced complete responses (CRs) even without the use of a conditioning regimen.

The phase I, dose-escalation study included nine patients (age range = 20-65 years) with relapsed/refractory CD30+ Epstein-Barr virus–negative HL (n=7) or ALCL (n=2) who were infused with autologous T cells that were gene-modified to express the CD30-specific CAR. All patients had received three or more prior lines of therapy.

Patients received a single infusion of anti-CD30 CAR T cells at one of three dose levels: 2×107 (level 1), 1×108 (level 2), or 2×108 (level 3) cells/m2. T cells were administered without a conditioning regimen, and all other treatments were discontinued at least four weeks prior to the study.

Seven patients received a second infusion of anti-CD30 CAR T cells, and one patient received four infusions.

“Anti-CD30 CAR T-cell infusions were well tolerated at all dose levels and after one or more infusions,” the authors noted, with no AEs attributable to anti-CD30 CAR T-cell treatment and no instances of cytokine release syndrome. The most frequently reported AEs included fatigue, hyper- or hypokalemia, and transient elevation of aspartate aminotransferase.

The researchers observed clinical responses in three patients (2 CRs and 1 continued CR), and three patients had stable disease. Two patients died during follow-up: one from heart disease and the other related to HL.

Among the patients with relapsed HL, one achieved CR that lasted more than 2.5 years after the second anti-CD30 CAR T-cell infusion. One patient remained in continuous CR for almost two years, and three patients had transient disease. The patient who received four infusions was alive at the time of follow-up and had achieved CR for nine months.

Anti-CD30 CAR T-cell expansion in peripheral blood peaked one week after infusion, the researchers reported, and it remained detectable for more than six weeks.

The researchers are conducting at the University of North Carolina in Chapel Hill the second phase of the study, in which patients are receiving lymphodepletion before the infusion of autologous anti-CD30 CAR T cells. “Since the optimal lymphodepletion regimen is unknown, we are exploring the use of bendamustine and bendamustine with fludarabine to effectively reduce the tumor burden and [achieve] appropriate levels of lymphodepletion, while containing the toxicity,” co-author Barbara Savoldo, MD, PhD, of the Department of Pediatric Hematology-Oncology at the University of North Carolina at Chapel Hill, told ASH Clinical News.

The study is limited by its small patient population. “In addition, due to the novelty of the target, host lymphodepletion before CAR T-cell infusion was not used to avoid potential unanticipated off-tumor toxicities,” Dr. Savoldo said, adding that “host lymphodepletion before CAR T-cell infusion [may be] beneficial in further improving their expansion and their antitumor activity.”

The authors report no conflicts.

Source: Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes. J Clin Invest. 2017;127:3462-71.