Are CAR T-Cell Therapies Moving to Hodgkin Lymphoma?

Results from two studies presented at the 2019 Transplantation & Cellular Therapy Meetings suggest that Hodgkin lymphoma (HL) may be the next target for chimeric antigen receptor (CAR) T-cell therapies that target the CD30 antigen.

Developing CD30-Targeting CAR T-Cell Therapies

In the first study, Carlos A. Ramos, MD, from the Center for Cell and Gene Therapy at Baylor College of Medicine in Houston, attempted to improve upon response rates seen in an earlier phase I trial of an anti-CD30 CAR T-cell product in patients with CD30-positive malignancies.

“CAR T cells are quite effective when targeting CD19 against B-cell malignancies, but targets for other lymphoproliferative disorders have lagged behind,” Dr. Ramos explained. The earlier phase I trial evaluated the CD30-targeting product, but without lymphodepleting chemotherapy prior to T-cell infusion. While no significant toxicities were observed, Dr. Ramos noted that the overall response rate “was still below what is commonly seen in studies of more active CAR T cells.”

To improve CAR T-cell expansion – and potentially to improve response rates – the investigators designed the RELY-30 trial, which included a preparative regimen of lymphodepleting chemotherapy (cyclophosphamide and fludarabine) prior to CAR T-cell infusion.

This phase I trial enrolled 14 patients (median age = 30 years; range = 17-69 years) with active CD30-positive HL that had not responded to standard treatment.. Participants were heavily pretreated, with a median of five prior regimens (range = 2-9); most had received a checkpoint inhibitor and the anti-CD30 monoclonal antibody brentuximab vedotin prior to enrollment.

After undergoing lymphodepletion, patients received a single infusion of CAR T-cells at one of three dose levels: 2×107 cells/m2, 1×108 cells/m2, or 2×108 cells/m2.

The authors noted that, as expected, CAR T-cell expansion was more robust in RELY-30, compared with previous trials without lymphodepleting chemotherapy. The expansion and persistence of CAR T cells also was dose-dependent.

Treatment with the anti-CD30 CAR T-cell therapy was associated with adverse events (AEs) that included transient cytopenias, gastrointestinal toxicities, and alopecia. Four patients developed cytokine release syndrome (CRS) – all instances of which were grade 1. Several patients also developed maculopapular rash, “all of which went away spontaneously without [additional] treatment,” Dr. Ramos said.

Of the 14 patients who were infused, 12 were evaluable for response at six weeks. Eight patients responded; seven had a complete response (CR) and one had a partial response (PR). Three patients in CR developed progressive disease, but the remaining five patients were in ongoing response at the time of data presentation (length of follow-up was not reported). The first patient treated on-study achieved CR by six weeks after infusion and has been in remission for longer than one year, Dr. Ramos reported.

“Follow-up is limited,” Dr. Ramos noted, “and we don’t know if the response duration is going to be comparable to what we’ve seen in other settings.” He added that the investigators are developing expansion cohorts to evaluate this CAR T-cell product in other CD30-positive malignancies.

Refining Lymphodepletion Regimen

In the second study, Natalie S. Grover, MD, from the Lineberger Comprehensive Cancer Center and University of North Carolina and researchers evaluated whether the type of lymphodepleting chemotherapy could improve CAR T-cell expansion of anti-CD30 CAR T-cell therapy in patients with CD30-positive lymphomas.

The phase Ib/II trial was conducted in two parts: The first dose-finding portion evaluated the safety of CAR T-cell infusions at one of two dose levels (1×108 cells/m2 or 2×108 cells/m2) in a 3+3 design; the second portion evaluated the efficacy of the recommended phase II dose.

A total of 29 patients (median age = 35 years; 23-69 years) were enrolled. This also was a heavily treated population, with a median of eight prior lines of treatment (range not reported).CAR T cells were successfully manufactured for 28 patients, but two patients did not undergo T-cell infusion – one patient elected to stop treatment because of asymptomatic disease, and the other no longer met criteria for lymphodepleting chemotherapy due to rapidly progressing disease. Bridging therapy was allowed during CAR T-cell manufacture.

Of the 26 patients infused, 24 had classic HL, and two had T-cell lymphomas.

Eight patients were treated in the first portion of the study. At six weeks after infusion, all three patients at the lower dose had progressive disease. At the higher dose, one patient had stable disease, one had progressive disease, and three had CR. After no dose-limiting toxicities were observed at the higher dose, 2×108 cells/m2 was selected as the recommended phase II dose.

Patients in the dose-finding portion received lymphodepleting chemotherapy with single-agent bendamustine, which was “chosen because of its demonstrated efficacy in HL,” Dr. Grover reported. However, he noted, responses and improvement in CAR T-cell expansion were modest with lymphodepletion.

The investigators determined that bendamustine did not support “an ideal cytokine milieu,” and IL-15 and IL-17, which are important for T-cell expansion, were not increased with single-agent bendamustine. Therefore, in the phase II portion, fludarabine was added to the lymphodepletion regimen.

Eighteen patients were treated in the phase II study. The authors did not observe any neurologic toxicity, although four patients developed CRS (3 with grade 1 CRS that resolved spontaneously and 1 with grade 2 CRS that responded to tocilizumab). As in RELY-30, nine patients also experienced mild rash after infusion.

The grade ≥3 or higher AEs observed included lymphopenia (n=4; 15%), thrombocytopenia (n=4; 15%), and neutropenia (n=3; 12%). The authors noted that these cytopenias were mostly transient and “most likely related to lymphodepleting chemotherapy.”

Fourteen of eighteen patients (78%) experienced a CR after CAR T-cell infusion; two patients had a CR for at least one year. Another two patients (11%) had a PR, one had stable disease (5%), and one had progressive disease (6%). CR rates were higher in the bendamustine/fludarabine cohort than in the bendamustine cohort (78% vs. 37%; p value not reported).

After a median follow-up of 108 days (range not reported), progression-free survival was 164 days for 19 evaluable patients who had active disease at the time of lymphodepletion. Patients who received the higher dose of CAR T cells with the combination lymphodepletion regimen appeared to have a longer survival than those treated with a lower dose and single-agent bendamustine (median = 389 days vs. 55 days; p=0.0004).

“Fludarabine is critical for enhancing circulating cytokines to improve growth and persistence of CAR T cells,” Dr. Grover concluded. The investigators are now looking to improve the efficacy of CD30 CAR T-cell constructs through adding a second infusion of CAR T cells and enrolling patients with other T-cell lymphomas.

Both studies are limited by the small number of participants, and longer follow-up is required to evaluate survival and durations of responses.

The authors report no relevant conflicts of interest.

References

  1. Ramos CA, Bilgi M, Gerken C, et al. CD30-chimeric antigen receptor (CAR) T cells for therapy of Hodgkin lymphoma (HL). Abstract #79. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 23, 2019; Houston, TX.
  2. Grover NS, Park SI, Ivanova A, et al. A phase Ib/II study of anti-CD30 chimeric antigen receptor T cells for relapsed/refractory CD30+ lymphomas. Abstract #83. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 23, 2019; Houston, TX.

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