Anti-CD30 CAR T-cell therapy appears safe, effective in advanced Hodgkin lymphoma
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A novel anti-CD30 chimeric antigen receptor T-cell therapy conferred a high rate of durable responses among patients with heavily pretreated Hodgkin lymphoma who underwent fludarabine-based lymphodepletion, according to study results.
The phase 1/phase 2 study, published in Journal of Clinical Oncology, also showed the agent had an acceptable safety profile, with no high-grade adverse events.
“We have observed some remarkable results,” Barbara Savoldo, MD, PhD, professor at The University of North Carolina at Chapel Hill School of Medicine and assistant director of the immunotherapy program at UNC Lineberger Comprehensive Cancer Center, told Healio. “We have seen durable responses in a heavily pretreated, heavily refractory population, many of whom have exhausted all of the standard therapies for this disease. Although these results are not exactly surprising, they are certainly as positive as I would have hoped for and are quite welcomed.”
The CAR T cells used in this study targeted the CD30 protein on the surface of cancer cells, which is more prevalent in Hodgkin lymphoma. Previously approved CAR T-cell therapies target the CD19 protein.
“It’s a very safe treatment,” Savoldo said of the anti-CD30 CAR T-cell therapy. “Cytokine release syndrome [CRS] was very mild in our patient population. This is significant because our therapy may not require hospitalization or treatment with other drugs that are used to control CRS.”
However, anti-CD30 CAR T cells are not necessarily safer, Savoldo said. She acknowledged that differences in the diseases being treated and the patient population may account for the safety results seen with this approach.
The study included 41 patients (median age, 35 years; range, 17-69; 67% men) with relapsed or refractory Hodgkin lymphoma who received anti-CD30 CAR T-cell therapy. Patients received a median seven (range, 2-23) previous lines of therapy.
All underwent lymphodepletion chemotherapy with bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine before receiving CAR T cells.
Safety served as the primary endpoint, with researchers seeking to establish the safest dose of the therapy for future trials. Secondary endpoints included overall response rate and OS.
Ten patients developed CRS; however, all had grade 1 cases that resolved without the need for subsequent tocilizumab (Actemra, Genentech) or steroids. Researchers observed no neurotoxicity.
Among the 32 patients with active disease who underwent lymphodepletion with a fludarabine-based regimen, results showed an ORR of 72%, with 19 patients (59%) achieving complete response. Four patients (13%) had a partial response to therapy, whereas three patients (9%) had stable disease and six (19%) had progressive disease.
After median follow-up of 533 days, researchers reported a 1-year PFS rate of 36% (95% CI, 21-51) and 1-year OS rate of 94% (95% CI, 79-99).
Only patients who underwent fludarabine-containing lymphodepletion had a response to anti-CD30 CAR T-cell therapy. The ORR was zero among the five patients who had lymphodepletion without fludarabine, 80% among 15 patients who underwent lymphodepletion with bendamustine plus fludarabine and 65% among 17 patients who received lymphodepletion with cyclophosphamide and fludarabine.
Failure to add lymphodepletion before CAR T-cell infusion will produce some responses, but not to the same effect, Savoldo said. She told Healio that her team learned this lesson from previous research using the anti-CD30 CAR T-cell approach in Hodgkin lymphoma.
The efficacy shown with two different regimens in this study means the added benefit of lymphodepletion can be achieved even if a patient cannot tolerate one of the drugs. It provides clinicians with options, Savoldo said.
“Our response rates are in line with what would typically be seen with rituximab [Rituxan; Genentech, Biogen] in this patient population, which is usually an outstanding result,” Savoldo said. “However, most of our patients have failed or relapsed after treatment with rituximab, so that makes these results particularly exciting.”
For more information:
Barbara Savoldo, MD, PhD, can be reached at bsavoldo@med.unc.edu.
Perspective
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Dennis Cooper, MD
For patients with diffuse large B-cell lymphoma and, more recently, mantle cell lymphoma, the introduction of CAR T cells has abruptly downgraded allogeneic transplant into a lower tier of consideration, and this study by Savoldo and colleagues provides hope that the same may eventually be true for Hodgkin lymphoma.
The data presented for CAR T-cell therapy in Hodgkin lymphoma are encouraging, but the follow-up is short and it is very possible — as the authors point out — that patients who make it onto a cell therapy clinical trial are healthier (despite the number of previous lines of therapy) than the average patient whose disease has progressed after an autologous transplant and therapy with brentuximab [vedotin] (Adcetris, Seattle Genetics) and an immune checkpoint inhibitor. Indeed, because OS at 1 year was 94%, despite 25% having disease progression on the first PET/CT scan, it seems that many of the patients had indolent disease biology despite treatment resistance. In contrast, in patients with DLBCL with evidence of disease progression after CAR T-cell therapy, median OS is generally less than 6 months, consistent with more virulent disease.
It is notable that in this study, there was no evidence that the CAR T-cell treatment functioned as a “living drug.” Thus, despite persistence of the CAR T cells for a reasonable period, there was no correlation between response and CAR T-cell persistence and, more importantly, no cases in which patient response improved over time. In contrast, in the axicabtagene [ciloleucel] (Yescarta, Kite Pharma/Gilead) trial in DLBCL, 11 of 35 patients with an initial partial response and 12 of 25 patients with stable disease later achieved complete response without further therapy.
Finally, it is somewhat disappointing that only about half of the patients who achieved complete response at the first PET/CT scan remained in remission at the end of the follow-up period. Thus, the durability of remissions remains uncertain. Because CD30 expression was retained in relapsed disease, the investigators speculate that loss of the CAR T cells may be the major reason for disease progression. Given the latter, it seems likely that CAR T-cell therapy with a checkpoint inhibitor added at disease progression may be explored in the future.
A large, multicenter phase 2 trial of anti-CD30 CAR T cells will begin soon and it is expected to accrue 90 patients. This study will provide further data on the role of CAR T cells in patients with Hodgkin lymphoma for whom chemotherapy, brentuximab and immune checkpoint inhibitors have failed. Until this trial is completed, allogeneic stem cell transplant will remain the best chance for durable survival of patients with multiple-relapsed Hodgkin lymphoma.
Reference
Neelapu et al. N Engl J Med. 2017:doi:10.1056/NEJMoa1707447.
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