CD30 CAR T Cells Active in Hodgkin Lymphoma

Carlos A. Ramos, MD

Chimeric antigen receptor (CAR) T cells targeting CD30 proved to be safe and active in relapsed/refractory Hodgkin lymphoma, according to results from an ongoing preliminary trial.¹

Among 12 evaluable patients, 7 achieved complete responses that have proved durable, including 1 patient with an ongoing response approaching 80 weeks. Use of cytoreductive chemotherapy prior to CAR T cell infusion significantly improved antitumor activity as compared with an earlier trial with T-cell infusion alone, Carlos A. Ramos, MD, of Baylor College of Medicine and Texas Children’s Hospital, reported at the 2019 Transplantation & Cellular Therapy Meetings.

“Adoptive transfer of CD30.CAR T cells is safe,” said Ramos. “Expansion and persistence are dose dependent. Responses are improved with lymphodepleting chemotherapy. The increased expansion may be associated with cytokine release syndrome (CRS) and limited skin toxicity.”

CD19-specific CAR T cells have proven to be highly successful in B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. Development of CAR T cells for targets associated with other lymphoproliferative disorders has lagged behind, said Ramos.

Almost all Hodgkin lymphoma cells express CD30 antigen, and monoclonal antibodies directed against CD30 (such as brentuximab vedotin [Adcetris]) produce objective responses. CD30-specific CARs demonstrated activity in preclinical models of Hodgkin lymphoma.^2,3

In a phase I clinical trial, 9 patients with relapsed/refractory Hodgkin lymphoma received a single infusion of 1 of 3 doses of the CD30.CAR T cells: 2 x 10⁷ cells/m², 1 x 10⁸ cells/m², or 2 x 10⁸ cells/m².⁴ None of the patients received lymphodepleting chemotherapy prior to CAR T-cell infusion, said Ramos.

The 9 patients had exposure to a median of 5 prior regimens, and 7 of the 9 progressed during or after treatment with brentuximab vedotin. The CD30.CAR T cells resulted in 2 complete responses, 1 clinical complete response, and stable disease in 3 patients. One patient had an ongoing response at 3 years. No significant toxicities were observed.

In an effort to enhance in vivo expansion of the infused cells and improve antitumor activity, Ramos and colleagues incorporated cytoreductive chemotherapy with cyclophosphamide and fludarabine, administered prior to CAR T cell infusion. The strategy had support from a previous study showing that lymphodepleting chemotherapy improved in vivo expansion of CAR T cells.⁵

Ramos reported initial findings from a phase I study of 14 patients with relapsed/refractory Hodgkin lymphoma. The patients had a median age of 30 and had received a median of five prior regimens. All but one of the patients had exposure to a PD-1 inhibitor, and 11 had been treated with brentuximab vedotin. Nine of the patients had undergone stem cell transplants, preceded by high-dose therapy.

Lymphodepletion chemotherapy consisted of cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² for 3 consecutive days prior to cell infusion. As compared with the prior phase I trial, preinfusion chemotherapy led to significant increases in CD30.CAR T cell expansion at all 3 dose levels.

The chemotherapy was associated with transient cytopenias, nausea, and alopecia. Toxicities attributed to the CAR T-cell infusion included grade 1 CRS and maculopapular rash.

“[The rash] is mild but can be quite dramatic, a generalized maculopapular rash,” said Ramos. “It is not pruritic or tender, so the patients are not bothered by it. It tends to occur with CRS and it usually goes away without any specific treatment.”

All but 2 of the 14 patients were evaluable for response. The CD30.CAR T-cell infusion with lymphodepletion led to durable responses. Five of the 7 compete responses were ongoing at 40 weeks and beyond.

The cohort has a limited follow-up period, and the response duration remains unknown, said Ramos. Investigators intend to evaluate the therapy in expansion cohorts.

References

1. Ramos CA, Bilgi M, Gerken C, et al. CD30-chimeric antigen receptor (CAR) T cells for therapy of Hodgkin lymphoma (HL). Presented at: 2019 Transplantation and Cellular Therapy Meetings; February 20-24, 2019; Houston TX. Abstract 79.
2. Hombach A, Heuser C, Sircar R, et al. An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin's lymphoma cells in the presence of soluble CD30. Cancer Res. 1998;58(6):1116-1119.
3. Savoldo B, Rooney CM, Di Stasi A. Epstein barr virus specific cytotoxic T lymphocytes expressing the anti-cd30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. 2007;110:2620—2630. doi: 10.1182/blood-2006-11-059139.
4. 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(9):3462-3471. doi: 10.1172/JCI94306.
5. Ramos CA, Rouce R, Robertson CS, et al. In vivo fate and activity of second- versus third-generation CD19-specific car-T cells in B cell non-Hodgkin's lymphomas. Mol Ther. 2018;26(12):2727-2737. doi: 10.1016/j.ymthe.2018.09.009.

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