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CD30-Targeted CAR T Cell Therapy Promising in Heavily Pretreated Hodgkin Lymphoma

A phase 2 clinical trial evaluating a T-cell memory enriched anti-CD30 CAR-T is now underway.

Results of a phase 1 clinical trial investigating the safety and feasibility of a refined anti-CD30 CAR T-cell therapy are promising, demonstrating good cell persistence up to 11 months post-infusion and a good safety profile.1

The findings were presented at the 2022 European Hematology Association (EHA) Annual Meeting, June 9-17, 2022, in Vienna, Austria and virtual, by investigator Ana Carolina Caballero, of the department of hematology at the Hospital de la Santa Creu I Sant Pau in Barcelona, Spain.

A research group consisting of Caballero and her colleagues developed a novel CD30 CAR T by using a targeted epitope within the non-cleavable part of the CD30 receptor and memory stem T cells in hopes of improving engraftment, cell persistence, and antitumor activity.

Results of a preclinical study published in 2021 in Clinical & Translational Immunology2 by Carmen Alvarez-Fernandez, et al, demonstrated good cell expansion ex vivo and good persistence and immunity in a mouse model of Hodgkin lymphoma, which was completely eradicated in vivo. In addition, the CAR T therapy showed greater tumor infiltration and an enhanced antitumor effect in vivo.

In this first in human, phase 1/2a dose escalation clinical trial (NCT04653649), Caballero and colleagues enrolled 11 patients (median age, 49.9 years) with relapsed/refractory Hodgkin lymphoma or CD30+ T-cell non-Hodgkin lymphoma, 10 of whom ultimately received treatment with HSP-CAR30. Primary end points were safety and to establish max tolerated dose for phase 2, with response rates among secondary end points.

Patients had received a median of 4.6 prior lines of treatment. Following leukapheresis, 3 patients received dose-level 1 (3x106 /kg), 3 received dose-level 2 (5x106 /kg), and 4 received dose-level 3 (10x106 /kg). Prior to infusion, patients with HL underwent lymphodepletion with fludarabine/bendamustine and those with T-NHL received ludarabine/cyclophosphamide. Mean HSP-CAR30 expression was 94.79±3.38% (±SD). Memory T-cell subset comprised 93.07±4.8% (±SD) in CD4+ and 91.64±4.9% (±SD) in CD8+. Peak levels of HSP-CAR30 cells were reached at a mean of 29 days post-infusion and were detectable via flow cytometry up to 11 months post-infusion.

Notably, no dose-limiting toxicities were observed and the therapy was generally well tolerated. Sixty percent of patients developed grade 1 cytokine release syndrome and 40% developed skin rash. In addition, 4 infections occurred, including a grade 4 case of pulmonary tuberculosis; grade 3 CMV pneumonia in a patient with a history of cytomegalovirus; grade 1 rhinovirus; and grade 1 COVID-19. No cases of neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Grade 3 and 4 cytopenias included anemia (5/10), thrombopenia (3/10), neutropenia (8/10), and long-lasting cytopenias (2/10). Notably, no non-relapse mortality events occurred.

In terms of efficacy, 100% of treated participants reached objective response, with 50% of the total cohort reaching complete response (CR) and 62% of patients with HL reaching CR. Three patients (2 with T-NHL and 1 with HL) succumbed to progressive disease. One patient with HL that achieved partial response with relapse at 6 months received treatment with nivolumab to again reach partial response, and received a second infusion of HSP-CAR30 between 13-14 months after initial treatment. Follow-up data is available through 14 months, with longest CR at data cutoff at 12 months.

Based on the significant antitumor efficacy observed and the good safety profile, a phase 2 study has begun examining the safety and efficacy of dose level 2 (5x106 /kg).

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REFERENCES
1. Caballero AC, Escriba-Garcia L, Montserrat-Torres R, et al. A phase 1, first-in-human, dose-escalation clinical trial of memory-enriched CD30-CAR T-cell therapy for the treatment of relapsed or refractory Hodgkin lymphoma and CD30+ T-cell lymphoma. Presented at: European Hematology Association Annual Meeting. June 9-17, 2022; Vienna, Austria, and virtual. S257.
2. Alvarez‐Fernández C, Escribà‐Garcia L, Caballero A, et al. Memory stem T cells modified with a redesigned CD30‐chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma. Clin Transl Immunol. 2021;10(4). doi:10.1002/cti2.1268