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164 Phase 1 Clinical Trial of Memory-Enriched Academic HSP-CAR30 for the Treatment of Relapsed/Refractory Hodgkin Lymphoma and CD30+ T-Cell Lymphoma: Clinical and Biological Studies

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Lymphoma
Hematology Disease Topics & Pathways:
Research, Hodgkin lymphoma, Biological therapies, Translational Research, Lymphomas, Chimeric Antigen Receptor (CAR)-T Cell Therapies, T Cell lymphoma, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Adverse Events
Saturday, December 10, 2022: 12:15 PM

Ana Carolina Carolina Caballero Gonzalez, MD1,2*, Laura Escribà-García, PhD3*, Rosanna Montserrat3*, Eva Escudero-López3*, Paula Pujol-Fernández3*, Cristina Ujaldón-Miró3*, Irene García-Cadenas, MD3*, Albert Esquirol, MD3*, Rodrigo Martino, MD3*, Jorge Sierra, MD, PhD4, Carmen Alvarez-Fernández, PhD3* and Javier Briones, MD, PhD5,6*

1Josep Carreras Leukaemia Research Institute, Barcelona, Spain
2Hematology Department, Hospital de la Santa Creu i Sant Pau, BARCELONA, Spain
3Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
4Hematology Department, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research (IIB) and Jose Carreras Leukemia Research Institutes, Autonomous University of Barcelona, Barcelona, Spain
5Josep Carreras Leukemia Research Institute, Barcelona, Spain
6Hematology Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain

Background: Patients with classical Hodgkin lymphoma (cHL) relapsed/refractory to immunotherapies (e.g., brentuximab, anti-PD-1 antibodies) have poor outcome. We developed an academic CART30 (HSP-CAR30) targeting a proximal epitope within the CD30 molecule to overcome soluble CD30. We generated products enriched in memory T-cells to ensure persistence, and enhancement of antitumor efficacy (Alvarez-Fernandez et al, 2021). Here, we report the results of our Phase 1 study evaluating HSP-CAR30 for the treatment of R/R cHL and CD30+T-cell non-Hodgkin lymphoma (T-NHL) (NCT04653649).

Aim: Primary endpoints were to assess safety of HSP-CAR30 and to establish maximum tolerated dose (MTD) recommended for the following phase 2. Secondary objectives included response rates and cellular kinetics.

Methods: We conducted a phase 1 dose-escalation study in 11 patients with R/R HL or CD30+ T-NHL. cHL patients were R/R to treatments including chemotherapy, brentuximab, and anti-PD-1 antibodies, while T-NHL patients were R/R to at least 2 chemotherapy treatments. T-cells isolated from fresh leukapheresis of enrolled patients were transduced with a lentivirus encoding a second-generation 4-1BB-costimulated CAR, containing a scFv directed against an epitope within the proximal non-cleavable part of CD30 protein. Three cell-dose levels in three cohorts of patients (3+3 design) were evaluated: DL1 (3x106/kg), DL2 (5x106/kg) and DL3 (10x106/kg) CAR30+ T-cells.

Results: From February 2021 to December 2021, 11 patients (9 cHL and 2 CD30+ T-NHL (1 ALK- ALCL and 1 PTCL NOS) were enrolled and underwent leukapheresis. Of these, 10 patients received HSP-CAR30: 3 patients at DL1, 3 at DL2 and 4 at DL3. Demographic characteristics and baseline disease features are summarized in Table 1. Median age was 50 years (range 21–65). Median number of prior lines of treatment was 5 (range 3–7). One patient was not infused due to lack of T-cell expansion. All patients received lymphodepletion before infusion: fludarabine/bendamustine for cHL patients (n=8) and fludarabine/cyclophosphamide for T-NHL (n=2).

Mean HSP-CAR30 expression of T-cell products was 94.79±1.07% (±SEM). Infusion products had a high proportion of CAR30+ memory T-cells: 26.09±6.06% memory stem (TSCM) and 67.52±6.07% central memory (TCM) in CD4+, while TSCM represented 42.2±5.4%, and TCM 50.5±5.7% of CD8+ CAR30 T-cells.

HSP-CAR30 was well tolerated; there were no dose limiting toxicities (DLTs). Relevant adverse events are shown in the Table 2. Cytokine release syndrome (CRS) was observed in 6 (60%) patients (all grade 1). No patient developed neurotoxicity. Self-limited skin rash was seen in 4 (40%) patients. One patient with history of cytomegalovirus (CMV) infections had CMV pneumonia. Another patient developed pulmonary tuberculosis. Long-lasting cytopenias (>3 months) occurred in 2 patients, with a complete recovery at 5 months in one of them. The other was diagnosed with myeloid neoplasm post-cytotoxic therapy (MN-pCT) with complex karyotype.

Best objective response was 100%, including 5 (50%) patients with complete response (CR), all with HL (DL1=1; DL2=3; DL3= 1). At data cutoff (July 25th, 2022), mean follow-up was 315 days (range 120–514) and mean PFS was 235 days (77– 444). All CRs were maintained during follow-up. Four patients died, 3 of them due to progressive disease (2 T-NHL and 1 cHL) and one with refractory MN-pCT while in CR of his cHL.

Mean time to HSP-CAR30 cell peak level across all doses was 21.5 days (range, 4–63). At the time of in vivo HSP-CAR30 expansion, memory T-cells (i.e., TSCM and TCM) were the dominant cell subset within CD4+ T-cells (TSCM 20.7±5% and TCM 56.33±6.2% of CAR30+ T-cells) and represented a high proportion of CD8+ T-cells (TSCM 18.36±4.9% and TCM 30.27±8.1% of CAR30+ T-cells). HSP-CAR30 was detected in blood samples by qPCR in all patients at 4 months and in all evaluable patients (n=7) at 9 months.

Conclusions: This is the first European academic CART clinical trial evaluating a T-cell memory-enriched CART 30. Our Phase 1 study provides evidence for feasibility and safety of HSP-CAR30. Additionally, HSP-CAR30 has shown promising efficacy in heavily treated cHL patient population, and this is being explored in the phase 2. Less-differentiated memory T-cells (TSCM and TCM) predominate at the time of in vivo HSP-CAR30 expansion. Updated clinical data and cellular kinetics studies will be presented at the meeting.

Disclosures: Caballero Gonzalez: Novartis, Gilead: Honoraria. Sierra: Jazz: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Briones: HOSPITAL SANTA CREU I SANT PAU: Current Employment; Celgene/BMS: Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy; GSK: Consultancy; Novartis: Consultancy, Honoraria.

*signifies non-member of ASH