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363 Phase I/II Clinical Trials of Donor-Derived Purified Regulatory T Cells for the Treatment of Steroid-Refractory Chronic Graft Versus Host Disease

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR T in Multiple Myeloma and T-cell Therapies After Allo-HCT
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, GVHD, Diseases, Immune Disorders, Therapies, Immunotherapy, Infusion
Saturday, December 10, 2022: 4:30 PM

Maria VD Soares, PhD1*, Virginia Escamilla Gomez2*, Rita I Azevedo, PhD1*, Paulo N.G. Pereira, PhD1*, Teresa Caballero Velázquez, MD, PhD2*, Clara B. Garcia-Calderón2*, Kukatharmini Tharmaratnam3*, Inês A Cabral, MSc1*, Ana C Ribeiro, MSc1*, Laura Mendes, MSc4*, Clara Juncal, MD4*, Susana Roncon, MD5*, Ana Teresa Pais, MSc1*, Ana C Alho, MD1,6*, Alfonso Rodriguez Gil, PhD2*, Eduardo L Espada, MD1,6*, Anabela Rodrigues, MD4*, Ana Garção, MD4*, Marie-Laure Yaspo, PhD7*, Hans-Jörg Warnatz, PhD7*, Hans Lehrach, PhD7*, Nuno L. Barbosa-Morais, PhD8*, Ana Miguel Quintas, MD9*, Paulo Palmela, MD10*, Cecilia Caldas, MD10*, Rosa Ferreira, MD11*, Luis Leite, MD11*, Carlos Martins, MD6*, Fernanda Lourenço, MD6*, Raúl Moreno, MD6*, João Raposo, MD12*, Fernando Campilho, MD11*, Christopher Paul Cheyne, PhD3*, Marta Garcia-Fiñana, PhD3*, António Campos, MD11*, Frédéric Baron, MD, PhD13*, Mario Arpinati, MD, PhD14, Matthias Edinger, MD, PhD15*, Jerome Ritz, MD, PhD16, Carlos Pinho Vaz, MD11*, Jose A. Perez-Simon, MD, PhD17 and Joao F Lacerda, M.D., PhD18,19

1JLacerda Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
2Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío of Sevilla, Sevilla, Spain
3Department of Health Data Science, University of Liverpool, Institute of Population Health, Liverpool, United Kingdom
4Serviço de Imuno-Hemoterapia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
5Serviço de Terapia Celular, Instituto Português de Oncologia do Porto FG, Porto, Portugal
6Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
7Max Planck Institute for Molecular Genetics, Berlin, Germany
8NMorais Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal
9Serviço de Oftalmologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
10Serviço de Estomatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
11Serviço de Transplantação de Medula Óssea, Instituto Português de Oncologia do Porto, Porto, Portugal
12Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
13Division of Hematology, Department of Medicine, CHU of Liège, Liège, Belgium
14Institute of Hematology "Seràgnoli", S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
15University Regensburg, Dept. of Hematology and Oncology, Regensburg, Germany
16Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
17Instituto de Biomedicina de Sevilla (IBiS), UGC-Hematología, Hospital Universitario Virgen del Rocío/ CSIC/ CIBERONC, Universidad de Sevilla, Sevilla, Spain
18Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
19Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Introduction

Chronic Graft versus Host Disease (cGvHD) remains a major complication of hematopoietic stem cells transplantation (HSCT) causing significant morbidity and mortality. We performed Phase I/II clinical trials to access the feasibility, safety and efficacy of infusing donor regulatory T cells (Treg) for the treatment of steroid-refractory/dependent cGvHD under the auspices of the EC-funded consortium TREGeneration.This is the first presentation of the Lisbon (iMM) and Seville (SAS) cohorts.

Methods

Treg were purified using CliniMACS (Miltenyi Biotec®) from fresh leukapharesis from the original HSCT donor by CD8 and CD20 depletion, followed by CD25bright positive selection. The dose escalation protocol comprised sequential groups of 3 (SAS) or 5 (iMM) patients per center receiving 0.5x106 (Dose A), 1x106 (Dose B) or 2-3x106 (Dose C) donor Treg/kg. After Phase I, 5 patients per center were included at the MTD, as a preliminary Phase II trial. We report feasibility and toxicity results on 33 patients (n=19, iMM; n=14, SAS) and efficacy on 31 patients (n=19, iMM; n=12, SAS) evaluable at month 12 post infusion (n=8, moderate; n=23, severe).

Patients were classified according to the NIH 2014 cGVHD criteria (Jagasia, MH et al, BBMT, 2015). Scores for the skin, eye, modified oral mucosa, GI tract, liver, lung, joint/fascia and cGvHD severity were used to calculate clinical responses at 3, 6 and 12 months, whereupon the final response was recorded. cGVHD treatment at iMM comprised primarily steroids and MMF, while all patients at SAS were on a ruxolitinib-containing regimen and had not obtained at least a partial response. Blood was collected for lymphocyte subsets monitoring by flow cytometry, evaluation of tissue damage biomarkers, homeostatic, pro-inflammatory and suppressive cytokines (sIL-2Ra, CXCL9/MIG, MMP3, Osteopontin, CXCL10/IP-10, CSTB, sCD13, Elafin, sTM, ST2, BAFF, IL-1R antagonist, IL-2, IL-7, IL-10, IFN-γ, TNF-α, CXCL11/I-TAC, IL-6, IL-17A/CTLA8 and TGF-β) by Multiplex, and tracking of infused Treg clonotypes by deep-level TCR RNA-based Next Generation Sequencing (NGS).

Univariate tests were carried out using Fisher’s exact test for categorical variables. t-test or Mann-Whitney tests were used for continuous variables as per normality analysis. Since no multiple testing correction was carried out, there were no corrections for multiple comparison or adjustments for other covariates.

Results and Conclusions

Donor Treg products preparation was feasible. Nevertheless, due to the paucity of circulating Treg, dose C required 2 separate leucapheresis in most patients. At SAS, achieving more than 1.5x106 donor Treg/kg was possible for only 4 patients. At iMM, the QC criteria were met in 20/20 products (mean Treg purity 67%; CD8 depletion 4.5 and 4 times for CD20). At SAS, 1 product did not meet the purity criteria and was not infused, the remaining 14 products were infused (mean purity 73%; CD8 log depletion of 4.9 and of 6.5 times for CD20). Infused cell doses were calculated based on Treg purity (CD4+CD25++CD127lowFoxP3+).

There were no dose limiting toxicities and dose C was used whenever reached in the Phase II trial. Efficacy analysis revealed that 22 out of 31 evaluable patients (70.9%) showed either complete response (CR) or partial response (PR) at month 12, whereas 29% progressed (P) or did not respond (NR). The median time from infusion to response was 6 months. The same efficacy trend was observed irrespective of a previous failure to ruxolitinib.

Time from cGvHD diagnosis to Treg infusion was significantly associated with response in the iMM cohort (p=0.003).

Interestingly, the Treg dose influenced outcomes. Hence, when patients receiving A+B doses (<1 x106Treg/Kg) were compared to patients receiving >1.3x106 Treg/Kg, 10/18 (56%) of patients in lower doses responded versus 12/13 (92%) in higher Treg doses (p=0.045). Furthermore, 39% of patients had the daily dose of prednisolone tapered by at least 50%.

Exploratory TCR tracking analysis revealed the persistence of infused Treg clones in 18 of the 20 patients analyzed thus far up to one year after infusion.

In summary, we report the feasibility and safety of donor Treg infusion in patients with moderate/severe cGVHD. Meaningful responses were observed in over 2/3 of the patients, further suggesting that early treatment with Treg is associated to improved clinical outcomes. Our results set the stage for larger Phase II trial.

Disclosures: Escamilla Gomez: Novartis: Research Funding. Ritz: Equillium: Research Funding; Gadeta: Research Funding; Kite/Gilead: Research Funding; Oncternal: Research Funding; Novartis: Research Funding; Akron Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvroBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clade Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Draper: Consultancy, Membership on an entity's Board of Directors or advisory committees; Garuda Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; LifeVault Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Smart Immune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perez-Simon: GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; ABBVIE: Research Funding; JAZZ: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; ALEXION: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; PFIZER: Research Funding.

*signifies non-member of ASH